Family history and risk of breast cancer: an analysis accounting for family structure

Abstract

Purpose

Family history is an important risk factor for breast cancer incidence, but the parameters conventionally used to categorize it are based solely on numbers and/or ages of breast cancer cases in the family and take no account of the size and age-structure of the woman's family.

Methods

Using data from the Generations Study, a cohort of over 113,000 women from the general UK population, we analyzed breast cancer risk in relation to first-degree family history using a family history score (FHS) that takes account of the expected number of family cases based on the family's age-structure and national cancer incidence rates.

Results

Breast cancer risk increased significantly (P _trend < 0.0001) with greater FHS. There was a 3.5-fold (95% CI 2.56–4.79) range of risk between the lowest and highest FHS groups, whereas women who had two or more relatives with breast cancer, the strongest conventional familial risk factor, had a 2.5-fold (95% CI 1.83–3.47) increase in risk. Using likelihood ratio tests, the best model for determining breast cancer risk due to family history was that combining FHS and age of relative at diagnosis.

Conclusions

A family history score based on expected as well as observed breast cancers in a family can give greater risk discrimination on breast cancer incidence than conventional parameters based solely on cases in affected relatives. Our modeling suggests that a yet stronger predictor of risk might be a combination of this score and age at diagnosis in relatives.

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Camera-based measurement of respiratory rates is reliable.

Objectives: Respiratory rate (RR) is one of the most important vital signs used to detect whether a patient is in critical condition. It is part of many risk scores and its measurement is essential for triage of patients in emergency departments. It is often not recorded as measurement is cumbersome and time-consuming. We intended to evaluate the accuracy of camera-based measurements as an alternative measurement to the current practice of manual counting. Materials and methods: We monitored the RR of healthy male volunteers with a camera-based prototype application and simultaneously by manual counting and by capnography, which was considered the gold standard. The four assessors were mutually blinded. We simulated normoventilation, hypoventilation and hyperventilation as well as deep, normal and superficial breathing depths to assess potential clinical settings. The volunteers were assessed while being undressed, wearing a T-shirt or a winter coat. Results: In total, 20 volunteers were included. The results of camera-based measurements of RRs and capnography were in close agreement throughout all clothing styles and respiratory patterns (Pearson's correlation coefficient, r=0.90-1.00, except for one scenario, in which the volunteer breathed slowly dressed in a winter coat r=0.84). In the winter-coat scenarios, the camera-based prototype application was superior to human counters. Conclusion: In our pilot study, we found that camera-based measurements delivered accurate and reliable results. Future studies need to show that camera-based measurements are a secure alternative for measuring RRs in clinical settings as well. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Editorial Board

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Chronology of mineralization of the permanent mandibular second molar teeth and forensic age estimation

Abstract

Forensic age estimation frequently relies upon the chronology of mineralization of the third molar teeth. However, even when present, third molar teeth cannot always be used for estimating age in people who are classified as minors. Seconds molars develop earlier and in a more predictable way, and therefore are often more reliable for age estimation in this age group. This study aims to contribute to forensic age estimation using an age threshold of 14-years, studying the stages of development of permanent mandibular second molar teeth mineralization. 367 orthopantograms of a Portuguese population group, aged between 3 and 19 years, were studied. The stages of mineralization of mandibular permanent second molar teeth were studied following the classification stages proposed by Demirjian et al. Stage descriptive analysis was performed, and associations between age and stage were studied. A logistic regression to determine age over 14 years, using maturation stages and sex as a predictive variables, was made. A second sample was used for testing the model. The significance level was set at 5%. The model correctly classified 92.0% of cases overall. The equation was tested in the second sample, and the results showed that there were no statistical significant differences between the binary real age (i.e. age < 14 and age ≥ 14 years) and the estimated age (p = 0.109). The developed model is useful for age estimation using 14-years as a threshold. However, stage maturation analyses showed that stage F, in males, and stages G and H, in both sexes, lead to an estimated age with significant statistical differences from chronological age.

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The 21-gene recurrence score in special histologic subtypes of breast cancer with favorable prognosis

Abstract

Background/purpose

The 21-gene recurrence score (RS) assay predicts the likelihood of distant recurrence and chemotherapy benefit in early-stage, estrogen receptor (ER)-positive, HER2-negative breast cancer. Data on the RS of special histologic subtypes of invasive breast carcinoma with favorable prognosis are limited.

Methods

We reviewed our institutional database to identify patients with special histologic subtypes of breast cancer associated with favorable prognosis and available RS results. Our cohort consists of fifty-seven women: thirty-three patients with pure mucinous carcinoma (MC), ten with tubular carcinoma (TC), nine with encapsulated papillary carcinoma (EPC), and five with solid papillary carcinoma (SPC).

Results

Most (44/57, 77.2%) carcinomas had low RS (≤17), and none had high RS (≥31). All EPCs had low RS, but other subtypes had RS 18–30. Higher RS was associated with lower progesterone receptor (PR) expression by immunohistochemistry and lower PR mRNA scores (P ≤ 0.007). No morphologic feature (tumor grade, biopsy site changes, cellular stroma, inflammatory cells) was associated with RS ≥ 18. At a median follow-up of 40 months, the distant recurrence-free survival was 100%. One patient with SPC developed locoregional recurrence at 22 months.

Conclusions

As the largest series to date, our study raises the question of whether the RS assay is necessary for breast cancers with favorable histology. Reflex testing of node-negative, ER+/HER2− breast cancers may be deferred for these special histologic subtypes, emphasizing the need for multidisciplinary discussions between breast pathologists and other members of the breast cancer team.

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The effectiveness of creatine treatment for Parkinson’s disease: an updated meta-analysis of randomized controlled trials

The effectiveness of creatine in treating Parkinson's disease (PD) has not been conclusively determined. Therefore, we performed a meta-analysis to address this issue.

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Evaluation of strategies for increasing response rates to postal questionnaires in quality control of nasal septal surgery

Postal questionnaires are often used to assess the results of nasal septoplasty, but response rates vary widely. This study assesses strategies designed to increase the response rate.

http://ift.tt/2ruBr1A

Prevalence of methicillin resistant Staphylococcus aureus in Lumbini Medical College and Teaching Hospital, Palpa, Western Nepal

Multidrug resistant Staphylococcus aureus is common in both tertiary and primary health care settings. Emergence of methicillin resistance in S. aureus (MRSA) along with macrolide, lincosamide, streptogramin B (M...

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A rare presentation of an acute abdomen: an ileal diverticular perforation

This case report highlights the value of prompt intervention of diagnostic laparoscopy in a patient suspects of having an acute abdomen due to an intestinal perforation, where there is a limitation of performi...

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High frequency of the recurrent c.1310_1313delAAGA BRCA2 mutation in the North-East of Morocco and implication for hereditary breast–ovarian cancer prevention and control

To date, a limited number of BRCA1/2 germline mutations have been reported in hereditary breast and/or ovarian cancer in the Moroccan population. Less than 20 different mutations of these two genes have been iden...

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BCAT1 Enhances BCAA Production to Drive Myeloid Leukemia [Research Watch]

BCAT1 is highly expressed in BC-CML and AML and promotes BCAA production to drive tumor progression.

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IFN{gamma} Induces FOXP3+ Treg Dysfunction to Promote Antitumor Immunity [Research Watch]

NRP^– Treg–derived IFN is a critical mediator of FOXP3⁺ Treg functional fragility.

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Overcoming the Immunosuppressive Tumor Microenvironment of Hodgkin Lymphoma Using Chimeric Antigen Receptor T Cells [Research Articles]

Some patients with otherwise treatment-resistant Hodgkin lymphoma (HL) could benefit from chimeric antigen receptor T cell (CART) therapy. However, HL lacks CD19 and contains a highly immunosuppressive tumor microenvironment (TME). We hypothesized that in HL, CART should target both malignant cells and the TME. We demonstrated CD123 on both HL cells and TME, including tumor-associated macrophages (TAM). In vitro, HL cells convert macrophages towards immunosuppressive TAM that inhibit T cell proliferation. In contrast, anti-CD123 CART recognized and killed TAM thus overcoming immunosuppression. Finally, we showed in immunodeficient mouse models that CART123 eradicate HL, and establish long-term immune memory. A novel platform that targets malignant cells and the microenvironment may be needed to successfully treat malignancies with an immunosuppressive milieu.

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CPS1 Promotes Tumor Growth in KRAS/LKB1-Mutant NSCLC [Research Watch]

LKB1 loss upregulates CPS1 to increase tumor growth by maintaining pyrimidine levels.

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Ceritinib Has Clinical Activity in Patients with ROS1-Rearranged NSCLC [Research Watch]

Ceritinib has manageable toxicity and achieves whole-body and intracranial responses.

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Atazanavir-Associated Crystalline Nephropathy

Crystalline nephropathy can occur following treatment with multiple therapeutic agents. We describe a human immunodeficiency virus (HIV)-infected patient treated for 2 years with combination antiretroviral therapy including atazanavir (ATV). Kidney biopsy revealed a crystalline nephropathy associated with diffuse chronic and granulomatous interstitial inflammation. Following the biopsy, treatment with ATV was discontinued and kidney function returned to pretreatment baseline levels. ATV, which has a well-established association with nephrolithiasis, is a rare but important cause of crystalline nephropathy.

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An Interactive Ambulatory Nephrology Curriculum for Internal Medicine Interns: Design, Implementation, and Participant Feedback

While diminishing nephrology fellow recruitment is a known issue, more work is needed to evaluate possible interventions to reverse this trend. We designed and implemented a curriculum to increase exposure to ambulatory nephrology among internal medicine interns. The curriculum focused on key aspects of outpatient nephrology practice, including supervised clinic visits, formal themed didactic content, and an online interactive forum with assigned evidence-based readings and small-group responses to relevant cases.

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Reflections on a Question: “Would You Offer Dialysis?”

A critically ill infant, child, or adolescent is rapidly deteriorating. The patient has kidney failure resulting in volume overload, metabolic disturbance, or both. A call is made to the pediatric nephrology service. The inevitable question is: "would you offer dialysis to this patient?" As a nephrologist, I find that I have increasing difficulty responding to this question. As I reflect on this difficulty, I realize that a great deal of the challenge in finding an answer is embedded in the wording of the question.

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Serum Phosphorus and Risk of Cardiovascular Disease, All-Cause Mortality, or Graft Failure in Kidney Transplant Recipients: An Ancillary Study of the FAVORIT Trial Cohort

Mild hyperphosphatemia is a putative risk factor for cardiovascular disease [CVD], loss of kidney function, and mortality. Very limited data are available from sizable multicenter kidney transplant recipient (KTR) cohorts assessing the potential relationships between serum phosphorus levels and the development of CVD outcomes, transplant failure, or all-cause mortality.

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The treatment of juvenile/adult GM1-gangliosidosis with Miglustat may reverse disease progression

Abstract

Juvenile and adult GM1-gangliosidosis are invariably characterized by progressive neurological deterioration. To date only symptomatic therapies are available. We report for the first time the positive results of Miglustat (OGT 918, N-butyl-deoxynojirimycin) treatment on three Italian GM1-gangliosidosis patients. The first two patients had a juvenile form (enzyme activity ≤5%, GLB1 genotype p.R201H/c.1068 + 1G > T; p.R201H/p.I51N), while the third patient had an adult form (enzyme activity about 7%, p.T329A/p.R442Q). Treatment with Miglustat at the dose of 600 mg/day was started at the age of 10, 17 and 28 years; age at last evaluation was 21, 20 and 38 respectively. Response to treatment was evaluated using neurological examinations in all three patients every 4–6 months, the assessment of Movement Disorder-Childhood Rating Scale (MD-CRS) in the second patient, and the 6-Minute Walking Test (6-MWT) in the third patient. The baseline neurological status was severely impaired, with loss of autonomous ambulation and speech in the first two patients, and gait and language difficulties in the third patient. All three patients showed gradual improvement while being treated; both juvenile patients regained the ability to walk without assistance for few meters, and increased alertness and vocalization. The MD-CRS class score in the second patient decreased from 4 to 2. The third patient improved in movement and speech control, the distance covered during the 6-MWT increased from 338 to 475 m. These results suggest that Miglustat may help slow down or reverse the disease progression in juvenile/adult GM1-gangliosidosis.

http://ift.tt/2s3DfBd

Associations of Newborn Brain Magnetic Resonance Imaging with Long-Term Neurodevelopmental Impairments in Very Preterm Children

To determine the relationship between brain abnormalities on newborn magnetic resonance imaging (MRI) and neurodevelopmental impairment at 7 years of age in very preterm children.

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Thyroid Disease and Type 1 Diabetes in Dutch Children: A Nationwide Study (Young Dudes-3)

To investigate the prevalence of overt thyroid disease in children in The Netherlands with and without type 1 diabetes mellitus (T1DM).

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Histologic Chorioamnionitis and Bronchopulmonary Dysplasia in Preterm Infants: The Epidemiologic Study on Low Gestational Ages 2 Cohort

To investigate the association between histologic chorioamnionitis (HCA) and bronchopulmonary dysplasia (BPD) in very preterm infants, both in a general population and for those born after spontaneous preterm labor and after preterm premature rupture of membranes (pPROM).

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Bronze Baby Syndrome

A male infant born at 37 weeks of gestation and weighing 2935 g was delivered by induced vaginal delivery to a 20-year-old multiparous mother after a pregnancy complicated by Rhesus isoimmunization. His serum total bilirubin was 10.6 mg/dL at 6 hours of age and 14.4 mg/dL at 10 hours of age. The family history was significant for a sibling who was also Coombs positive with hemolytic jaundice requiring several days of phototherapy. The infant was placed under a multiple-bank LED phototherapy device and treated with intravenous fluids and immune globulin to avoid exchange transfusion.

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Evaluation of haematological and serum biochemical changes associated with constant rate infusion tramadol hydrochloride as an adjunct to ketoprofen in laparotomized and ovariohysterectomized dogs

Abstract

Tramadol hydrochloride (an opioid-like analgesic) and ketoprofen (a non-steroidal anti-inflammatory drug) are routinely used in human and veterinary medicine for the management of post-surgical pain. However, data on the safety of constant rate infusion tramadol as an adjunct to ketoprofen for peri-operative analgesia is lacking. This study evaluated changes in haematology and serum biochemistry associated with constant rate infusion (CRI) tramadol hydrochloride as an adjunct to ketoprofen for analgesia in adult female dogs following laparotomy (LP) and ovariohysterectomy (OVH). Thirty (30) adult female dogs randomly assigned into six groups of five dogs each were used in studies 1 and 2. In both studies, group 3 served as the control which received normal saline while groups 1 and 2 were given 1.0 and 2.0 mg/kg/h of tramadol Hcl, respectively. Dogs in study 1 were laparotomized while OVH was performed on dogs in study 2. Ketoprofen (4 mg/kg) was given subcutaneously for 3 days post-surgery (PS) to all the groups. There was no significant difference in the haematological parameters of treated and control groups. There was a transient significant rise in some serum biochemical parameters of the treated groups but these decreased to baseline values by day 7 post-surgery. Based on the findings in this study, it was concluded that constant rate infusion of 1 and 2 mg/kg/h of tramadol hydrochloride as an adjunct to ketoprofen caused no clinically observable deleterious effect on haematology and serum biochemistry of dogs post-laparotomy and ovariohysterectomy.

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Aims and scope

Publication date: April 2017
Source:Women and Birth, Volume 30, Issue 2





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Pregnant women: What do they need to know during pregnancy? A descriptive study

Publication date: April 2017
Source:Women and Birth, Volume 30, Issue 2
Author(s): Mona M.A. Almalik, Sultan M. Mosleh
BackgroundAntenatal education programs provide women with essential knowledge and skills in various aspects of maternal and fetal health. Antenatal education is based on improving women's health, reducing the risks of complications and enhancing couples' positive experience during childbirth. There is a lack of formal antenatal educational programs based on women's needs in Jordan.AimThis study sought to identify and prioritize the learning needs for women during pregnancy.MethodsA descriptive cross-sectional design was employed. The study sample was recruited from three maternal and child health centers. Data were collected from a convenient sample of 150 pregnant women during their antenatal visits. One hundred and twenty three participants (response rate=82%) completed the self-reported antenatal learning needs questionnaire.FindingsWomen identified their most important learning needs were related to managing major complications of pregnancy (mean=3.49, SD=0.78), investigations and physician follow-up visit during pregnancy (mean=3.42, SD=0.71), appropriate diet (mean=3.36, SD=0.84) and information about medication and supplements (mean=3.22, SD=0.97). Spearman correlation showed negative association between participants' age and physical (r=−0.536, p=0.015) and emotional concerns (r=−0.490, p=0.001). Women who had a diploma or higher degree reported greater concern regarding physical (median=4.00, IQR=3.00–4.00, p=0.047) and emotional changes (median=3.33, IQR=3.00–4.00, p=0.004). Finally, migrant participants showed greater significant concern regarding emotional changes and coping with minor complications.ConclusionA large proportion of pregnant women in this study reported a high degree of importance of specific learning topics that were closely relevant to their current period of pregnancy. The lack of focusing on issues related to maternal emotional status and possible complications suggests a need for a national strategy to provide antenatal education based on women's perceptions of their needs.



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Cold Fusion: Massive Karyotype Evolution in the Antarctic Bullhead Notothen Notothenia coriiceps

Half of all vertebrate species share a series of chromosome fusions that preceded the teleost genome duplication, but we don't understand the causative evolutionary mechanisms. The "Robertsonian-translocation hypothesis" suggests a regular fusion of each ancestral acro- or telocentric chromosome to just one other by centromere fusions, thus halving the karyotype. An alternative "genome-stirring hypothesis" posits haphazard and repeated fusions, inversions, and reciprocal and non-reciprocal translocations. To study large-scale karyotype reduction, we investigated the decrease of chromosome numbers in Antarctic notothenioid fish. Most notothenioids have 24 haploid chromosomes, but bullhead notothen (Notothenia coriiceps) has eleven. To understand mechanisms, we made a RAD-tag meiotic map with about 10,000 polymorphic markers. Comparative genomics aligned about a thousand orthologs of platyfish and stickleback genes along bullhead chromosomes. Results revealed that nine of eleven bullhead chromosomes arose by fusion of just two ancestral chromosomes and two others by fusion of three ancestral chromosomes. All markers from each ancestral chromosome remained contiguous, implying no inversions across fusion borders. Karyotype comparisons support a history of: 1) Robertsonian fusions of 22 ancestral chromosomes in pairs to yield 11 fused plus two small unfused chromosomes, like N. angustata; 2) fusion of one of the remaining two ancestral chromosomes to a pre-existing fused pair, giving 12 chromosomes like N. rossii; and 3) fusion of the remaining ancestral chromosome to another fused pair, giving 11 chromosomes in N. coriiceps. These results raise the question of what selective forces promoted the systematic fusion of chromosomes in pairs and the suppression of pericentric inversions in this lineage and provide a model for chromosome fusions in stem teleosts.

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RNA Binding Protein Vigilin Collaborates with miRNAs To Regulate Gene Expression for Caenorhabditis elegans Larval Development

Extensive studies have suggested that most miRNA functions are executed through complex miRNA-target interaction networks, and such networks function semi-redundantly with other regulatory systems to shape gene expression dynamics for proper physiological functions. We found that knocking down vgln-1, which encodes a conserved RNA-binding protein associated with diverse functions, causes severe larval arrest at the early L1 stage in animals with compromised miRISC functions (an ain-2/GW182 mutant). Through an enhancer screen, we identified five specific miRNAs and miRNA families that act semi-redundantly with VGLN-1 to regulate larval development. By RIP-Seq analysis, we identified mRNAs that are directly bound by VGLN-1 and highly enriched for miRNA binding sites, leading to a hypothesis that VGLN-1 may share common targets with miRNAs to regulate gene expression dynamics for development.

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Need for updating safety recommendations on repetitive transcranial magnetic stimulation in stroke patients

A paper entitled "Inhibition versus facilitation of contralesional motor cortices in stroke: Deriving a model to tailor brain stimulation" was published by Sankarasubramanian et al. in Clinical Neurophysiology in March 2017 (Sankarasubramanian et al., 2017). That article reported the results of a study that aimed at investigating whether facilitation of contralesional dorsal premotor cortex by repetitive transcranial magnetic stimulation (rTMS) permitted to improve upper-limb function in severely affected post-stroke patients.

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Reply to “Need for updating safety recommendations on repetitive transcranial magnetic stimulation in stroke patients”

We are pleased to receive the correspondence from Glize et al. in regards to our paper published recently in Clinical Neurophysiology (Sankarasubramanian et al., 2017). We thank the authors for their interest and insightful comments regarding approaches used in our study. In brief, our study investigated the effectiveness of facilitating excitability of the contralesional dorsal premotor cortex (PMd) in patients severely affected by stroke. PMd was targeted using high-frequency (5 Hz) repetitive transcranial magnetic stimulation (rTMS).

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Early evaluation of circulating tumor DNA as marker of therapeutic efficacy in metastatic colorectal cancer patients (PLACOL study)

Purpose. Markers of chemotherapy efficacy in metastatic colorectal cancer (mCRC) are essential for optimization of treatment strategies. We evaluated the applicability of early changes in circulating tumor DNA (ctDNA) as a marker of therapeutic efficacy. <p>Experimental design. This prospective study enrolled consecutive mCRC patients receiving a first- or second-line chemotherapy. CtDNA was assessed in plasma collected before the first (C₀), second (C₁) and/or third (C₂) chemotherapy cycle, using picodroplet-digital PCR assays based either on detection of gene mutation (KRAS, BRAF, TP53) or hypermethylation (WIF1, NPY). Computed tomography scans were centrally assessed using RECIST v1.1 criteria. Multivariate analyses were adjusted on age, gender, ECOG performance status (PS), metastatic synchronicity and treatment line.</p> <p>Results. Eighty-two mCRC patients treated in first (82.9%) or second (17.1%) line chemotherapy were included. Patients with a high (>10ng/mL) versus low (≤0.1ng/mL) ctDNA concentration at C₀ had a shorter overall survival (OS) (6.8 versus 33.4 months: adjusted HR=5.64; CI_95%[2.5-12.6], P<0.0001). By analyzing the evolution of the ctDNA concentration between C₀ and C₂ or C₁ (C_2or1), we classified the patients in two groups (named "good" or "bad ctDNA responders"). In multivariate analysis, patients belonging to the group called "good ctDNA responder" (n=58) versus "bad ctDNA responder" (n=15) had a better objective response rate (P<0.001), and a longer median progression-free survival (8.5 vs 2.4 months: HR=0.19, CI_95%[0.09-0.40], P<0.0001) and OS (27.1 vs 11.2 months: HR=0.25, CI_95%[0.11-0.57], P<0.001).</p> <p>Conclusion. This study suggests that early change in ctDNA concentration is a marker of therapeutic efficacy in mCRC patients.</p> <p> 

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Prevalence and type distribution of human papillomavirus in squamous cell carcinoma and intraepithelial neoplasia of the vulva: A systematic review and meta-analysis

Abstract

In this updated systematic review and meta-analysis we estimate the pooled prevalence of human papillomavirus (HPV) DNA and HPV type distribution in squamous cell carcinoma of the vulva (vulvar cancer) and vulvar intraepithelial neoplasia (VIN). PubMed, Embase, and Cochrane Library databases were used to identify studies published between 1990 and 2015 and using a PCR-based or hybrid capture test to evaluate the presence of HPV DNA in vulvar cancer or VIN. Pooled estimates of the HPV prevalence with corresponding 95% confidence intervals (CI) were calculated based on a random effects model. The I² statistic was used to describe the amount of heterogeneity. In meta-regression analyses potential sources of heterogeneity were evaluated. We identified 92 eligible papers, comprising altogether 5015 cases of vulvar cancer (64 papers) and 2764 cases of VIN (48 papers). The pooled prevalence of HPV in vulvar cancer was 39.7% (95% CI: 35.1–44.4%). Overall, 76.3% (95% CI: 70.1–82.1%) of VIN lesions tested HPV-positive, while the HPV prevalence in new subcategories of VIN, uVIN and dVIN, was 86.2% (95% CI: 73.5–95.5%) and 2.0% (95% CI: 0–10.0%), respectively. Substantial between-study heterogeneity was observed (vulvar cancer: I² = 88.4%; VIN: I² = 90.7%) with the largest variation between geographical regions. Among HPV-positive cases the predominant high-risk HPV type was HPV16, followed by HPV33 and HPV18. HPV6 was detected as a single infection in a small subset of VIN and vulvar cancer samples. Thus, HPV vaccination targeting these HPV types may prevent a substantial number of vulvar lesions. This article is protected by copyright. All rights reserved.

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Elucidating the molecular basis of msh2-deficient tumors by combined germline and somatic analysis

Abstract

In a proportion of patients presenting mismatch repair (MMR)-deficient tumors, no germline MMR mutations are identified, the so-called Lynch-like syndrome (LLS). Recently, MMR-deficient tumors have been associated with germline mutations in POLE and MUTYH or double somatic MMR events. Our aim was to elucidate the molecular basis of MSH2-deficient LS-suspected cases using a comprehensive analysis of colorectal cancer (CRC)-associated genes at germline and somatic level.

Fifty-eight probands harboring MSH2-deficient tumors were included. Germline mutational analysis of MSH2 (including EPCAM deletions) and MSH6 was performed. Pathogenicity of MSH2 variants was assessed by RNA analysis and multifactorial likelihood calculations. MSH2 cDNA and methylation of MSH2 and MSH6 promoters were studied. Matched blood and tumor DNA were analyzed using a customized next generation sequencing panel.

Thirty-five individuals were carriers of pathogenic or probably pathogenic variants in MSH2 and EPCAM. Five patients harbored 4 different MSH2 variants of unknown significance (VUS) and one had 2 novel MSH6 promoter VUS. Pathogenicity assessment allowed the reclassification of the 4 MSH2 VUS and 6 probably pathogenic variants as pathogenic mutations, enabling a total of 40 LS diagnostics. Predicted pathogenic germline variants in BUB1, SETD2, FAN1 and MUTYH were identified in 5 cases. Three patients had double somatic hits in MSH2 or MSH6, and another 2 somatic alterations in other MMR genes and/or proof-reading polymerases.

In conclusion, our comprehensive strategy combining germline and somatic mutational status of CRC-associated genes by means of a subexome panel allows the elucidation of up to 86% of MSH2-deficient suspected LS tumors. This article is protected by copyright. All rights reserved.

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The association between individual metabolic syndrome components, primary liver cancer and cirrhosis: a study in the Swedish AMORIS cohort

Abstract

Metabolic syndrome (MetS) is associated with non-alcoholic fatty liver disease, which may progress to cirrhosis, a significant risk factor of hepatocellular carcinoma (HCC), the commonest malignant primary liver cancer (PLC). We investigated the association between the individual components of MetS (lipids, apolipoproteins, raised glucose, diabetes and obesity), PLC and cirrhosis.

A total of 509,436 participants from the Swedish AMORIS cohort, recruited between January 1985 to December 1996 (end-date December 2011), aged ≥20 with baseline triglycerides (TG), total cholesterol (TC), glucose and liver enzymes were included. Those with baseline benign liver tumours, PLC or cirrhosis were excluded. Multivariate Cox regression, adjusted for age, gender, socio-economic status, liver disease (excluding cirrhosis) and MetS factors were used to estimate the association with PLC and cirrhosis.

There were 766 PLC and 2,775 cirrhosis cases over 13-years. Raised TG, low TC, raised glucose, diabetes and low HDL were associated with an increased risk of developing PLC and cirrhosis. ApoB/ApoA-I ratio were also associated with PLC, whilst low LDL, raised TG/HDL, low ApoA-I and low ApoB were associated with cirrhosis. Obesity was significantly associated with PLC but not cirrhosis. Raised TG, low TC, raised glucose and diabetes showed stronger associations with PLC in participants with cirrhosis but many participants developed PLC without cirrhosis.

Individual components of MetS (lipids, apolipoproteins, raised glucose, diabetes and obesity) were associated with an increased risk of developing PLC or cirrhosis. MetS components were more strongly associated with PLC with preceding cirrhosis history but many participants developed PLC without cirrhosis. This article is protected by copyright. All rights reserved.

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Cetuximab or Nimotuzumab plus Intensity-modulated Radiotherapy Versus Cisplatin plus Intensity-modulated Radiotherapy for Stage II-IVb Nasopharyngeal Carcinoma

Abstract

To compare intensity-modulated radiotherapy (IMRT) with cisplatin (CDDP) versus cetuximab (CTX) and nimotuzumab (NTZ) for Stage II-IVb Nasopharyngeal Carcinoma (NPC). A total of 1,837 patients with stage II - IV_b NPC who received IMRT plus CTX or NTZ, or CDDP between January 2009 and December 2013 were included in the current analysis. Using propensity scores to adjust for potential prognostic factors, a well-balanced cohort of 715 patients was created by matching each patient who underwent IMRT plus concomitant NTZ/CTX with four patients who underwent IMRT plus concomitant CDDP (1:4). Efficacy and safety were compared between the CTX/NTZ and CDDP groups of this well-balanced cohort. Furthermore, we conducted multivariate analysis and subgroup analysis based on all the 1,837 eligible cases. There was no significant difference between CTX/NTZ group and CDDP group in terms of DFS (3-year, 86.7% vs. 86.2%, P>0.05), LRRFS (96.2% vs. 96.3%, P>0.05), DMFS (91.1% vs. 92.3%, P>0.05), and OS (91.7% vs. 91.9%, P>0.05). Subgroup analysis demonstrated a significant interaction effect between patients with IMRT plus CTX/NTZ and N3 node stage on LRRFS with the highest risk of loco-regional relapse (HR 8.85, P=0.001). Significantly increased hematologic toxicities, gastrointestinal reactions were observed in the CDDP group (P<0.05). 3.4-4.7% patients experienced severe hematologic toxicities during the treatment with concomitant CTX and NTZ. Increased rate of CTX related-skin reaction and mucositis was observed in the CTX group. CTX/NTZ used concurrently with IMRT may be comparable to those of the standard CDDP-IMRT combination for maximizing survival for patients with stage II-IVb NPC. This article is protected by copyright. All rights reserved.

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uPA/uPAR system activation drives a glycolytic phenotype in melanoma cells

Abstract

In the present manuscript we show the involvement of the uPA/uPAR system in the regulation of aerobic glycolysis of melanoma cells. uPAR over-expression in human melanoma cells controls an invasive and glycolytic phenotype in normoxic conditions. uPAR down-regulation by siRNA or its uncoupling from integrins, and hence from integrin-linked tyrosine kinase receptors (IL-TKRs), by an antagonist peptide induced a striking inhibition of the PI3K/AKT/mTOR/HIF1α pathway, resulting into impairment of glucose uptake, decrease of several glycolytic enzymes and of PKM2, a checkpoint that controls metabolism of cancer cells. Further, binding of uPA to uPAR regulates expression of molecules that govern cell invasion, including extracellular matrix metallo-proteinases inducer (EMPPRIN) and enolase, a glycolytyc enzyme that also serves as a plasminogen receptor, thus providing a common denominator between tumor metabolism and phenotypic invasive features. Such effects depend on the α5β1-integrin-mediated uPAR connection with EGFR in melanoma cells with engagement of the PI3K-mTOR-HIFα pathway. HIF-1α trans-activates genes whose products mediate tumor invasion and glycolysis, thus providing the common denominator between melanoma metabolism and its invasive features. These findings unveil a unrecognized interaction between the invasion-related uPAR and IL-TKRs in the control of glycolysis and disclose a new pharmacological target (i.e. uPAR/IL-TKRs axis) for the therapy of melanoma. This article is protected by copyright. All rights reserved.

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The 5D Framework: A Clinical Primer for Fecal Microbiota Transplantation to Treat Clostridium difficile infection

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Pancreatic pseudocyst localized in the gastric wall after EUS-guided fine-needle aspiration of type 1 autoimmune pancreatitis

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Intra-pulse modulation recognition using short-time ramanujan Fourier transform spectrogram

Intra-pulse modulation recognition under negative signal-to-noise ratio (SNR) environment is a research challenge. This article presents a robust algorithm for the recognition of 5 types of radar signals with ...

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The 4th Edition of the Head and Neck WHO Blue Book: Editor's Perspectives

In the 4th Edition of the World Health Organization (WHO) Classification of Head and Neck tumors [1], the editors were committed to maintain the familiar classification and nomenclature of previous editions while updating and introducing new entities [2]. At the outset, the editors agreed to exclude themselves from authoring or co-authoring any chapters others than Introduction to their respective Chapters, wherein approaches and modifications where to be highlighted. Broadly, efforts were exercised to reduce redundancy by limiting multiple discussions of the same entities to their commonest anatomic sites.

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Antagonistic Effect of Laver, Pyropia yezonensis and P. haitanensis , on Subchronic Lead Poisoning in Rats

Abstract

Lead, one of the most harmful heavy metals, can cause various hazardous effects on living organisms. This study was undertaken to evaluate the antagonistic and protective effects of two economically important laver species, Pyropia yezoensis and P. haitanensis, against subchronic lead poisoning in rats by a 30-day feeding test. Sixty-four healthy Wistar rats were randomly divided into eight groups with eight rats (4♂ + 4♀) per group, among which, one group was served as the control, the others were respectively treated with lead acetate (5 mg/kg b w), and a combination of lead acetate and P. yezoensis or P. haitanensis at different dosages. Weight gain of rats was observed and recorded. Changes in antioxidant indexes, and liver and renal function markers were determined to evaluate the antagonistic effect. Lead content in rats was determined to investigate lead excretion effect of laver. The results showed that exposure to lead caused lead accumulation in kidney and liver, thus leading to significant oxidative damage and impaired liver and renal function compared to the control group. The co-treatment of laver slightly increased body weight compared to the lead-treated group. The co-administration of laver restored liver and renal function of rats by preventing the increment in the activities of alanine transaminase (ALT), alkaline phosphatase (ALP), and aspartate transaminase (AST), and the levels of blood urea nitrogen (BUN) and creatinine (Cr). The increasing of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities, and lowering of the enhanced malondialdehyde (MDA) contents of rats were observed in the laver co-treated groups, which indicated that laver enhanced the antioxidative capacity of rats. The laver also enhanced lead content in feces and reduced it in liver and kidney. The results indicated that P. yezoensis and P. haitanensis could maintain or promote the normal physiological and biochemical function of lead-induced subchronic poisoning of rats, probably owing to their enhancements of antioxidant capacity and lead excretion.

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Dietary Iodine Affected the GSH-Px to Regulate the Thyroid Hormones in Thyroid Gland of Rex Rabbits

Abstract

Iodine (I) is an essential trace element that can influence animal health and productivity. In this study, we investigated the effects of dietary iodine on the antioxidant indices of organ (liver and thyroid gland) and messenger RNA (mRNA) expression of glutathione peroxidase (GSH-Px) in Rex rabbits. A total of 120 4-month-old Rex rabbits (2235.4 ± 13.04 g BW) were divided into four equal groups, and their diets were supplemented with iodine (0, 0.2, 2, or 4 mg/kg dry matter (DM)). The iodine concentration in basal diet (control group) was 0.36 mg/kg DM. In most of measured parameters, supplemental iodine exerted no significant effect. Growth and slaughter performance and organ weight were not influenced significantly by iodine supplementation. Serum T₃ was significantly lower in 2-mg I group than in 0.2 and 4-mg I groups (P < 0.05). Superoxide dismutase (SOD), GSH-Px, methane dicarboxylic aldehyde (MDA), and thyroperoxidase (TPO) in the serum and liver were not influenced (P > 0.05). Conversely, serum catalase (CAT) was significantly reduced (P < 0.05). In the thyroid, GSH-Px was higher in the 2-mg I group than in the 0.2- and 4-mg I groups (P < 0.05). RT-PCR results showed that the mRNA expression level of GSH-Px in the liver was not significantly influenced (P > 0.05). In the thyroid gland, the mRNA expression level of GSH-Px was higher in the 2-mg I group than in the 4-mg I group (P < 0.05), which agreed with the activity of GSH-Px. In conclusion, iodine supplementation exerted no effect on the performance and antioxidant capacity of the body, but dietary iodine influenced serum T₃ or GSH-Px in the thyroid gland. Thus, on the basis of serum T₃ and GSH-Px levels in the thyroid gland, we hypothesized that GSH-Px secretion was increased by adding dietary iodine in the thyroid, which may inhibit the H₂O₂ generation and further influence the thyroid hormone synthesis.

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Grant funding for rural EMS-Hospital mobile telemedicine

RURAL AMERICA — GD is pleased to share this important information with you. In short, the US Department of Agriculture (USDA) Distance Learning and Telemedicine Grant Program (DLT) is designed to provide access to healthcare resources that benefit rural communities. Of specific interest, this year's program has prioritized $1.6 million dollars specifically for Mobile Telemedicine (communications upgrades ...

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Editorial introductions

No abstract available

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Vasopressin and diabetic nephropathy

Purpose of review: The prevalence of diabetic kidney disease (DKD) is increasing worldwide. Despite major therapeutic advances in the last decades in DKD, the current standard of care let many people progress to severe stages. Vasopressin secretion is increased in diabetes, and its potential role in the onset and progression of DKD is being re-investigated. Recent findings: Recently, observational studies evidenced an association between surrogates of vasopressin secretion (daily fluid intake or urine volume, and plasma copeptin concentration) and chronic kidney disease in the community, but also specifically in type 1 and in type 2 diabetes. Causality is strongly supported by a series of studies in rats conducted more than a decade ago, and by additional recent experimental data. The mechanism underlying these adverse effects likely involves the hyperfiltration induced indirectly as a consequence of the tubular effects of the hormone mediated by the V2 receptor. Summary: If chronic vasopressin action on the kidney is detrimental in diabetes as suggested so far, intervention studies should be designed. Available tools include V2 receptor blockade, and changes in daily water intake in vulnerable patients. Safety and effectiveness should be tested, as it is currently done in patients with CKD (NCT01766687).

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Pathophysiology and implications of intradialytic hypertension

Purpose of review: Intradialytic hypertension occurs regularly in 10--15% of hemodialysis patients. A large observational study recently showed that intradialytic hypertension of any magnitude increased mortality risk comparable to the most severe degrees of intradialytic hypotension. The present review review discusses the most recent evidence underlying the pathophysiology of intradialytic hypertension and implications for its management. Recent findings: Patients with intradialytic hypertension typically have small interdialytic weight gains, but bioimpedance spectroscopy shows these patients have significant chronic extracellular volume excess. Intradialytic hypertension patients have lower albumin and predialysis urea nitrogen levels, which may contribute to small reductions in osmolarity that prevents blood pressure decreases. Intradialytic vascular resistance surges remain implicated as the driving force for blood pressure increases, but mediators other than endothelin-1 may be responsible. Beyond dry weight reduction, the only controlled intervention shown to interrupt the blood pressure increase is lowering dialysate sodium. Summary: Patients with recurrent intradialytic hypertension should be identified as high-risk patients. Dry weight should be re-evaluated, even if patients do not clinically appear volume overloaded. Antihypertensive drugs should be prescribed because of the persistently elevated ambulatory blood pressure. Dialysate sodium reduction should be considered, although the long term effects of this intervention are uncertain.

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Something old, something new, something borrowed, something black

No abstract available

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Renal arteriovenous oxygen shunting

Purpose of review: Renal arteriovenous oxygen shunting has been proposed as a mechanism by which oxygen supplied to the kidney can bypass the renal parenchyma. Shunting could, therefore, play a crucial role in renal hypoxia and hyperoxia. In the absence of suitable quantitative experimental methods, computational modeling has been employed in recent years to estimate the extent and potential impact of oxygen shunting. Recent findings: Overestimation of the separation distance between arteries and veins was suggested to be responsible for previous findings that only negligible amounts of oxygen are shunted in the preglomerular vasculature. However, models considering the correct separation distance and wrapping of artery–vein pairs still showed shunting at negligible levels of less than 1% of total renal oxygen delivery. The effect of reverse CO2 shunting on the oxygen–hemoglobin dissociation curve was found to impair, rather than promote, preglomerular oxygen shunting. Summary: Oxygen is unlikely to be shunted along the preglomerular vasculature in sufficient quantities to affect renal oxygenation. There may be substantial shunting at the level of the postglomerular vasculature, but more extensive efforts in structural imaging and computational modeling are needed to quantify it reliably.

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Resurgence of parathyroidectomy: evidence and outcomes

Purpose of review: Parathyroidectomy (PTx) is the definitive therapy for refractory secondary hyperparathyroidism (SHPT). The drastic effects of PTx on biochemical parameters of SHPT increases the possibility that this intervention will lead to a reduction in the adverse outcomes related to uncontrolled SHPT. Recent findings: The effect of PTx on mortality and cardiovascular outcomes among dialysis patients with severe SHPT have been evaluated in many observational studies from different regions of the world, including Asia, Europe, North America, and South America. In all but one small study, there was a significant association of PTx with lower all-cause mortality. In addition, in all studies, there was a trend in favor of PTx for cardiovascular morbidity and mortality. The effect of PTx on fractures has been evaluated in only one epidemiological study from the United States, which demonstrated a significant association of PTx and lower hip and combined fractures. Summary: Although randomized evidence is lacking, these highly consistent results may suggest a strong beneficial effect of PTx on long-term clinical outcomes and eliminate the potential concern of low parathyroid hormone after PTx.

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An update on the treatment of IgA nephropathy

Purpose of review: The treatment of IgA nephropathy (IgAN) has been limited by several controversies in the literature, including the benefits of corticosteroids in addition to optimized renin–angiotensin system blockers (RASBs), in those with lower estimated glomerular filtration rate (eGFR), or in different ethnic groups. Recent studies have attempted to address these issues. Recent findings: Two observational studies suggest the efficacy of corticosteroids in those with lower eGFR, but with a higher risk of adverse events. The Supportive versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) trial compared immunosuppression with supportive care in addition to optimized RASB, and suggests that corticosteroids (but not cyclophosphamide/azathioprine) may reduce proteinuria but the effect on renal function is not clear, that immunosuppression is associated with a high risk of adverse events and that optimal RASB is very effective at lowering proteinuria and the short-term risk of renal function decline. The Therapeutic Evaluation of Steriods in IgA Nephropathy Global (TESTING) trial compared corticosteroids with placebo in addition to optimized RASB, and demonstrated a decreased risk of renal function decline and lower proteinuria, but a higher risk of adverse events. Additional trials demonstrate the potential efficacy of enteric-budesonide but not rituximab on proteinuria reduction, and conflicting findings with mycophenolate mofetil. Summary: Until less toxic therapies for IgAN are available, treatment with corticosteroids will need to be made in the context of conflicting evidence, and should likely be limited to patients at highest risk of disease progression who understand the significant risk of adverse events.

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Hungry bone syndrome

Purpose of review: In the United States, the number of parathyroidectomies among patients with chronic dialysis has remained stable in the last decade. A fall in serum calcium concentration is common postparathyroidectomy in patients with hyperparathyroidism, which usually resolves in 2–4 days. A severe drop in serum total calcium concentration less than 2.1 mmol/L and/or prolonged hypocalcemia for more than 4 days postparathyroidectomy is called hungry bone syndrome (HBS). Concomitant hypophosphatemia, hypomagnesemia, and hyperkalemia can be seen. Hypocalcemia and hypophosphatemia can persist for months to years. In contemporary clinical practice, HBS may be more commonly seen in patients with secondary compared to primary hyperparathyroidism. Preoperative radiological changes in bone, elevated serum alkaline phosphatase and parathyroid hormone (PTH) levels, and high numbers of osteoclasts on bone biopsy may identify patients at risk. Treatment consists of high-dose oral calcium and calcitriol supplementation. A low-dose pamidronate infusion 1–2 days prior to surgery may prevent HBS. Recent findings: Recent in-vitro studies reported net calcium movement into bone because of a sudden fall in serum PTH level after a prolonged period of elevation. This supports a previous hypothesis that a sudden drop in serum PTH level after surgery results in the unopposed action of osteoblasts and influx of calcium into bone. Summary: Incidence of HBS and its association with morbidity and mortality remains unclear in contemporary clinical practice. It is more common to encounter HBS in chronic dialysis patients with secondary hyperparathyroidism than those with primary hyperparathyroidism that undergo parathyroidectomies. Use of bisphosphonates to prevent HBS should be explored in future studies.

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Therapeutic microRNAs in polycystic kidney disease

Purpose of review: microRNAs (miRNAs) are short noncoding RNAs that function as sequence-specific inhibitors of gene expression. Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of end-stage kidney failure with limited treatment options. The realization that miRNA upregulation, and thus its gain-of-function, can drive the progression of ADPKD has raised the possibility that anti-miRs represent a novel drug class for this disorder. Recent findings: A common set of miRNAs are aberrantly expressed in various murine models of polycystic kidney disease. In particular two miRNAs, miR-17 family and miR-21, are both upregulated in kidney cysts and promote ADPKD progression in mouse models. miR-17 rewires cyst epithelial metabolism to enhance cyst proliferation. On the other hand, miR-21 represses proapoptotic genes and thus inhibits cyst apoptosis. Importantly, an anti-miR-17 drug has advanced through preclinical ADPKD studies, whereas an anti-miR-21 drug has already cleared phase I clinical trial. Summary: miRNAs have emerged as new regulators of ADPKD pathogenesis. Anti-miRs represent a feasible and an entirely new class of drugs for the treatment of ADPKD.

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Molecular modifiers of kidney stones

Purpose of review: This review discusses the role of molecular modifiers as inhibitors of kidney stone formation, drawing largely from in-vitro evidence while also citing relevant in-vivo studies. An emphasis is placed on physical observations of crystal growth inhibition, including mechanisms of action that focus predominantly on the literature of calcium oxalate and L-cystine. Recent findings: The last decade has witnessed several breakthroughs in the identification of molecules with promise to curb kidney stone formation, as well as discoveries of the mechanisms by which these molecules (or combinations thereof) function as inhibitors of pathological crystal growth. Studies of L-cystine and calcium oxalate crystallization have uncovered inhibitors that are more effective than current therapies. In-vitro assays using advanced techniques such as atomic force microscopy have been able to characterize modifier–crystal interactions and the mechanisms of crystal growth inhibition. A recent study of calcium oxalate crystals uncovered a new inhibition pathway leading to crystal dissolution at relatively low modifier concentrations. Summary: Advanced methods of identifying therapeutics for kidney stone disease have created a greater awareness of the potential impact of crystal modifiers in pathological crystallization. Many natural and synthetic species have the capacity to act as growth inhibitors; however, the challenge of bridging in-vitro and in-vivo evidence has proven to be difficult. Future effort to better integrate laboratory research, clinical trials and animal studies has the potential to broaden our understanding of crystal growth modification and its role in mitigating pathological crystallization.

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Pathophysiologic insight into MesoAmerican nephropathy

Purpose of review: Mesoamerican nephropathy (MeN) is an emerging pathophysiological entity of Chronic kidney desease (CKD) not related to traditional risk factors (diabetes and hypertension) that have caused thousands of deaths in Central America, mainly in sugarcane workers. The focus of this review is to discuss the risk factors and probable mechanisms involved in the initiation and progression of this devastating disease. Recent findings: Frequent episodes of subclinical Acute kidney injury caused by repetitive heat stress, dehydration, and strenuous work have been regarded as the main risk factors for MeN. The combination of them chronically activates vasopressin, renin angiotensin aldosterone system, and polyol-fructokinase pathway in the kidney. Also, subclinical rhabdomyolysis compound the framework of the disease by exacerbating systemic inflammation and inducing uricosuria. Exposure to nephrotoxins, high fructose intake, and use of NSAIDs could also contribute to further accelerating the progression of the disease. Summary: The evidence supports the notion that recurrent cycles of heat stress, dehydration, and strenuous work may cause CKD. The chronic activation of such mechanisms likely occurs in other conditions of reduced water intake and probably explains why the current management of CKD has not been effective to revert or halt the progression to end-stage CKD.

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Iron-induced hypophosphatemia: an emerging complication

Purpose of review: Iron-induced hypophosphatemia is a well documented side-effect but associated complications are largely neglected, because the results from single dosing studies suggest that transient decreases in plasma phosphate concentrations are asymptomatic and fully reversible. However, an increasing number of case reports and case series suggest that some patients develop severe and symptomatic hypophosphatemia. Long-term complications from hypophosphatemia include osteomalacia and bone fractures, which can result from repeated intravenous administration of certain high-dose iron preparations. Recent findings: Results from clinical trials suggest that the highest risk for the development of hypophosphatemia is associated with ferric carboxymaltose, iron polymaltose, and saccharated iron oxide. Clinical studies show that renal phosphate wasting mediated by increased fibroblast growth factor 23 causes hypophosphatemia after iron therapy. Impaired renal function therefore protects from hypophosphatemia, whereas the highest incidences and most severe manifestations have been reported in patients in whom the underlying cause of iron deficiency cannot be corrected. Summary: Diagnosis of iron-induced hypophosphatemia requires clinical suspicion. Treatment is guided by the severity of hypophosphatemia, and most patients will require oral or intravenous phosphate substitution. Future treatment options could involve therapeutic anti-FGF23 antibody (KRN23). Prevention and correction of vitamin D deficiency represents a supportive treatment option.

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Calciphylaxis

Purpose of review: Calciphylaxis remains a poorly understood vascular calcification disorder with predilection for patients with end-stage renal disease (ESRD). Recent data from large patient registries and databases have begun to provide information regarding incidence, risk factors, and outcomes in patients with calciphylaxis. Recent findings: The most recent estimate places the incidence of calciphylaxis at 3.5 new cases/1000 patient-years among the patients with ESRD on chronic hemodialysis. It is possible that misdiagnosis or subclinical disease may attribute to lower than the true incidence. There is a suggestion that the incidence is higher in peritoneal dialysis patients compared with patients with hemodialysis. Recent studies have identified a number of risk factors and point to the effects of vitamin K deficiency mediated impairment in Matrix Gla Protein carboxylation as one of the likely pathogenic mechanisms. The outcomes in calciphylaxis patients remain poor with mortality approaching 30% at 6 months and 50% at 12 months. Summary: The present review describes recent literature in the field of calciphylaxis. Calciphylaxis registries and specimen biorepositories promise to provide insights into the pathogenesis of calciphylaxis and will pave the way for much needed clinical trials.

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Palliative and end-of-life care in nephrology: moving from observations to interventions

Purpose of review: In comparison with patients who have other serious illnesses, patients with advanced kidney disease have a higher rate of intensive care utilization at the end of life and receive palliative care less frequently. Consensus and clinical practice guidelines have therefore recommended the incorporation of palliative care earlier in the disease trajectory. This review summarizes recent literature on this aspect of care and will highlight future directions for patient-centered care within palliative nephrology. Recent findings: Patients with advanced kidney disease and their families frequently do not engage effectively with their clinicians to make informed treatment decisions or plan for care at the end of life. Furthermore, racial and ethnic minority patients continue to receive a lower rate of palliative care services compared to other racial groups. Interventions that promote better palliative care communication and education among nephrology clinicians, patients and their families are becoming increasingly more common in nephrology. Summary: Overall, improved understanding of the unique care needs of patients with advanced and end-stage kidney disease provides a solid foundation to improve palliative and end-of-life care delivery among diverse populations in nephrology.

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MicroRNA-211-5p suppresses tumour cell proliferation, invasion, migration and metastasis in triple-negative breast cancer by directly targeting SETBP1

MicroRNA-211-5p suppresses tumour cell proliferation, invasion, migration and metastasis in triple-negative breast cancer by directly targeting SETBP1

British Journal of Cancer advance online publication, June 1 2017. doi:10.1038/bjc.2017.150

Authors: Liang-liang Chen, Zhou-jing Zhang, Zhan-bo Yi & Jian-jun Li

http://ift.tt/2qH1rJU

MicroRNA-7 suppresses the homing and migration potential of human endothelial cells to highly metastatic human breast cancer cells

MicroRNA-7 suppresses the homing and migration potential of human endothelial cells to highly metastatic human breast cancer cells

British Journal of Cancer advance online publication, June 1 2017. doi:10.1038/bjc.2017.156

Authors: Yu-Xin Cui, Robyn Bradbury, Valentina Flamini, Bo Wu, Nicola Jordan & Wen G Jiang

http://ift.tt/2rqpGcD

CBF1 is clinically prognostic and serves as a target to block cellular invasion and chemoresistance of EMT-like glioblastoma cells

CBF1 is clinically prognostic and serves as a target to block cellular invasion and chemoresistance of EMT-like glioblastoma cells

British Journal of Cancer advance online publication, June 1 2017. doi:10.1038/bjc.2017.157

Authors: D Maciaczyk, D Picard, L Zhao, K Koch, D Herrera-Rios, G Li, V Marquardt, D Pauck, T Hoerbelt, W Zhang, D M Ouwens, M Remke, T Jiang, H J Steiger, J Maciaczyk & U D Kahlert

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A novel anti-CD22 scFv–apoptin fusion protein induces apoptosis in malignant B-cells

CD22 marker is a highly internalizing antigen which is located on the surface of B-cells and is being used as a promising target for treatment of B cell malignancies. Monoclonal antibodies targeting CD22 have ...

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The impact of DO and salinity on microbial community in poly(butylene succinate) denitrification reactors for recirculating aquaculture system wastewater treatment

The interactions between environmental factors and bacterial community shift in solid-phase denitrification are crucial for optimum operation of a reactor and to achieve maximum treatment efficiency. In this s...

http://ift.tt/2rtYHgi

Degradation of aflatoxin B1 from naturally contaminated maize using the edible fungus Pleurotus ostreatus

Aflatoxins are highly carcinogenic secondary metabolites that can contaminate approximately 25% of crops and that cause or exacerbate multiple adverse health conditions, especially in Sub-Saharan Africa and So...

http://ift.tt/2qKZyMb

A novel constructed SPT15 mutagenesis library of Saccharomyces cerevisiae by using gTME technique for enhanced ethanol production

During the last few years, the global transcription machinery engineering (gTME) technique has gained more attention as an effective approach for the construction of novel mutants. Genetic strategies (molecula...

http://ift.tt/2rtCmzi

Misdiagnosis of HIV treatment failure based on clinical and immunological criteria in Eastern and Central Kenya

Routine laboratory monitoring is part of the basic care package offered to people living with the Human Immunodeficiency Virus (PLHIV). This paper aims to identify the proportion of PLHIVs with clinical and im...

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Inguinal and anorectal Lymphogranuloma Venereum: a case series from a sexually transmitted disease center in Rome, Italy

Lymphogranuloma venereum (LGV) is a sexually transmitted infection caused by L1, L2, L3 serovars of C. trachomatis (CT). Since 2003, LGV cases have been increasing in Europe. Aim of this report is to describe the...

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Clinical failure with and without empiric atypical bacteria coverage in hospitalized adults with community-acquired pneumonia: a systematic review and meta-analysis

Both typical and atypical bacteria can cause community-acquired pneumonia (CAP); however, the need for empiric atypical coverage remains controversial. Our objective was to evaluate the impact of antibiotic re...

http://ift.tt/2qJAnpr

Endovascular treatment of thoracic aortic pseudoaneurysm due to brucellosis: a rare case report

Arterial damage is a known complication of brucellosis, but the occurrence of a thoracic aortic pseudoaneurysm secondary to brucellosis has not been previously reported.

http://ift.tt/2s2BHHZ

Tuberculosis screening among persons with diabetes mellitus in Pune, India

Diabetes mellitus (DM) increases tuberculosis (TB) risk, and there is increasing concern over the public health implications of the convergence of these two epidemics. Screening for TB among people with DM is ...

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How externalities impact an evaluation of strategies to prevent antimicrobial resistance in health care organizations

The rates of antimicrobial-resistant organisms (ARO) continue to increase for both hospitalized and community patients. Few resources have been allocated to reduce the spread of resistance on global, national ...

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Tumor infiltrating lymphocytes in acral lentiginous melanoma: a study of a large cohort of cases from Latin America

Abstract

Purpose

Acral lentiginous melanoma (ALM) is a poor prognosis subtype and is the most prevalent in non-Caucasian populations. The presence of tumor infiltrating lymphocytes (TILs) has been associated with poor prognosis in melanoma. A large cohort of ALM cases was studied to determine status of TIL and its association with outcome.

Methods

All patients with cutaneous melanoma presenting from 2005 to 2012 at Instituto Nacional de Enfermedades Neoplasicas in Peru were retrospectively identified. Clinicopathological information was obtained from the medical charts. A prospective evaluation of TIL was performed. Analysis of association between ALM and clinicopathological features including TIL as well as survival analysis compared the outcome of ALM to whole group and extremity NALM was performed.

Results

537 ALM from a total of 824 cutaneous melanoma cases were studied. Older age (p = 0.022), higher Breslow (p = 0.008) and ulceration (p < 0.001) were found to be more frequent in ALM. Acral had worse overall survival (OS) compared with the whole group (p = 0.04). Clinical stage (CS) I–II patients had a median OS of 5.3 (95% CI 4.3–6.2) for ALM and 9.2 (95% CI 5.0–7.0) for extremity NALM (p = 0.016). Grade 0 (absence of TIL), I, II and III were found in 7.5, 34.5, 32.1, and 25.9%, respectively. Lower TIL grade was associated with larger tumor size (p = 0.003), higher Breslow (p = 0.001), higher Clark level (p = 0.007), higher CS (p = 0.002), extremity location (p = 0.048), histological subtype ALM (p = 0.024) and better OS (p = 0.001).

Conclusions

ALM is highly prevalent in Peru and carries poor outcome. Lower TIL levels were associated with poor outcome and ALM.

http://ift.tt/2rtdAiM

Population pharmacokinetic analyses of the effect of carboplatin pretreatment on olaparib in recurrent or refractory women’s cancers

Abstract

Purpose

Combining olaparib with carboplatin was recently shown to be active in both BRCA and non-BRCA mutant cancers in a recent phase I/Ib combination trial. The optimal drug sequence recommended was carboplatin 1-day before olaparib. However, carboplatin pre-treatment induced a ~50% faster olaparib clearance.

Methods

To further explore this drug interaction, a population pharmacokinetic (PK) model was designed that included a lag time parameter, a second absorption compartment from tablet formulation, a single distribution/elimination compartment, and covariance among the clearance and volume parameters.

Results

Clearance (6.8 L/h) and volume (33 L) estimates were comparable with literature. The only significant covariate was the presence of carboplatin on olaparib clearance, consistent with published noncompartmental PK and in vitro data.

Conclusions

Simulations predicted lower steady-state peak/trough olaparib exposure through 24–36 h post carboplatin pre-treatment, but this effect was lost by day 2 and thus no dose adjustment is recommended.

http://ift.tt/2rtp0De

Fabrication of Polymer Microspheres for Optical Resonator and Laser Applications

Protocols for the synthesis of microspheres from polymers, the manipulation of microspheres, and micro-photoluminescence measurements are presented.

http://ift.tt/2rNJWrm

Receptor activator of nuclear factor kappa B (RANK) expression in primary breast cancer correlates with recurrence-free survival and development of bone metastases in I-SPY1 (CALGB 150007/150012; ACRIN 6657)

Abstract

Purpose

The receptor activator of nuclear factor kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) axis may contribute to the development of bone metastases (BM). We studied gene expression in this pathway in primary breast cancer (BC) to determine correlations with clinical characteristics and outcomes in the neoadjuvant I-SPY1 study.

Methods

We evaluated RANK/RANKL/OPG expression using expression microarrays in I-SPY1 (n = 149). Associations with clinical features were determined using t test and ANOVA. Associations between biomarker high versus low groups (dichotomized at an optimal cutpoint) and recurrence-free survival (RFS) were evaluated using the log-rank test and in a multivariate Cox proportional hazard model. A pooled external neoadjuvant cohort with gene expression data (GSE25066) (Hatzis et al. in JAMA 305(18):1873–1881, 30) (n = 425) was used for validation. Associations with site-specific relapse were evaluated using the t-test and multivariate logistic regression adjusting for hormone receptor (HR) status.

Results

RANK was significantly higher in HR negative versus HR positive (p = 0.027), in basal versus non-basal disease (p = 0.004), and in those achieving pathologic complete response (p = 0.038); the associations with HR negative and basal BC were also significant in GSE25066. In both datasets, higher RANK associated with significantly worse RFS (I-SPY1: p = 0.045, GSE25066: p = 0.044). However, this association did not remain significant after adjusting for HR status. In I-SPY1 patients with recurrence, higher RANK correlated with BM versus non-BM (p = 0.045), even after adjusting for HR status (p = 0.035).

Conclusions

RANK is increased in HR negative and basal BC, and correlates with worse RFS and risk of BM. The RANK pathway is a potential therapeutic target in BC.

http://ift.tt/2qP6Rxu

Exposure to heavy metals may increase risk of autism

New research finds higher concentrations of heavy metals in the baby teeth of children with autism spectrum disorder, compared with children without.

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A Novel Method for In Situ Electromechanical Characterization of Nanoscale Specimens

Isolating electrical and thermal effects on electrically assisted deformation (EAD) is very difficult using macroscopic samples. Metallic sample micro- and nanostructures together with a custom test procedure have been developed to evaluate the impact of applied current on the formation without joule heating and evolution of dislocations on these samples.

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Abnormal γ-aminobutyric acid neurotransmission in a Kcnq2 model of early onset epilepsy

Summary

Objective

Mutations of the KCNQ2 gene, which encodes the K_v7.2 subunit of voltage-gated M-type potassium channels, have been associated with epilepsy in the neonatal period. This developmental stage is unique in that the neurotransmitter gamma aminobutyric acid (GABA), which is inhibitory in adults, triggers excitatory action due to a reversed chloride gradient.

Methods

To examine whether KCNQ2-related neuronal hyperexcitability involves neonatally excitatory GABA, we examined 1-week-old knockin mice expressing the K_v7.2 variant p.Tyr284Cys (Y284C).

Results

Brain slice electrophysiology revealed elevated CA1 hippocampal GABAergic interneuron activity with respect to presynaptic firing and postsynaptic current frequency. Blockade with the GABA_A receptor antagonist bicuculline decreased ictal-like bursting in brain slices with lowered divalent ion concentration, which is consistent with GABA mediating an excitatory function that contributes to the hyperexcitability observed in mutant animals.

Significance

We conclude that excitatory GABA contributes to the phenotype in these animals, which raises the question of whether this special type of neurotransmission has broader importance in neonatal epilepsy than is currently recognized.

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EMT competing for Miss Arkansas

By EMS1 Staff PAFFORD, Ark. — An EMT is on a quest to win the Miss Arkansas pageant. Suzie Gresham, 23, is an EMT with Pafford AIR MED and recently graduated from college. She hopes to win a scholarship with her EMS-themed platform, "First aid first-don't wait, initiate." Gresham also plans to attend paramedic school in the fall.

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Production of Metal Nanoparticles by Pulsed Laser-ablation in Liquids: A Tool for Studying the Antibacterial Properties of Nanoparticles

The antimicrobial properties of metals such as copper and silver have been recognized for centuries. This protocol describes pulsed laser-ablation in liquids, a method of synthesizing metal nanoparticles that provides the ability to fine tune the properties of these nanoparticles to optimize their antimicrobial effects.

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2D and 3D Matrices to Study Linear Invadosome Formation and Activity

This protocol describes how to prepare a 2D mixed matrix, consisting of gelatin and collagen I, and a 3D collagen I plug to study linear invadosomes. These protocols allow for the study of linear invadosome formation, matrix degradation activity, and the invasion capabilities of primary cells and cancer cell lines.

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The effect of a maternal history of childhood abuse on adrenocortical attunement in mothers and their toddlers

Abstract

We investigated circadian mother–child adrenocortical attunement in the context of a maternal history of childhood abuse (HoA). Mothers were screened after birth using the Childhood Trauma Questionnaire. Women reporting moderate or severe abuse formed the HoA group (n = 37; HoAG) and were compared with a non-maltreated comparison group (n = 45; CG). Three years later, cortisol awakening response (CAR) and diurnal slope (DSL) were assessed. Mother–child interaction was coded using the Emotional Availability Scales at 12 months of age. For the CAR, we found adrenocortical attunement only in the HoAG (2-way interaction: p = .004), particularly if mothers scored low on structuring (3-way interaction: p = .042) and children scored low on responsiveness (3-way interaction: p = .044). DSL-attunement was dependent on maternal sensitivity (3-way interaction: p = .012) and child involvement (3-way interaction: p = .012). In the context of a maternal HoA, it seems possible for mother-child-dyads to show less optimal interactional quality but be stronger attuned to each other biologically.

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Subscriptions

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Abstract from the Chinese Journal of Hypertension

Investigation on Prevalence of Hypertension and Risk Factors Among Urban and Rural Residents in Jiangxi Province

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Abstract from the Chinese Journal of Hypertension

Clinical Characteristics of Postprandial Hypotension in Elderly Hypertensive Patients

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Editorial_Board

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Arterial Blood Pressure and Lifestyle Variability: In Quest of a Comprehensive Approach

The role of blood pressure variability (BPV) in the development of symptoms and target organs disease is a lasting object of investigations.^1,2 These were primarily triggered by the subjective reports of patients, a step usually not quoted specifically; subsequently, pioneering clinical observations³ were carried out, supported also by animal models research,⁴ but the effects of drugs on BPV⁵ and on clinical outcome and epidemiological studies⁶ are still the core of our present knowledge. BPV is approached as a clue distinct from and inclusive of the fluctuations related to the circadian rhythm, namely the day–night changes.⁷ However, the separate effects of physical exercise, sleep, digestive and other body functions, mood and emotional reactions are not fully detected, thus missing clues potentially useful for personalized intervention. Handy and friendly reference measurement, with an adequate timing of recording suitable for the purpose of guiding diagnosis for better targeting and monitoring interventions, is still a requirement that is not sufficiently satisfied.

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Serum Uric Acid and Childhood Hypertension: Association to Causation to Prevention

In last 5 decades, serum uric acid (SUA) has emerged as an existential biomarker of lifestyle that predisposes to metabolic syndrome, hypertension, diabetes, cardiovascular, and renal disorders.¹

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Erratum

"Effect of Vitamin D on Endothelial Function: A Randomized, Double-Blind, Placebo-Controlled Trial" by Borgi et al. (Am J Hypertens 2017; 30:124–129). The incorrect version of Figure 3 was published. The corrected version is below.

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Trends in Hospitalization for Hypertensive Emergency, and Relationship of End-Organ Damage With In-Hospital Mortality

Abstract

BACKGROUND

There are no comprehensive guidelines on management of hypertensive emergency (HTNE) and complications. Despite advances in antihypertensive medications HTNE is accompanied with significant morbidity and mortality.

METHODS

We queried the 2002–2012 nationwide inpatient sample database to identify patients with HTNE. Trends in incidence of HTNE and in-hospital mortality were analyzed. Logistic regression analysis was used to assess the relationship between end-organ complications and in-hospital mortality.

RESULTS

Between 2002 and 2012, 129,914 admissions were included. Six hundred and thirty (0.48%) patients died during their hospital stay. There was an increase in the number of HTNE admissions (9,511–15,479; P_trend < 0.001) with concurrent reduction of in-hospital mortality (0.8–0.3%; P_trend < 0.001) by the year 2012 compared to 2002. Patients who died during hospitalization were older, had longer length of stay, higher cost of stay, more comorbidities, and higher risk scores. Presence of acute cardiorespiratory failure [adjusted odds ratio (OR), 15.8; 95% confidence interval (CI), 13.2–18.9], stroke or transient ischemia attack (TIA) (adjusted OR, 7.9; 95% CI, 6.3–9.9), chest pain (adjusted OR, 5.9; 95% CI, 4.4–7.7), stroke/TIA (adjusted OR, 5.9; 95% CI, 4.5–7.7), and aortic dissection (adjusted OR, 5.9; 95% CI, 2.8–12.4) were most predictive of higher in-hospital mortality in addition to factors such as age, aortic dissection, acute myocardial infarction, acute renal failure, and presence of neurological symptoms.

CONCLUSION

A rising trend in hospitalization for HTNE, with an overall decrease in in-hospital mortality was observed from 2002 to 2012, possibly related to changes in coding practices and improved management. Presence of acute cardiorespiratory failure, stroke/TIA, chest pain, and aortic dissection were most predictive of higher hospital mortality.

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Elevated Pulse Pressure Levels Are Associated With Increased In-Hospital Mortality in Acute Spontaneous Intracerebral Hemorrhage

Abstract

OBJECTIVES

Clinical outcome after intracerebral hemorrhage (ICH) remains poor. Definitive phase-3 trials in ICH have failed to demonstrate improved outcomes with intensive systolic blood pressure (SBP) lowering. We sought to determine whether other BP parameters—diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP)—showed an association with clinical outcome in ICH.

METHODS

We retrospectively analyzed a prospective cohort of 672 patients with spontaneous ICH and documented demographic characteristics, stroke severity, and neuroimaging parameters. Consecutive hourly BP recordings allowed for computation of SBP, DBP, PP, and MAP. Threshold BP values that transitioned patients from survival to death were determined from ROC curves. Using in-hospital mortality as outcome, BP parameters were evaluated with multivariable logistic regression analysis.

RESULTS

Patients who died during hospitalization had higher mean PP compared to survivors (68.5 ± 16.4 mm Hg vs. 65.4 ± 12.4 mm Hg; P = 0.032). The following admission variables were associated with significantly higher in-hospital mortality (P < 0.001): poorer admission clinical condition, intraventricular hemorrhage, and increased admission normalized hematoma volume. ROC analysis showed that mean PP dichotomized at 72.17 mm Hg, provided a transition point that maximized sensitivity and specific for mortality. The association of this increased dichotomized PP with higher in-hospital mortality was maintained in multivariable logistic regression analysis (odds ratio, 3.0; 95% confidence interval, 1.7–5.3; P < 0.001) adjusting for potential confounders.

CONCLUSION

Widened PP may be an independent predictor for higher mortality in ICH. This association requires further study.

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Blood Pressure in Acute Intracerebral Hemorrhage: Have We Been Looking in the Wrong Direction?

The role of hypertension in the pathogenesis of primary intracerebral hemorrhage (ICH) is indisputable. Large epidemiologic cohort studies have identified it as the most potent risk factor¹ and in other, observational studies elevated blood pressure (BP) in the acute phase of ICH was robustly associated with hematoma expansion, increased mortality and poor functional outcome.² In light of these findings and in the absence of any other medical or surgical intervention with proven benefit, BP has attracted substantial attention as a potential therapeutic target in the acute phase of ICH. Following encouraging results in early phase trials,³ 2 large, prospective phase III trials evaluated the effect of rapid, intensive systolic BP reduction in acute ICH: The INTERACT-2⁴ and ATACH-2⁵ trials both confirmed safety of the intervention but without benefits in mortality or functional outcome and these findings were confirmed in a recent meta-analysis pooling results of 5 randomized trials involving 4,360 patients.⁶ Naturally, the topic is hotly debated in the vascular neurology community, but the reasons for the trial failures and, most importantly, the optimal way to manage BP in acute ICH are far from resolved.

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Blood Pressure With Nitrate Exposure: Back-to-Basics With Fresh Fruits and Vegetables

"Let food be thy medicine and medicine be thy food"—Hippocrates

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Accuracy—Limiting Factor of Home Blood Pressure Monitors?

In this issue of the American Journal of Hypertension, Padwal et al. report data that is extremely relevant clinically.¹ A significant number of automatic oscillometric blood pressure (BP) monitors, owned by Albertans with hypertension, are inaccurate. In particular, in this well-designed study, the difference between systolic or diastolic BP taken simultaneously by the patient's own automated oscillometric home BP device and by a 2-observer auscultatory reference standard BP measurement (mercury sphygmomanometer) was more than 5, 10, and 15 mm Hg in 69%, 29%, and 7% cases, respectively.¹

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Relationship Between Urinary Nitrate Excretion and Blood Pressure in the InChianti Cohort

Abstract

BACKGROUND

Inorganic nitrate from the oxidation of endogenously synthesized nitric oxide (NO) or consumed in the diet can be reduced to NO via a complex enterosalivary circulation pathway. The relationship between total nitrate exposure by measured urinary nitrate excretion and blood pressure in a large population sample has not been assessed previously.

METHODS

For this cross-sectional study, 24-hour urinary nitrate excretion was measured by spectrophotometry in the 919 participants from the InChianti cohort at baseline and blood pressure measured with a mercury sphygmomanometer.

RESULTS

After adjusting for age and sex only, diastolic blood pressure was 1.9 mm Hg lower in subjects with ≥2 mmol urinary nitrate excretion compared with those excreting <1 mmol nitrate in 24 hours: systolic blood pressure was 3.4 mm Hg (95% confidence interval (CI): −3.5 to −0.4) lower in subjects for the same comparison. Effect sizes in fully adjusted models (for age, sex, potassium intake, use of antihypertensive medications, diabetes, HS-CRP, or current smoking status) were marginally larger: systolic blood pressure in the ≥2 mmol urinary nitrate excretion group was 3.9 (CI: −7.1 to −0.7) mm Hg lower than in the comparison <1 mmol excretion group.

CONCLUSIONS

Modest differences in total nitrate exposure are associated with lower blood pressure. These differences are at least equivalent to those seen from substantial (100 mmol) reductions in sodium intake.

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An Assessment of the Accuracy of Home Blood Pressure Monitors When Used in Device Owners

Abstract

OBJECTIVE

To examine the accuracy of home blood pressure (BP) devices, on their owners, compared to auscultatory reference standard BP measurements.

METHODS

Eighty-five consecutive consenting subjects ≥18 years of age, who owned an oscillometric home BP device (wrist or upper-arm device), with BP levels between 80–220/50–120 mm Hg, and with arm circumferences between 25–43 cm were studied. Pregnancy and atrial fibrillation were exclusion criteria. Device measurements from each subject's home BP device were compared to simultaneous 2-observer auscultation using a mercury sphygmomanometer. Between-group mean comparisons were conducted using paired t-tests. The proportion of patients with device-to-auscultatory differences of ≥5, 10, and 15 mm Hg were tabulated and predictors of systolic and diastolic BP differences were identified using linear regression.

RESULTS

Mean age was 66.4 ± 11.0 years, mean arm circumference was 32.7 ± 3.7 cm, 54% were female and 78% had hypertension. Mean BPs were 125.7 ± 14.0/73.9 ± 10.4 mm Hg for home BP devices vs. 129.0 ± 14.7/72.9 ± 9.3 for auscultation (difference of −3.3 ± 7.3/0.9 ± 6.1; P values <0.0001 for systolic and 0.17 for diastolic). The proportion of devices with systolic or diastolic BP differences from auscultation of ≥5, 10, and 15 mm Hg was 69%, 29%, and 7%, respectively. Increasing arm circumference was a statistically significant predictor of higher systolic (parameter estimate 0.61 per cm increase; P value 0.004) and diastolic (0.38; 0.03) BP.

CONCLUSIONS

Although mean differences from 2-observer auscultation were acceptable, when tested on their owners, most home BP devices were not accurate to within 5 mm Hg. Ensuring acceptable accuracy of the device-owner pairing should be prioritized.

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Erratum

"Abstract from the Chinese Journal of Hypertension" by Chen et al. (Am J Hypertens 2017; 30:102). The incorrect author was listed in the correspondence line. All correspondence should be addressed to Godfrey Chi-Fung Chan (Gcfchan@hku.hk).

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Response to Tautological Nature of Guyton’s Theory of Blood Pressure Control

In a recent issue of the American Journal of Hypertension, we published an analysis¹ supporting the assertion by Beard² that the Guyton–Coleman "laws" of long term blood pressure (BP) control are tautologies, i.e., propositions that must be true simply by virtue of saying the same thing twice. Like all tautologies (e.g., the tautology that "people with chronically high blood pressure must have hypertension"), the Guyton–Coleman "laws" lack scientific rationale and cannot be scientifically tested.

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Tautological Nature of Guyton’s Theory of Blood Pressure Control

To the Editor: In a recent short paper, I pointed out the tautological nature of Arthur Guyton's so-called "Laws of Blood Pressure Control".¹ Kurtz et al. have presented a review of the consequences that the tautological nature of these laws have had on research on blood pressure control and hypertension.² While Lohmeier and Pruett³ demonstrate a breath of knowledge of the field, it is discouraging to find that in accusing Kurtz et al. of illogic for not "providing evidence discrediting these laws" they have missed the central thesis. As Kurtz et al. and other commentators⁴ recognize, a tautology is a self-evident statement that is true by definition and "cannot" be disproven. So indeed, Lohmeier and Pruett are entirely correct in pointing out that Kurtz et al. fail to disprove Guyton's laws. However, in doing so, Lohmeier and Pruett are attacking a straw man since it is central thesis of Kurtz et al. that Guyton's laws of blood pressure control are technically (and absolutely) correct. One can only hope that other readers of Kurtz et al. do not avoid the opportunity to critically evaluate the current state of understanding of blood pressure control and hypertension.

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Healthy Lifestyle and Blood Pressure Variability in Young Adults

Abstract

BACKGROUND

The aim of this study was to assess the relationships between healthy lifestyle metrics and blood pressure variability (BPV) in young and healthy adults.

METHODS

A population-based sample of 1,999 individuals aged 25–41 years was investigated. A lifestyle-score from 0 (most unhealthy) to 7 (most healthy) was calculated by giving one point for each of the following components: never smoking cigarettes, adhering to a healthy diet, performing moderate or intense physical activity, having a body mass index <25 kg/m², a total cholesterol <200 mg/dl, a glycated hemoglobin <5.7%, or a conventional BP <120/80 mm Hg. Standardized ambulatory 24-hour BP measurements were obtained in all individuals. BPV was defined as the SD of all individual ambulatory BP recordings. We constructed multivariable linear regression models to assess the relationships between the lifestyle-score and BPV. None of the results were adjusted for multiple testing.

RESULTS

Median age was 37 years and 46.8% were men. With increasing lifestyle-score, systolic and diastolic BPV is decreasing linearly (P for trend <0.0001), even after multivariable adjustment. Per 1-point increase in lifestyle-score, the β-coefficient (95% confidence interval) for systolic and diastolic 24-hour BPV was −0.03 (−0.03; −0.02) and −0.04 (−0.05; −0.03), respectively, both P for trend <0.0001. These relationships were attenuated but remained statistically significant after additional adjustment for mean individual BP.

CONCLUSION

In this study of young and healthy adults, adopting a healthy lifestyle was associated with a lower BPV. These associations were independent of mean BP levels.

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Association Between Serum Levels of Uric Acid and Blood Pressure Tracking in Childhood

Abstract

BACKGROUND

Recent studies suggest that high levels of serum uric acid of very early life are a result of the in-utero environment and may lead to elevated blood pressure (BP) in adulthood. However, serum uric acid levels can change throughout life. We investigated the effect of serum uric acid levels in childhood on the BP tracking and analysed BP according to changes in serum uric acid levels in early life.

METHODS

A total of 449 children from the Ewha Birth and Growth Cohort study underwent at least 2 follow-up examinations. Data were collected across 3 check-up cycles. Serum uric acid levels, BP, and anthropometric characteristics were assessed at 3, 5, and 7 years of age.

RESULTS

Children with a serum uric acid level higher than the median values had significantly increased systolic BP (SBP) and diastolic BP at 3 years of age. Baseline serum uric acid levels measured at 3 years of age, significantly affected subsequent BP in the sex and body mass index adjusted longitudinal data analysis (P < 0.05). Considering the changing pattern of serum uric acid over time, subjects with high uric acid levels at both 3 and 5 years of age had the highest SBP at 7 years of age.

CONCLUSIONS

These findings suggest the importance of maintaining an adequate level of serum uric acids from the early life. Appropriate monitoring and intervention of uric acid levels in a high-risk group can reduce the risk of a future increased BP.

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Erratum

"Logical issues with the pressure natriuresis theory of chronic hypertension" by Kurtz et al. (Am J Hypertens 2016; 29:1326–1331). An additional acknowledgment is needed for this article. The revised full acknowledgment is listed below.

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Voluntary movement reverses the effect of cathodal transcranial direct current stimulation (tDCS) on corticomotor excitability

Abstract

Motor cortex activity level is a critical part of the effect of transcranial direct current stimulation (tDCS) on corticomotor excitability. Based on homeostatic plasticity, the state of the stimulated cortical area influences the direction of neuroplastic changes induced by stimuli. Owing to homeostatic plasticity, cathodal tDCS (c-tDCS) would likely have a pronounced inhibitory effect on corticomotor excitability during a motor task, compared with the resting state. To test this hypothesis, we detected motor evoked potential (MEP) amplitude changes before and during c-tDCS with voluntary movement. Twelve healthy right-handed volunteers (9 males, 27–48 years) were enrolled in the study. Subjects performed little finger abduction motor task. Passive (APB) and active (ADM) muscles were studied. MEP amplitudes were measured during resting (baseline) and movement stages, and subsequently with the contralateral M1 modulated by c-tDCS. c-tDCS caused reduced baseline MEP amplitude in the ADM (p < 0.05) and APB (p < 0.001) muscles. Sham stimulation had no effect on the baseline MEP amplitudes. MEP amplitude ratio (MEP amplitude _{triggered by movement}/baseline MEP amplitude) was higher during c-tDCS than before c-tDCS (p < 0.01). Our results suggested that during voluntary contraction, c-tDCS has an opposite effect on corticospinal excitability compared with resting state modulation effect. This contrast effect could be related to modulation of movement preparation and execution.

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Translating cough mechanisms into better cough suppressants

Chronic cough is a significant problem and in many patients' cough remains refractive to both disease specific therapies and current cough suppressing medicines, creating a need for improved anti-tussive therapies. Most patients with chronic cough also display heightened sensitivity such that they experience a persistent sense of the need to cough and often innocuous stimuli can trigger their coughing. This hypersensitivity underpins the newly described concept of Cough Hypersensitivity Syndrome (CHS), a term that encapsulates the notion of common underlying mechanisms producing neuronal activation, sensitization and/or dysfunction, which are at the core of excessive coughing. Understanding these mechanisms has been a focus of recent research efforts in the field in the hope that new therapies can be developed to selectively target sensitized unproductive cough whilst maintaining the reflexive cough essential for airway protection. However, efforts to achieve this have been slower than expected, in part because of some significant challenges and limitations translating current cough models. In this review, we will summarize recent advances in our understanding of the sensory circuits innervating the respiratory system important for cough, how cough sensory pathways become hypersensitive, and some of the recently described neural targets under development for treating chronic coughing. We will present the case that better use of current cough models and/ or the development of new models is ultimately needed to advance our efforts to translate the discovery of basic cough mechanisms into effective medicines for treating patients with chronic cough.

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A randomised control trial of atorvastatin in bronchiectasis patients infected with Pseudomonas aeruginosa - a proof of concept study

Introduction

There are no randomised control trials of statin therapy in patients with severe bronchiectasis, chronically infected with Pseudomonas aeruginosa.

Methods

32 patients chronically infected with P. aeruginosa were recruited in this double blind cross over RCT. 16 patients were recruited in each arm, given atorvastatin 80mg or placebo for 3months, followed by a washout period for 6weeks, crossed over and administered the alternative therapy for 3months.

Results

27 patients completed the study. Atorvastatin did not significantly improve the primary endpoint of cough as measured by Leicester Cough Questionnaire [mean difference=1.92, 95% CI for difference (-0.57, 4.41), p=0.12]. However, atorvastatin treatment resulted in improved St Georges Respiratory Questionnaire (-5.62points, p=0.016), reduced serum CXCL8 (p=0.04), TNF (p=0.01) and ICAM1 (p=0.04). There was a trend towards improvement in serum CRP and serum neutrophil counts (p=0.07 and p=0.06 respectively).In vitro, we demonstrated that atorvastatin 10μM reduced fMLF induced upregulation of CD11b expression and changes in calcium flux reflecting an ability to decrease neutrophil activation.

Conclusion

We demonstrated that atorvastatin reduced systemic inflammation and improved quality of life in bronchiectasis patients infected with P. aeruginosa. These effects may be due to an ability of atorvastatin to modulate neutrophil activation.

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Pulmonary Manifestations in the Rheumatic Diseases

Lung disease in the rheumatic diseases presents unique challenges for diagnosis and management and is a source of significant morbidity and mortality for patients. Unlike the idiopathic interstitial pneumonias, patients with rheumatic diseases experience lung disease in the context of a systemic disease that may make it more difficult to recognize and that may present greater risks with treatment. Despite recent advances in our awareness of these diseases, there is still a significant lack of understanding of natural history to elucidate which patients will develop disease that is progressive and thus warrants treatment. What we do know is that a subset of patient with rheumatic disease develop parenchymal lung disease that can prognostically resemble idiopathic pulmonary fibrosis, such as in rheumatoid arthritis, and that others can have aggressive inflammatory lung disease in the context of idiopathic inflammatory myopathies, systemic sclerosis, or an undifferentiated autoimmune process. As we enter an era of therapy directed against fibrosis in addition to novel anti- inflammatory therapies, and as we improve our ability to identify those at the highest risk for disease progression, we may be entering a paradigm shift in our ability to treat these complex patients and potentially offer better outcomes.

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High-mobility group box-1 contributes tumor angiogenesis under interleukin-8 mediation during gastric cancer progression

Abstract

Many soluble factors are involved in tumor angiogenesis. Thus, it is valuable to identify novel soluble factors for effective control of tumor angiogenesis in gastric cancer (GC). We investigated the role of extracellular high-mobility group box-1 (HMGB1) and its associated soluble factors in tumor angiogenesis of gastric cancer (GC). Clinically, we measured serum levels of HMGB1 and GC-associated cytokines/chemokines using GC serum samples (n=120), and calculated microvessel density (MVD) by performing CD34 immuno-staining using human GC tissues (n=27). Then, we analyzed the correlation of serum HMGB1 levels with MVD or that with cytokine/chemokine levels by linear regression. As in vitro angiogenesis assay for HMGB1, human umbilical vein endothelial cell (HUVEC) migration and capillary tube formation assay were conducted using different histological types of human GC cells (N87, KATOIII). Resultingly, CD34-positive microvessels were detected from early GC (EGC), but MVD increased according to GC stages, and were closely correlated with serum HMGB1 levels (R=0.608, P=0.01). HUVECs cultured in conditioned media (CM) derived from rhHMGB1-treated or HMGB1-TF GC cells showed remarkably enhanced migration and tube formation activities. These effects were abrogated by anti-HMGB1 antibody or HMGB1 siRNA in both N87 and KATOIII cells (all P<0.05). Among tested cytokines/chemokines, IL-8 was the most remarkable cytokine correlated with serum HMGB1 (P<0.001), and enhanced HUVEC migration and tube formation activities by rhHMGB1 or HMGB1-TF were significantly reversed by IL-8 inhibition. These results indicate overexpressed HMGB1 contributes to tumor angiogenesis through IL-8 mediation, and combined targeting of HMGB1 and IL-8 can control tumor angiogenesis in GC.

This article is protected by copyright. All rights reserved.

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