Alkaptonuria—an atypical case: multi-modality imaging review

Abstract

Alkaptonuria is a rare inborn metabolic disorder due to a mutation in the homogentisic acid oxidase enzyme (HGO) gene on chromosome 3q. As HGO is deficient in alkaptonuria patients, there is an accumulation of homogentisic acid in the blood and urine. Homogentisic acid gets deposited in the soft tissues, tendons, cartilages, large joints and intervertebral discs. Ochronosis usually affects the dorsolumbar spine and typically spares the cervical spine and sacroiliac joints. However, in this case of isolated ochronosis, we report co-existent extensive cervical spine degenerative changes and cervical vertebral fusion, which has not been described in the literature so far.

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Correction to: Strategies for Predicting Response to Checkpoint Inhibitors

The original version of this article unfortunately contained a mistake. The conflict of interest statement was incorrect. The corrected statement is given below.

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Coding patterns used by ophthalmologists for hydroxychloroquine retinal toxicity

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Highlights of the special scientific sessions of the 45th Annual Scientific Meeting of the International Skeletal Society (ISS) 2018, Berlin, Germany

https://ift.tt/2F9zeTJ

Dairy Consumption and Cardiometabolic Diseases: Systematic Review and Updated Meta-Analyses of Prospective Cohort Studies

Abstract

Purpose of Review

Dairy products contain both beneficial and harmful nutrients in relation to cardiometabolic diseases. Here, we provide the latest scientific evidence regarding the relationship between dairy products and cardiometabolic diseases by reviewing the literature and updating meta-analyses of observational studies.

Recent Findings

We updated our previous meta-analyses of cohort studies on type 2 diabetes, coronary heart disease (CHD), and stroke with nine studies and confirmed previous results. Total dairy and low-fat dairy (per 200 g/d) were inversely associated with a 3–4% lower risk of diabetes. Yogurt was non-linearly inversely associated with diabetes (RR = 0.86, 95% CI: 0.83–0.90 at 80 g/d). Total dairy and milk were not associated with CHD (RR~1.0). An increment of 200 g of daily milk intake was associated with an 8% lower risk of stroke.

Summary

The latest scientific evidence confirmed neutral or beneficial associations between dairy products and risk of cardiometabolic diseases.

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The effects of intraoperative ICG fluorescence angiography in laparoscopic low anterior resection: a propensity score-matched study

Abstract

Background

It remains unclear whether indocyanine green (ICG) angiography could reduce the rate of postoperative anastomotic leakage (AL) following rectal surgery. The aim was to determine whether intraoperative ICG angiography could decrease symptomatic AL following laparoscopic low anterior resection (LAR).

Methods

This is a retrospective study of 149 patients with rectal cancer who underwent laparoscopic LAR at a single institution. Propensity score matching (PSM) was employed to compare groups with and without ICG angiography.

Results

Before PSM, the symptomatic AL rate was 10.4% (5/48) in patients with ICG angiography, compared with 6.9% (7/101) in cases without ICG angiography (P = 0.52). In patients with ICG angiography, poor perfusion of the proximal colon judged by ICG angiography led to additional colon resection in 27.1% (13/48). Symptomatic AL occurred in 30.8% (4/13) of the patients who had revision of the transection site, whereas it occurred in only 2.9% (1/35) of the patients who did not need revision of the transection site (P = 0.015). After PSM, the symptomatic AL rate was 8.8% (3/34) in patients with ICG angiography, compared with 14.7% (5/34) in cases without ICG angiography (P = 0.71). In univariate analysis, high BMI, preoperative chemotherapy, and lateral lymph node dissection were significantly associated with symptomatic AL. Multivariate analysis indicated that only lateral lymph node dissection remained significantly associated with AL (odds ratio, 10.05; 95% confidence interval, 1.75–58.61; P = 0.011).

Conclusions

Intraoperative ICG angiography is useful for prediction of AL following laparoscopic LAR.

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Functional Analysis of a Putative Target of Spatially Varying Selection in the Menin1 Gene of Drosophila melanogaster

While significant effort has been devoted to investigating the potential influence of spatially varying selection on genomic variation, relatively little effort has been devoted to experimental analysis of putative variants or genes experiencing such selection. Previous population genetic work identified an amino acid polymorphism in the Mnn1 gene as one of the most strongly latitudinally differentiated SNPs in the genome of Drosophila melanogaster in the United States and Australia. Here we report the results of our transgenic analysis of this amino acid polymorphism. Genotypes carrying alternative Mnn1 alleles differed in multiple phenotypes in a direction generally consistent with phenotypic differences previously observed along latitudinal clines. These results support inferences from earlier population genomic work that this variant influences fitness, and support the idea that the alleles exhibiting clines may be likely to have pleiotropic effects that are correlated along the axes favored by natural selection.

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Are Women More Likely than Men Are to Care Excessively about Maintaining Positive Social Relationships? A Meta-Analytic Review of the Gender Difference in Sociotropy

Abstract

Sociotropy is defined as the tendency to overemphasize maintaining positive social relationships (Beck 1983). Although the stereotype that women care more about interpersonal relationships than men do is well-documented (Cross and Madson 1997), the literature provides mixed support as to whether women are more sociotropic than men are. This is important to establish because sociotropy consistently correlates positively with depression (Robins et al. 1994) and thus a gender difference in sociotropy could contribute to the well-documented gender difference in depression (Girgus and Nolen-Hoeksema 2006). The present meta-analysis asks whether the gender difference in sociotropy exists, and if so, at what magnitude, by aggregating 108 independent effect sizes from 90 papers (n = 30,372 participants). The average weighted effect size of the gender difference was d = .34, with women scoring higher than men on sociotropy. Culture was a significant moderator: The gender difference in sociotropy was significantly smaller in research from collectivist countries, where interpersonal harmony and cooperation are emphasized for both genders, than in research from individualistic countries, where men are supposed to be independent and agentic and women are supposed to be communal and concerned with relationships. Further research is needed to explore the development of this gender difference and its relationship to the gender difference in depression.

https://ift.tt/2zExfR9

Gender Difference of Chinese High School Students’ Math Anxiety: The Effects of Self-Esteem, Test Anxiety and General Anxiety

Abstract

The present study aimed to explore gender differences in, and the effects of, self-esteem on math anxiety. A total of 751 (450 young women) junior and senior high school students (12–18 years-old) from China were recruited and requested to report their math anxiety, self-esteem, control beliefs, test anxiety, and general anxiety. Results revealed that young women showed a higher level of math anxiety compared with young men; no gender difference was found in math performance. Further, the pathway from self-esteem to math anxiety was different for young men and young women. For young men, apart from a direct effect on math anxiety, self-esteem had an indirect effect on math anxiety as mediated by control beliefs, test anxiety, and general anxiety. For young women, self-esteem only had an indirect effect on math anxiety as mediated by test anxiety and general anxiety. Our results indicated that improving self-esteem, test anxiety and general anxiety would be helpful for students' math anxiety.

https://ift.tt/2SVipyv

Medicaid Expansion Approved in Three Republican-Leaning States

WEDNESDAY, Nov. 7, 2018 -- Hundreds of thousands more low-income Americans could get health insurance after voters in three Republican-leaning states approved Medicaid expansion in the midterm elections. Public support for expansion in Utah,...

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Possible Salmonella Prompts Duncan Hines Cake Mix Recall

WEDNESDAY, Nov. 7, 2018 -- Four varieties of Duncan Hines cake mix have been recalled due to possible Salmonella contamination. The recalled products include the Classic White, Classic Butter Golden, Classic Yellow, and Signature Confetti cake...

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Naloxone Products Stay Effective Long After Expiration Date

WEDNESDAY, Nov. 7, 2018 -- Two naloxone products used to treat opioid overdose patients remain chemically stable long after their expiration dates, according to a study presented at PharmaSci 360, the annual meeting of the American Association of...

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HTN in Young Adulthood Linked to CVD Later in Life

WEDNESDAY, Nov. 7, 2018 -- High blood pressure (BP) in early adulthood is associated with an increased risk for cardiovascular disease (CVD) later in life, according to two studies published in the Nov. 6 issue of the Journal of the American Medical...

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Addition of Elotuzumab Ups PFS in Refractory Multiple Myeloma

WEDNESDAY, Nov. 7, 2018 -- For patients with multiple myeloma in whom treatment with lenalidomide and a proteasome inhibitor has failed, progression-free survival is longer in those receiving the immunostimulatory monoclonal antibody elotuzumab in...

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The Effect of CD86 Expression on the Proliferation and the Survival of CLL Cells

Abstract

Micro-environment plays important role in the pathogenesis of CLL by providing protective niche for CLL cells. Several molecules play important role in communication between CLL cells and immune cells like CD86.Some of the data suggest that CLL patients with high CD86 level need earlier treatments and cells with higher CD86 expression has higher proliferation rate but the role of CD86 in the survival and proliferation of CLL cells is unclear. We investigated the effect of CD86 expression to CLL cells in 50 peripheral blood and 15 lymph node biopsy samples from CLL patients. Our results showed that the expressions of CD86 increased significantly after 7 day culturing in medium, or in the presence of bone marrow stromal cells (BMSCs). We found positive correlation between CD86 and CD23 expression (p < 0.05), but no correlation with other markers. Furthermore, no correlation were found between the CD86 expression and the proliferation of CLL cells. Analysis of clinical data showed that cases with high CD86 expression had lower level of serum lymphocyte count (p < 0.04) at the time of the diagnosis. CD86 shows multiple appearances in the lymph nodes containing pseudofollicules, but no correlation was found between CD86 positivity, and Ki67 positivity. Our results suggest that the use of CD86 molecule as a proliferation marker for CLL is highly questionable. However, the CD86 molecule may interfere with the immune system of patients with CLL by activating and depleting immune functions. That can be the reason why CD86 positivity may mean worse prognosis.

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Metabolic Syndrome as a Predictor of Adrenal Functional Status: A Discriminant Multivariate Analysis Versus Logistic Regression Analysis

Horm Metab Res
DOI: 10.1055/a-0754-6464

Patients harboring adrenal tumors are characterized by higher prevalence of metabolic syndrome (MetS) components and a higher incidence of cardiovascular complications, especially in cases of subclinical or overt hormonal hypersecretion. Early detection and referral of those patients in tertiary centers could prevent unfavorable outcomes. In this cross-sectional, retrospective study, we evaluated 111 consecutive patients with adrenal incidentalomas and 14 patients with known hypersecretory adrenal lesions (autonomous cortisol secretion, primary aldosteronism, and pheochromocytoma), who were investigated in our clinic. Based on the different distribution of MetS components in patients with non-functional and functional adrenal lesions we introduced a predictive model of hormonal hypersecretion using those components. We performed multivariate discriminant analysis and compared predictive results with conventional multiple logistic regression analysis. Diabetes, impaired glucose tolerance, impaired fasting glucose, hypertension, body mass index, HDL-cholesterol levels, triglyceride levels, drug treatment for lipid disorder (statins, fenofibrate, and fish oils, alone or in combination), and maximal adrenal lesion diameter were used as discriminating covariates. Multivariate discriminant function exhibited a sensitivity of 77.27% and specificity of 73.08% in predicting adrenal hormonal hypersecretion. Receiver operating characteristic curve of discriminant predictive function had an area under the curve value of 0.785, S.E. 0.04. Logistic function delivered comparable results. MetS components exhibit a good predictive feature of hormonal hypersecretion in patients with adrenal tumors. Predictive functions may help in the search for an easy and generally available algorithm to validly predict the functional activity of adrenal masses.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Cytidine deaminase enzymatic activity is a prognostic biomarker in gemcitabine/platinum-treated advanced non-small-cell lung cancer: a prospective validation study

Cytidine deaminase enzymatic activity is a prognostic biomarker in gemcitabine/platinum-treated advanced non-small-cell lung cancer: a prospective validation study

Cytidine deaminase enzymatic activity is a prognostic biomarker in gemcitabine/platinum-treated advanced non-small-cell lung cancer: a prospective validation study, Published online: 08 November 2018; doi:10.1038/s41416-018-0307-3

Cytidine deaminase enzymatic activity is a prognostic biomarker in gemcitabine/platinum-treated advanced non-small-cell lung cancer: a prospective validation study

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Selected Abstracts from the 2018 NCRI Cancer Conference of National Cancer Research Institute

Selected Abstracts from the 2018 NCRI Cancer Conference of National Cancer Research Institute

Selected Abstracts from the 2018 NCRI Cancer Conference of National Cancer Research Institute, Published online: 08 November 2018; doi:10.1038/s41416-018-0299-z

Selected Abstracts from the 2018 NCRI Cancer Conference of National Cancer Research Institute

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High-Dose Seasonal Influenza Vaccine in Patients Undergoing Dialysis

Background and objectives

High-dose influenza vaccine, which contains fourfold more antigen than standard dose, is associated with fewer cases of influenza and less influenza-related morbidity in the elderly general population. Whether the high-dose influenza vaccine benefits patients on dialysis, whose immune response to vaccination is less robust than that of healthy patients, is uncertain.

Design, setting, participants, & measurements

We compared hospitalizations and deaths during the 2015–2016 and 2016–2017 influenza seasons by vaccine type (standard trivalent, standard quadrivalent, and high-dose trivalent influenza vaccine) administered within a national dialysis organization. The association of vaccine type with outcomes was estimated using Cox proportional hazards regression with adjustment for patient factors and "center effect." Analyses were stratified by age and dialysis modality.

Results

Between September 1 and December 31, 2015, standard dose trivalent, standard dose quadrivalent, and high-dose trivalent influenza vaccines were administered to 3057 (31%), 5981 (61%), and 805 (8%) patients, respectively. The adjusted rates of first hospitalizations by vaccine type during the influenza season were 8.43, 7.88, and 7.99 per 100 patient-months, respectively, and the adjusted rates of death were 1.00, 0.97, and 1.04, respectively. These differences were not significant. In 2016, 3614 (39%) received quadrivalent vaccine, and 5700 (61%) received high-dose trivalent vaccine. The adjusted rates of first hospitalization by vaccine type were 8.71 and 8.04 per 100 patient-months, respectively, and the adjusted rates of death were 0.98 and 1.02, respectively. Receipt of high dose was associated with a significant reduction in hospitalization (hazard ratio, 0.93; 95% confidence interval, 0.86 to 1.00; P=0.04); there was no significant association with death. There was no significant heterogeneity of either association by age group or dialysis modality.

Conclusions

Receipt of high-dose compared with standard dose influenza vaccine in 2016–2017 was associated with lower rates of hospitalization in patients on dialysis, although that was not seen in 2015–2016.

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The Kidney Accelerator: Innovation Wanted, Nephrologists Needed

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Treatment Adherence in Young Adults Receiving Kidney Replacement Therapy: A Caregiver Perspective

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The Patient Receiving Automated Peritoneal Dialysis with Volume Overload

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Kidney Biopsy in Hospitalized Patients with Acute Kidney Disease: Is There an Increased Risk?

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Regulatory T Cells and Kidney Transplantation

The ability of the immune system to differentiate self from nonself is critical in determining the immune response to antigens expressed on transplanted tissue. Even with conventional immunosuppression, acceptance of the allograft is an active process often determined by the presence of regulatory T cells (Tregs). Tregs classically are CD4⁺ cells that constitutively express high levels of the IL-2 receptor α chain CD25, along with the transcription factor Foxp3. The use of Tregs in the field of solid organ transplantation is related specifically to the objective of achieving tolerance, with the goal of reducing or eliminating immunosuppressive drugs as well as maintaining tissue repair and managing acute rejection. A key issue in clinical use of Tregs is how to effectively expand the number of Tregs, either through increasing numbers of endogenous Tregs or by the direct infusion of exogenously expanded Tregs. In order to realize the benefits of Treg therapy in solid organ transplantation, a number of outstanding challenges need to be overcome, including assuring an effective expansion of Tregs, improving long-term Treg stability and reduction of risk-related to off-target, nonspecific, immunosuppressive effects related specially to cancer.

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Better Patient Ambulatory Care Experience: Does It Translate into Improved Outcomes among Patients with CKD?

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Acute Kidney Injury in Children with Kidney Transplantation

Background and objectives

AKI is associated with progression of CKD. Little is known about AKI after kidney transplantation in pediatric recipients. We aim to describe the epidemiology, risk factors, consequences, and outcomes of AKI in this population.

Design, setting, participants, & measurements

We performed a retrospective longitudinal analysis of pediatric kidney transplant recipients followed at The Hospital for Sick Children (Toronto, Canada) from 2001 to 2012. AKI was defined as an increase in serum creatinine ≥1.5 times baseline, and a rise of serum creatinine ≥1.25 but <1.5 times baseline defined subacute AKI.

Results

Of 179 children, 122 were eligible for analysis. At baseline (3 months post-transplant), median age of the children was 13 years old (interquartile range, 9–16 years old), and 53% had CKD stage 2. Congenital anomalies of the kidney and urinary tract accounted for 46% of children. Over the study period (12 years), the incidence of AKI was 37% (n=45 children), and 65% (79 children) experienced subacute AKI. Twenty-seven percent (33 children) did not develop AKI or subacute AKI. The main causes of AKI were infections other than urinary tract infections, rejection, and urinary tract infections. In a multivariable Poisson regression analysis, independent risk factors for AKI included younger age, girls, grafts from deceased donors, and lower baseline eGFR. AKI was significantly associated with lower long-term GFR and graft loss independent of rejection episodes. Moreover, subacute AKI was associated with progression of CKD.

Conclusions

AKI and subacute AKI were common after pediatric kidney transplantation, and they were associated with graft loss, lower eGFR, and more rapid progression of CKD.

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ACCORDION: Ensuring That We Hear the Music Clearly

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Medication Safety Principles and Practice in CKD

Ensuring patient safety is a priority of medical care because iatrogenic injury has been a primary concern. Medications are an important source of medical errors, and kidney disease is a thoroughfare of factors threatening safe administration of medicines. Principal among these is reduced kidney function because almost half of all medications used are eliminated via the kidney. Additionally, kidney patients often suffer from multimorbidity, including diabetes, hypertension, and heart failure, with a range of prescribers who often do not coordinate treatments. Patients with kidney disease are also susceptible to further kidney injury and metabolic derangements from medications, which can worsen the disease. In this review, we will present the key issues and threats to safe medication use in kidney disease, with a focus on predialysis CKD, as the scope of medication safety in ESKD and transplantation are unique and deserve their own consideration. We discuss drugs that need to be avoided or dose modified, and review the complications of a range of medications routinely administered in CKD, as these also call for cautious use.

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Increasing Protection of Dialysis Patients against Influenza

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Women in Nephrology Today

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Urea for the Treatment of Hyponatremia

Background and objectives

Current therapies for hyponatremia have variable effectiveness and tolerability, and in certain instances, they are very expensive. We examined the effectiveness, safety, and tolerability of urea for the treatment of inpatient hyponatremia.

Design, setting, participants, & measurements

We identified all patients hospitalized at the University of Pittsburgh Medical Center between July 2016 and August 2017 with hyponatremia (plasma sodium <135 mEq/L) who received urea, including a subgroup of patients who received urea as the sole drug therapy for hyponatremia (urea-only treated). We matched urea only–treated patients to a group of patients with hyponatremia who did not receive urea (urea untreated) and compared changes in plasma sodium at 24 hours and the end of therapy as well as the proportion of patients who achieved plasma sodium ≥135 mEq/L. We abstracted data on adverse events and reported side effects of urea.

Results

Fifty-eight patients received urea (7.5–90 g/d) over a median of 4.5 (interquartile range, 3–8) days and showed an increase in plasma sodium from 124 mEq/L (interquartile range, 122–126) to 131 mEq/L (interquartile range, 127–134; P<0.001). Among 12 urea only–treated patients, plasma sodium increased from 125 mEq/L (interquartile range, 122–127) to 131 mEq/L (interquartile range, 129–136; P=0.001) by the end of urea therapy. There was a larger increase in plasma sodium at 24 hours in urea only–treated patients compared with urea-untreated patients (2.5 mEq/L; interquartile range, 0–4.5 versus –0.5 mEq/L; interquartile range, –2.5 to 1.5; P=0.04), with no difference in change in plasma sodium by the end of therapy (6 mEq/L; interquartile range, 3.5–10 versus 5.5 mEq/L; interquartile range, 3–7.5; P=0.51). A greater proportion of urea only–treated patients achieved normonatremia, but this difference was not statistically significant (33% versus 8%; P=0.08). No patients experienced overly rapid correction of plasma sodium, and no serious adverse events were reported.

Conclusions

Urea seems effective and safe for the treatment of inpatient hyponatremia, and it is well tolerated.

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Treatment Adherence in Young Adults Receiving Kidney Replacement Therapy: A Patient Perspective

https://ift.tt/2DuRDcb

Kidney Biopsy-Related Complications in Hospitalized Patients with Acute Kidney Disease

Background and objectives

Patients are informed of the risk of kidney biopsy–related complications using data from nonhospitalized patients, which may underestimate the risk for hospitalized patients. We evaluated the rate and risk factors of kidney biopsy–related complications in hospitalized patients with acute kidney disease (AKD) to better estimate the risk in this population.

Design, setting, participants, & measurements

We used data from the Yale biopsy cohort to evaluate rates of kidney biopsy–related complications including adjudicated procedure-related bleeding requiring blood transfusions or angiographic interventions, medium- or large-sized hematomas, reimaging after biopsy including abdominal ultrasonography or computed tomography, and death in hospitalized patients with AKD (including AKI). We evaluated univariable and multivariable association of risk factors with transfusions. We compared rates of complications between hospitalized and nonhospitalized patients.

Results

Between 2015 and 2017, 159 hospitalized patients underwent a kidney biopsy for AKD evaluation, of which 80 (51%) had stage 1 AKI, 42 (27%) had stage 2 (or higher) AKI, and 27 (17%) had AKD (without AKI). Of these, 12 (8%; 95% confidence interval [95% CI], 5% to 15%) required a transfusion, three (2%; 95% CI, 1% to 5%) required an intervention, 11 (7%; 95% CI, 4% to 12%) had hematoma, and 31 (20%; 95% CI, 14% to 26%) required reimaging after biopsy. Of the four (3%; 95% CI, 1% to 6%) deaths during hospitalization, none were related to the biopsy. Female sex, lower platelet count, and higher BUN were associated with postbiopsy transfusions on univariable and multivariable analyses. Trainee as proceduralist and larger needle gauge were associated with transfusions in univariable, but not multivariable, analysis. Nonhospitalized patients had lower rates of transfusion than hospitalized patients, although the latter also had lower prebiopsy hemoglobin and greater surveillance after biopsy.

Conclusions

Hospitalized patients experience higher risk of postbiopsy complications than previously reported and several factors, such as lower platelet count, female sex, and higher BUN, are associated with this risk.

https://ift.tt/2RKqWTR

MicroRNA-21 and Venous Neointimal Hyperplasia of Dialysis Vascular Access

Background and objectives

There is increasing evidence that microRNAs (miRNAs) play crucial roles in the regulation of neointima formation. However, the translational evidence of the role of miRNAs in dialysis vascular access is limited.

Design, setting, participants, & measurements

miRNA expression in tissues was assessed by using venous tissues harvested from ten patients on dialysis who received revision or removal surgery, and ten patients who were predialysis and received creation surgery of arteriovenous fistulas served as controls. To extend these findings, 60 patients who received angioplasty of dialysis access were enrolled and the levels of circulating miRNAs were determined before and 2 days after angioplasty. Clinical follow-up was continued monthly for 6 months. The primary outcome of angioplasty cohort was target lesion restenosis within 6 months after angioplasty.

Results

In the surgery cohort, the expressions of miR-21, miR-130a, and miR-221 were upregulated in stenotic tissues, whereas those of miR-133 and miR-145 were downregulated. In situ hybridization revealed similar expression patterns of these miRNAs, localized predominantly in the neointima region. Twenty eight patients in the angioplasty cohort developed restenosis within 6 months. The levels of circulating miR-21, miR-130a, miR-221, miR-133, and miR-145 significantly increased 2 days after angioplasty. Kaplan–Meier plots showed that patients with an increase of miR-21 expression level >0.35 have a higher risk of patency loss (hazard ratio, 4.45; 95% confidence interval, 1.68 to 11.7). In a multivariable analysis, postangioplasty increase of miR-21 expression was independently associated with restenosis (hazard ratio, 1.20; 95% confidence interval, 1.07 to 1.35 per one unit increase of miR-21 expression level; P=0.001).

Conclusions

Certain miRNAs are differentially expressed in the stenotic venous segments of dialysis accesses. An increase in blood miR-21 level with angioplasty is associated with a higher risk of restenosis.

https://ift.tt/2DuRBB5

End-Stage Kidney Disease following Surgical Management of Kidney Cancer

Background and objectives

We investigated the incidence of ESKD after surgical management of kidney cancer in the Australian state of Queensland, and described patterns in the initiation of kidney replacement therapy resulting from kidney cancer across Australia.

Design, setting, participants, & measurements

All newly diagnosed cases of kidney cancer in the Australian state of Queensland between January of 2009 and December of 2014 were ascertained through the Queensland Cancer Registry. There were 2739 patients included in our analysis. Patients who developed ESKD were identified using international classification of disease–10–coded hospital administrative data. Incidence rate and 3-year cumulative incidence were calculated, and multivariable Cox proportional hazards models were used to identify factors associated with ESKD. Additional descriptive analysis was undertaken of Australian population data.

Results

The incidence rate of ESKD in all patients was 4.9 (95% confidence interval [95% CI], 3.9 to 6.2) per 1000 patient-years. The 3-year cumulative incidence was 1.7%, 1.9%, and 1.0% for all patients, and patients managed with radical or partial nephrectomy, respectively. Apart from preoperative kidney disease, exposures associated with increased ESKD risk were age≥65 years (adjusted hazard ratio [aHR], 2.0; 95% CI, 1.2 to 3.2), male sex (aHR, 2.3; 95% CI, 1.3 to 4.3), preoperative diabetes (aHR, 1.8; 95% CI, 1.0 to 3.3), American Society of Anesthesiologists classification ≥3 (aHR, 4.0; 95% CI, 2.2 to 7.4), socioeconomic disadvantage (aHR, 1.6; 95% CI, 0.9 to 2.7), and postoperative length of hospitalization ≥6 days (aHR, 2.1; 95% CI, 1.4 to 3.0). Australia-wide trends indicate that the rate of kidney replacement therapy after oncologic nephrectomy doubled between 1995 and 2015, from 0.3 to 0.6 per 100,000 per year.

Conclusions

In Queensland between 2009 and 2014, one in 53 patients managed with radical nephrectomy and one in 100 patients managed with partial nephrectomy developed ESKD within 3 years of surgery.

Podcast

This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_09_28_CJASNPodcast_18_1_.mp3

https://ift.tt/2RKHdbn

Changes in Transfusion Coding Among Hospitalized Medicare Beneficiaries after Implementation of ICD-10

https://ift.tt/2DspJNL

CKD in Patients with Bilateral Oophorectomy

Background and objectives

Premenopausal women who undergo bilateral oophorectomy are at a higher risk of morbidity and mortality. Given the potential benefits of estrogen on kidney function, we hypothesized that women who undergo bilateral oophorectomy are at higher risk of CKD.

Design, setting, participants, & measurements

We performed a population-based cohort study of 1653 women residing in Olmsted County, Minnesota who underwent bilateral oophorectomy before age 50 years old and before the onset of menopause from 1988 to 2007. These women were matched by age (±1 year) to 1653 referent women who did not undergo oophorectomy. Women were followed over a median of 14 years to assess the incidence of CKD. CKD was primarily defined using eGFR (eGFR<60 ml/min per 1.73 m² on two occasions >90 days apart). Hazard ratios were derived using Cox proportional hazards models, and absolute risk increases were derived using Kaplan–Meier curves at 20 years. All analyses were adjusted for 17 chronic conditions present at index date, race, education, body mass index, smoking, age, and calendar year.

Results

Women who underwent bilateral oophorectomy had a higher risk of eGFR-based CKD (211 events for oophorectomy and 131 for referent women; adjusted hazard ratio, 1.42; 95% confidence interval, 1.14 to 1.77; absolute risk increase, 6.6%). The risk was higher in women who underwent oophorectomy at age ≤45 years old (110 events for oophorectomy and 60 for referent women; adjusted hazard ratio, 1.59; 95% confidence interval, 1.15 to 2.19; absolute risk increase, 7.5%).

Conclusions

Premenopausal women who undergo bilateral oophorectomy, particularly those ≤45 years old, are at higher risk of developing CKD, even after adjusting for multiple chronic conditions and other possible confounders present at index date.

Podcast

This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_10_11_CJASNPodcast_18_1

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Hepatitis C Virus Infection in ESKD Patients

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The protective effect of coenzyme Q10 and berberine on sperm parameters, with and without varicocelectomy in rats with surgically induced varicoceles

Abstract

The current study aimed to investigate the protective effects of coenzyme Q10 (Co Q10) and berberine (BB) with and without varicocelectomy on sperm parameters in postoperative varicocele rats. For the current purpose, a total of 60 mature male Wistar rats were randomly divided into control (n = 6 rats), control-sham (n = 6 rats), and experimental (n = 6 rats) groups. The animals in the experimental groups were undergone experimental varicocele, and simple laparotomy was performed in control-sham group. The experimental group was subdivided into the following groups 60 days after varicocele (VCL) induction: non-treated VCL-induced rats (n = 6 rats), VCL-induced rats administered 100 mg (kg per day) BB (n = 6 rats), VCL-induced rats administered Co Q10 75 mg (kg per day) (n = 6 rats), VCL-induced rats administered 100 mg (kg per day) BB + Co Q10 75 mg (kg per day) (n = 6 rats), varicocelectomy rats (n = 6 rats), varicocelectomy rats administered 100 mg (kg per day) BB (n = 6 rats), varicocelectomy rats administered Co Q10 75 mg (kg per day) (n = 6 rats), varicocelectomy rats administered 100 mg (kg per day) BB + Co Q10 75 mg (kg per day) (n = 6 rats). Following 60 days, the animals were euthanized and sperm parameters were evaluated. Non-treated VCL-induced animals indicated a significant (P < 0.05) decrease in sperm parameters and a significant (P < 0.05) increase in sperm DNA damage compared to control and control-sham groups. Insignificant changes were found between control and control-sham groups. Meanwhile, each treatment group showed a remarkable (P < 0.05) increase in sperm parameters as well as a significant (P < 0.05) decrease in sperm DNA damage. Based on current results, BB and Co Q10 alone and/or together could improve sperm parameters and reduce sperm DNA damage in varicocele-induced rats compared to control and control-sham groups. Varicocelectomy alone will improve sperm parameters, but this recovery will be greater when combined with Co Q10 and BB.

https://ift.tt/2qAL1jI

Neuroprotective effects of matrine on scopolamine-induced amnesia via inhibition of AChE/BuChE and oxidative stress

Abstract

The present study was designed to evaluate the effects of matrine (MAT) on scopolamine (SCOP)-induced learning and memory impairment. After successive oral administration of MAT to mice for three days at doses of 0.4, 2, and 10 mg/kg, we assessed improvements in learning and memory and investigated the mechanism of action of SCOP-induced amnesia. Donepezil at a dose of 3 mg/kg was used as a standard memory enhancer. MAT significantly improved SCOP-induced learning and memory impairment in novel object recognition and Y-maze tests at doses of 0.4, 2, and 10 mg/kg. Furthermore, MAT inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and decreased oxidative stress in the brain, as evidenced by increased total antioxidant capacity, total superoxide dismutase levels, and catalase activities as well as decreased malondialdehyde levels. Additionally, there was a significant negative correlation between the percentage of spontaneous alternation in the Y maze and AChE activity in the cortex and hippocampus. MAT ameliorated SCOP-induced amnesia by the inhibition of both AChE/BuChE activities and oxidative stress. This study provides further evidence to encourage the development of MAT as a drug for the prevention or treatment of Alzheimer's disease.

https://ift.tt/2FmMxAv

A case of advanced pancreatic neuroendocrine tumor in which octreotide long-acting repeatable was effective after failure of everolimus and sunitinib

Abstract

Molecular targeted drugs, such as everolimus and sunitinib, have shown efficacy against advanced pancreatic neuroendocrine tumors. Octreotide, a somatostatin analogue, improves the hormone-related symptoms in patients with neuroendocrine tumors. Furthermore, it has been reported that octreotide has antitumor activity in patients with metastatic midgut neuroendocrine tumors. However, whether octreotide has anti-proliferative effects in patients with advanced pancreatic neuroendocrine tumors is not fully understood. We report a 71-year-old man with multiple liver metastases of pancreatic neuroendocrine tumor. He was treated with everolimus 10 mg daily and sunitinib 25 mg daily on days 1–14 every 3 weeks at the physician's discretion. However, these molecular targeted drugs were discontinued due to disease progression or severe adverse effects. Octreotide long-acting repeatable was administered continuously from the initiation of everolimus treatment. The tumor marker level markedly decreased and the metastatic liver lesions showed shrinkage with octreotide treatment. Immunohistochemistry of tumor specimens obtained before treatment showed that somatostatin receptor 2, a high-affinity receptor for octreotide, was highly expressed. The clinical course of this patient suggested that octreotide long-acting repeatable may be a treatment option for advanced pancreatic neuroendocrine tumors after failure of everolimus and sunitinib. Further clinical trials are warranted to determine whether the expression of somatostatin receptor 2 in tumor tissues is predictive of octreotide efficacy.

https://ift.tt/2F8fD6r

Clinical Results of Minimally Invasive Spine Stabilization for the Management of Metastatic Spinal Tumors Based on the Epidural Spinal Cord Compression Scale

Purpose. Minimally invasive spine stabilization (MISt) using percutaneous pedicle screws plays a significant role in palliative surgery for metastatic spinal tumors. However, few studies have investigated surgical outcomes based on the epidural spinal cord compression scale (ESCCS). The purpose of this study was to examine outcomes of metastatic spinal tumors as evaluated by ESCCS in patients treated by MISt. Methods. The subjects were 56 patients who underwent MISt for metastatic spinal tumors, including 34 patients with ESCCS 2 or milder (group A) and 22 patients with ESCCS 3 (group B). We analyzed baseline characteristics, perioperative factors and clinical results such as postoperative survival time, neurological outcomes, Barthel Index for activities of daily living (ADL), visual analogue scale (VAS), and the rate of discharge to home. Results. The baseline age (P=0.07), tumor diagnosis (P=0.23), spinal level of compression (P=0.35), American Spinal Injury Association classification (P=0.49), revised Tokuhashi score (P=0.92), spinal instability neoplastic score (P=0.28), VAS (P=0.35), Barthel Index (P=0.07), American Society of Anesthesiologists physical status classification (P=0.76), and type of surgery (P=0.40) did not differ significantly between the two groups. The median postoperative survival time did not differ significantly between the groups (12.0 versus 15.0 months, P=0.60). Neurological improvement by at least 1 grade or maintenance of grade E was favorable in group A. Patients in group A had less posterior decompression (P=0.006), a higher rate of chemotherapy (P=0.009), a higher postoperative Barthel Index (P=0.04), and a higher rate of discharge to home (P=0.01) and no patients died in the hospital (P=0.004). Conclusions. No significant difference was noted in the postoperative survival time between the 2 groups. Patients in the ESCCS 2 or milder group had favorable neurological improvement, higher rates of chemotherapy, better postoperative ADL, and the higher rate of discharge to home.

https://ift.tt/2FcHcvj

Old and New NICE Guidelines for the Evaluation of New Onset Stable Chest Pain: A Real World Perspective

Stable chest pain is a common clinical presentation that often requires further investigation using noninvasive or invasive testing, resulting in a resource-consuming problem worldwide. At onset of 2016, the National Institute for Health and Care Excellence (NICE) published an update on its guideline on chest pain. Three key changes to the 2010 version were provided by the new NICE guideline. First, the new guideline recommends that the previously proposed pretest probability risk score should no longer be used. Second, they also recommend that a calcium score of zero should no longer be used to rule out coronary artery disease (CAD) in patients with low pretest probability. Third, the new guideline recommends that all patients with new onset chest pain should be investigated with a coronary computed tomographic angiography (CTA) as a first-line investigation. However, in real world the impact of implementation of CTA for the evaluation of new onset chest pain remains to be evaluated, especially regarding its cost effectiveness. The aim of the present report was to discuss the results of the studies supporting new NICE guideline and its comparison with European and US guidelines.

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α-Tocopherol Ameliorates Redox Equilibrium and Reduces Inflammatory Response Caused by Chronic Variable Stress

Chronic exposure to stress factors contributes to the development of depression by generating excess of reactive oxygen species which leads to oxidative stress and inflammatory processes. The aim of the study was to assess the potential protective properties of α-tocopherol supplementation on the rats exposed to chronic variable stress (CVS). Male Wistar rats (50-55 days old, weighing 200-250 g) were divided into three groups (n=10): control, stressed, and stressed and receiving (+)-α-tocopherol solution in a dose of 100 mg/kg/day. Rats in the stressed groups were exposed to CVS for 40 days. Markers of redox disorders (glutathione reduced and oxidized levels, GSH/GSSG ratio, glutathione peroxidase, glutathione reductase activities, total antioxidant status, and lipid peroxidation) and inflammatory response (IL-1β, IL6, and TNF-α) were determined in the blood. Additionally, molecular biomarkers of depression (expression of Fkbp5 and Tph2) were studied in hippocampus. The biochemical analysis was inconclusive about the presence of oxidative stress in the blood of rats exposed to CVS. However, changes in all parameters suggest presence of redox equilibrium disorders. Similarly, activation of inflammatory processes was observed as a result of CVS. Molecular effects of environmental stress in hippocampus were also observed. Generally, α-tocopherol ameliorated redox equilibrium disorders, tempered inflammatory response, and protected from changes in determined molecular markers of depression.

https://ift.tt/2F9iRXb

Circadian disruption: What do we actually mean?

Abstract

The circadian system regulates physiology and behavior. Acute challenges to the system, such as those experienced during travel across time zones, will eventually result in re‐synchronization to the local environmental time cues, but this re‐synchronization is oftentimes accompanied by adverse short‐term consequences. When such challenges are experienced chronically, adaptation may not be achieved, as for example in the case of rotating night shift workers. The transient and chronic disturbance of the circadian system is most frequently referred to as "circadian disruption", but many other terms have been proposed and used to refer to similar situations. It is now beyond doubt that the circadian system contributes to health and disease, emphasizing the need for clear terminology when describing challenges to the circadian system and their consequences. The goal of this review is to provide an overview of the terms used to describe disruption of the circadian system, discuss proposed quantifications of disruption in experimental and observational settings with a focus on human research, and highlight limitations and challenges of currently available tools. For circadian research to advance as a translational science, clear, operationalizable, and scalable quantifications of circadian disruption are key, as they will enable improved assessment and reproducibility of results, ideally ranging from mechanistic settings, including animal research, to large‐scale randomized clinical trials.

This article is protected by copyright. All rights reserved.

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Parallel learning processes of a visuomotor adaptation task in a changing environment

Abstract

During the control of reaching movements, a key contribution of the visual system is the localization of relevant environmental targets. In motor adaptation processes, the visual evaluation of effector motor behavior enables learning from errors, which demands continuous visual attentional focus. However, most current adaptation paradigms include static targets; therefore, when a learning situation develops in a highly variable environment and there is a double demand for visual resources (environment and motor performance), the evolution of learning processes is unknown. In order to understand how learning processes evolve in a variable environment, a video game task was designed in which subjects were asked to manage a sixty‐degree counterclockwise‐rotated cursor to capture descending targets with initially unpredictable trajectories. During the task, the cursor and eye movements were recorded to dissect visuomotor coordination. We observed that the pursuit of the targets conditioned a predominant and continuous visual inspection of the environment instead of the rotated cursor. As learning progressed, subjects exhibited a linear reduction in directional error and selected a motor strategy based on the degree of reward, which improved the performance. These results suggest that when the environment demands high visual attention, error‐based and reinforced motor learning processes are implemented simultaneously, thus enabling efficient predictive behavior.

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The COMT Val158Met polymorphism does not modulate the after‐effect of tDCS on working memory

Abstract

Transcranial direct current stimulation (tDCS) can alter cortical excitability, neural plasticity and cognitive‐behavioral performance, however its effects are known to vary across studies. A partial account of this variability relates to individual differences in dopamine function. Indeed, dopaminergic manipulations alter the physiological and cognitive‐behavioral effects of tDCS, and gene polymorphisms related to dopamine have predicted individual response to online tDCS (i.e., stimulation overlapping with the critical task). Notably, the role of individual differences in dopamine has not yet been properly assessed in the effect of offline tDCS (i.e., stimulation prior to the critical task). We investigated if and how the COMT Val¹⁵⁸Met polymorphism (rs4680) modulates the after‐effect of prefrontal tDCS on verbal working memory (WM). 139 participants were genotyped for the COMT Val¹⁵⁸Met polymorphism and received anodal‐over‐left, cathodal‐over‐right (AL‐CR), cathodal‐over‐left, anodal‐over‐right (CL‐AR), or sham stimulation over the dorsolateral prefrontal cortex in a between‐subjects, pretest‐posttest study design. WM was assessed using the N‐back task. The results provide no evidence that the COMT polymorphism impacts the after‐effect of prefrontal tDCS on WM. Taken together with previous findings on dopamine and tDCS interactions, the results of the present study suggest that (i) indirect markers of dopamine (such as COMT) are differently related to online and offline effects of tDCS, and (ii) findings from studies involving pharmacological manipulation should be generalized with caution to findings of inter‐individual differences. In sum, we argue that state (i.e., a manipulation of) and trait (i.e., baseline) differences in dopamine may exert different effects on online and offline tDCS.

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Distinct Effects of (R)‐Modafinil and its (R)‐ and (S)‐Fluoro‐Analogs on Mesolimbic Extracellular Dopamine Assessed by Voltammetry and Microdialysis in Rats

Abstract

Psychostimulant use disorders remain an unabated public health concern worldwide, but no FDA approved medications are currently available for treatment. Modafinil (MOD), like cocaine is a dopamine reuptake inhibitor, and one of the few drugs evaluated in clinical trials that has shown promise for the treatment of cocaine or methamphetamine use disorders, in some patient sub‐populations. Recent structure‐activity relationship and preclinical studies on a series of MOD analogs have provided insight into modifications of its chemical structure that may lead to advancements in clinical efficacy.

Here we have tested the effects of the clinically available (R)‐enantiomer of MOD on extracellular dopamine levels in the nucleus accumbens shell, a mesolimbic dopaminergic projection field that plays significant roles in various aspects of psychostimulant use disorders, measured in vivo by fast‐scan cyclic voltammetry and by microdialysis in Sprague‐Dawley rats. We have compared these results with those obtained under identical experimental conditions, with two novel and enantiopure bis(F) analogs of MOD, JBG1‐048 and JBG1‐049.

The results show that (R)‐modafinil (R‐MOD), JBG1‐048, and JBG1‐049, when administered intravenously with cumulative drug doses, will block the dopamine transporter and reduce the clearance rate of dopamine, increasing its extracellular levels. Differences among the compounds in their maximum stimulation of dopamine levels, and in their time course of effects were also observed. These data highlight mechanistic underpinnings of R‐MOD and its bis(F) analogs as pharmacological tools to guide the discovery of novel medications to treat psychostimulant use disorders.

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Circuit development in the master clock network of mammals

Abstract

Daily rhythms are generated by the circadian timekeeping system, which is orchestrated by the master circadian clock in the suprachiasmatic nucleus (SCN) of mammals. Circadian timekeeping is endogenous and does not require exposure to external cues during development. Nevertheless, the circadian system is not fully formed at birth in many mammalian species and it is important to understand how SCN development can affect the function of the circadian system in adulthood. The purpose of the current review is to discuss the ontogeny of cellular and circuit function in the SCN, with a focus on work performed in model rodent species (i.e., mouse, rat, hamster). Particular emphasis is placed on the spatial and temporal patterns of SCN development that may contribute to the function of the master clock during adulthood. Additional work aimed at decoding the mechanisms that guide circadian development is expected to provide a solid foundation upon which to better understand the sources and factors contributing to aberrant maturation of clock function.

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Periodicity, repression, and the molecular architecture of the mammalian circadian clock

Abstract

Large molecular machines regulate daily cycles of transcriptional activity and help generate rhythmic behavior. In recent years, structural and biochemical analyses have elucidated a number of principles guiding the interactions of proteins that form the basis of circadian timing. In its simplest form, the circadian clock is composed of a transcription/translation feedback loop. However, this description elides a complicated process of activator recruitment, chromatin decompaction, recruitment of coactivators, expression of repressors, formation of a repressive complex, repression of the activators, and ultimately degradation of the repressors and reinitiation of the cycle. Understanding the core principles underlying the clock requires careful examination of molecular and even atomic level details of these processes. Here we review major structural and biochemical findings in circadian biology and make the argument that shared protein interfaces within the clockwork are critical for both the generation of rhythmicity and timing of the clock.

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Naltrexone differentially modulates the neural correlates of motor impulse control in abstinent alcohol‐dependent and poly‐substance dependent individuals

Abstract

Identifying key neural substrates in addiction disorders for targeted drug development remains a major challenge for clinical neuroscience. One emerging target is the opioid system, where substance‐dependent populations demonstrate prefrontal opioid dysregulation that predicts impulsivity and relapse. This may suggest that disturbances to the prefrontal opioid system could confer a risk for relapse in addiction due to weakened "top‐down" control over impulsive behaviour. Naltrexone is currently licensed for alcohol dependence and is also used clinically for impulse control disorders. Using a go/no‐go (GNG) task we examined the effects of acute naltrexone on the neural correlates of successful motor impulse control in abstinent alcoholics (AUD), abstinent poly substance‐dependent (poly‐SUD) individuals, and controls during a randomized double blind placebo controlled fMRI study. In the absence of any differences on GNG task performance, the AUD group showed a significantly greater BOLD response compared to the control group in lateral and medial prefrontal regions during both placebo and naltrexone treatments; effects that were positively correlated with alcohol abstinence. There was also a dissociation in the positive modulating effects of naltrexone in the orbitofrontal cortex (OFC) and anterior insula cortex (AIC) of the AUD and poly‐SUD groups respectively. Self‐reported trait impulsivity in the poly‐SUD group also predicted the effect of naltrexone in the AIC. These results suggest that acute naltrexone differentially amplifies neural responses within two distinct regions of a salience network during successful motor impulse control in abstinent AUD and poly‐SUD groups, which are predicted by trait impulsivity in the poly‐SUD group.

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Adaptive neurogenesis in the cerebral cortex and contralateral subventricular zone induced by unilateral cortical devascularisation: Possible modulation by dopamine neurotransmission

Abstract

Understanding endogenous neurogenesis and neuronal replacement to mature circuits is a topic of discussion as a therapeutic alternative under acute and chronic neurodegenerative disorders. Adaptive neurogenic response may result as a result of ischemia which could support long term recovery of behavioral functions. Endogenous sources of neural progenitors may be stimulated by changes in blood flow or neuromodulation. Using a mouse model of unilateral cortical devascularisation we have observed reactive neurogenesis in the perilesional cortex and subventricular zone neurogenic niche. C57BL/6L four weeks male mice were craneotomized at 1 mm caudal from frontal suture and 1 mm lateral from midline to generate a window of 3 mm side. Brain injury was produced by removal of the meninges and superficial vasculature of dorsal parietal cortex. BrdU agent (50 mg/Kg, ip) was injected to lesioned and sham animals, during days 0 and 1 after surgery. Sagittal sections were analyzed at 1, 4, 7, and 10 days post‐injury. A time‐dependent increase of BrdU⁺ cells in the perilesional parietal cortex was accompanied by augmented BrdU⁺ cells in the sub ventricular and rostral migratory stream of ipsilateral and contralateral hemispheres. Neural progenitors and neuroblasts proliferated in the lesioned and non lesioned subventricular zone and rostral migratory stream day 4 after injury. Augmented contralateral neurogenesis was associated with an increase of vesicular monoamine transporter 2 protein in the striosomal sub ventricular neurogenic niche of non‐lesioned hemisphere.

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Effects of ketamine/xylazine and isoflurane on rat brain glucose metabolism measured by 18F‐fluorodeoxyglucose‐positron emission tomography

Abstract

The aim of the present study was to investigate changes in glucose metabolism in male Wistar rats induced by the anesthetics isoflurane and ketamine combined with xylazine via ¹⁸F‐fluorodeoxyglucose‐positron emission tomography. We analyzed the differential effects of the anesthetics on ¹⁸F‐fluorodeoxyglucose uptake and pharmacokinetics in 33 rats using quantification methods: 1) the standardized uptake value, 2) voxel‐based analyses, and 3) kinetic analysis. Both anesthetics reduced glucose uptake in the entire brain. The voxel‐based analyses detected smaller uptake reductions in the bilateral primary somatosensory system cortex and part of the limbic system in the ketamine‐xylazine (KX) group and in the vestibular nucleus in the isoflurane group. Through kinetic analysis, we found that the volume of distribution and the membrane transport rate K₁ were reduced in the KX group. Through various methods of ¹⁸F‐fluorodeoxyglucose‐positron emission tomography quantification, the present study found that anesthesia with the ketamine‐xylazine combination induced a global reduction of glucose metabolism compared with isoflurane; this reduction of metabolism was relatively lower in the primary somatosensory cortex and part of the limbic system. The volume of distribution of ¹⁸F‐fluorodeoxyglucose and its Glut1‐mediated transport across the brain membranes (K₁) were decreased in the KX group.

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Mood‐Related Central and Peripheral Clocks

Abstract

Mood disorders, including major depression, bipolar disorder, and seasonal affective disorder, are debilitating disorders that affect a significant portion of the global population. Individuals suffering from mood disorders often show significant disturbances in circadian rhythms and sleep. Moreover, environmental disruptions to circadian rhythms can precipitate or exacerbate mood symptoms in vulnerable individuals. Circadian clocks exist throughout the central nervous system and periphery, where they regulate a wide variety of physiological processes implicated in mood regulation. These processes include monoaminergic and glutamatergic transmission, HPA axis function, metabolism, and immune function. While there seems to be a clear link between circadian rhythm disruption and mood regulation, the mechanisms that underlie this association remain unclear. This review will touch on the interactions between the circadian system and each of these processes and discuss their potential role in the development of mood disorders. While clinical studies are presented, much of the review will focus on studies in animal models, which are attempting to elucidate the molecular cellular mechanisms in which circadian genes regulate mood.

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Pregnancy after cancer: Does timing of conception affect infant health?

Background

The objective of this retrospective cohort study was to determine whether women who conceive soon after treatment for cancer have higher risks of adverse pregnancy outcomes.

Methods

Vital records data were linked to cancer registry diagnosis and treatment information in 3 US states. Women who conceived their first pregnancy after diagnosis between ages 20 and 45 years with any invasive cancer or ductal carcinoma in situ were eligible. Log‐binomial models were used to compare risks in cancer survivors who conceived in each interval to the risks in matched comparison births to women without cancer.

Results

Women who conceived ≤1 year after starting chemotherapy for any cancer had higher risks of preterm birth than comparison women (chemotherapy alone: relative risk [RR], 1.9; 95% confidence interval [CI], 1.3‐2.7; chemotherapy with radiation: RR, 2.4; 95% CI, 1.6‐3.6); women who conceived ≥1 year after starting chemotherapy without radiation or ≥2 years after chemotherapy with radiation did not. In analyses imputing the treatment end date for breast cancer survivors, those who conceived ≥1 year after finishing chemotherapy with or without radiation had no higher risks than women without cancer. The risk of preterm birth in cervical cancer survivors largely persisted but was somewhat lower in pregnancies conceived after the first year (for pregnancies conceived ≤1 year after diagnosis: RR, 3.5; 95% CI, 2.2‐5.4; for pregnancies conceived >1 year after diagnosis: RR, 2.4; 95% CI, 1.6‐3.5).

Conclusions

In women who received chemotherapy, the higher risk of preterm birth was limited to those survivors who had short intervals between treatment and conception. Cancer 2018;0:1‐7.

https://ift.tt/2JLpaz3

The Long Noncoding RNA HOST2 Promotes Gemcitabine Resistance in Human Pancreatic Cancer Cells

Abstract

Our study was aimed to identify the fundamental role of lncRNA HOST2 in gemcitabine resistance regulation in human pancreatic cancer cells. The levels of HOST2 in pancreatic cancer cell lines were measured by quantitative real-time PCR (qRT-PCR). Due to high expression and strong gemcitabine resistance, Hs766T and AsPC-1 cell lines were selected to be knockdown the expression of HOST2 by transfection sh-HOST2. After manipulation of HOST2, the cell proliferation induced by gemcitabine was examined by CCK-8 assay. Next, colony formation ability of Hs766T and AsPC-1 cell lines was determined by clone-forming assay. At last, the relationship between HOST2 and cell apoptosis in Hs766T and AsPC-1 cell lines was evaluated by flow cytometry. QRT-PCR revealed that HOST2 was overexpressed in six pancreas neoplasm cell lines compared with normal cell lines HPDE6-C7. HOST2 expression levels in group resistant to gemcitabine were higher than the group sensitive to gemcitabine. Additionally, CCK-8 assay verified that cell proliferation was inhibited by sh-HOST2 with or without gemcitabine treatment. Furthermore, clone-forming assay revealed that colony formation ability was weakened by down-regulated HOST2 with or without gemcitabine treatment. Flow cytometry revealed that cell apoptosis induced by gemcitabine was promoted by sh-HOST2. In conclusion, down-regulated HOST2 inhibited proliferation and promoted apoptosis of pancreas cancer cells with or without gemcitabine treatment. Thus, HOST2 is a potential therapeutic target for gemcitabine chemoresistance in pancreatic neoplasms.

https://ift.tt/2yWq4EE

Fibroblast Growth Factor Receptor Inhibition for Cholangiocarcinoma: Looking Through a Door Half‐Opened

https://ift.tt/2yXWApL

Natural Compounds with xanthine oxidase inhibitory activity: A review

Purine metabolism results the formation of uric acid in human body due to catalysis of (hypoxanthine and xanthine) by xanthine oxidase enzyme. The over production of uric acid results hyperuricemia, gout, cardiovascular diseases etc. Plant drive bioactive compounds bind with xanthine oxidase enzyme due to their special structural features and hinder the entrance of hypoxanthine and xanthine with enzyme, thus prevent from uric acid synthesis.

Abstract

Hyperuricemia (HUA), a disease due to an elevation of BUA (body uric acid) level and responsible for various diseases like gout, cardiovascular disorders, and renal failure, is a major ground debate for the medical science these days. Considering the risk factors linked with allopathic drugs for the treatment of this disease, the debate has now become a special issue. Previously, we critically discussed the role of dietary polyphenols in the treatment of HUA. Besides dietary food plants, many researchers figure out the tremendous effects of medicinal plants derived phytochemicals against HUA. Keeping in mind all these aspects, we reviewed all possible managerial studies related to HUA through medicinal plants (isolated compounds). In the current review article, we comprehensively discussed various bioactive compounds, chemical structures and structure‐activity relationship with responsible key enzyme xanthine oxidase.

This article is protected by copyright. All rights reserved.

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Cytidine deaminase enzymatic activity is a prognostic biomarker in gemcitabine/platinum-treated advanced non-small-cell lung cancer: a prospective validation study

https://ift.tt/2OuLiyg

Selected Abstracts from the 2018 NCRI Cancer Conference of National Cancer Research Institute

https://ift.tt/2yZrcY6

A roadmap for important centers of growth in the pediatric skeleton to consider during radiation therapy and associated clinical correlates of radiation-induced growth toxicity

With the increasing use of advanced radiation techniques such as intensity modulated radiation therapy, stereotactic radiation therapy, and proton therapy, radiation oncologists now have the tools to mitigate radiation-associated toxicities. This is of utmost importance in the treatment of a pediatric patient. To best utilize these advanced techniques to mitigate radiation-induced growth abnormalities, the radiation oncologist should be equipped with a nuanced understanding of the anatomy of centers of growth.

https://ift.tt/2qzDd1F

A quest for sphincter-saving surgery in ultralow rectal tumours—a single-centre cohort study

Abstract

Introduction

Despite the progress in the treatment of colorectal cancer, there is still no optimal strategy for tumours located adjacent to the anal sphincter. This study aims to evaluate oncological and functional results of surgery for rectal cancer in unfavourable locations in proximity to anal sphincters.

Materials and methods

Patients with rectal cancer, which was either initially infiltrating the anal sphincter or located in the close proximity of the sphincter, were included in the study. Patients were submitted to extralevator abdominoperineal resection (APR), intersphincteric resection, or transanal total mesorectal excision (TaTME). Primary outcomes were perioperative data: operative time, blood loss, complications, length of stay (LOS), and 30-day mortality. Secondary outcomes were pathological quality of the specimens and functional outcome 6 months after defunctioning ileostomy closure.

Results

Among patients with cancer adjacent to the anal sphincter, 13 (25%) underwent APR, 14 (27%) patients were submitted to intersphincteric resection, and 25 (48%) patients were treated with the TaTME approach. Operative time was 240 (210–270 IQR) for APR, 212.5 (170–260 IQR) for intersphincteric resection, and 270 (240–330 IQR) for TaTME (p = 0.018). Perioperative morbidity was 31% for APR, 36% for intersphincteric resections, and 12% for the TaTME group (p = 0.181). Complete mesorectal excision was achieved in 92% of specimens in the TaTME group, 93% in intersphincteric resections, and 78% in the APR group (p = 0.72). Median circumferential resection margin in APR was 6 mm (4–7 IQR), in intersphincteric resections 7.5 mm (2.5–10 IQR), and in the TaTME group 4 mm (2.8–8 IQR). All patients after intersphincteric resections developed major low anterior resection syndrome (LARS). Four patients in the TaTME group developed minor LARS, and 21 had major LARS.

Conclusion

Sphincter-saving rectal resections are a feasible alternative to APR with good clinical, pathological, and oncological outcomes. Intersphincteric resections and TaTME seem to be equal in terms of clinicopathological results. The functional outcome is yet to be investigated.

Trial registration

The study was retrospectively registered in Thai Clinical Trials Registry (23-07-2018, ID TCTR20180724001).

https://ift.tt/2PgfRNf

Muscle Fitness Cut Points for Early Assessment of Cardiovascular Risk in Children and Adolescents

To study the cross-sectional and longitudinal (2-year follow-up) association between muscle fitness and cardiovascular disease (CVD) risk factors in youth; whether there are muscle fitness cut points associated with CVD risk (cross-sectional); and whether the health-related muscle fitness cut points identified at baseline are associated with CVD risk 2 years later.

https://ift.tt/2F8R6y3

Neonatal Lung Disease Associated with TBX4 Mutations

Variable lung disease was documented in 2 infants with heterozygous TBX4 mutations; their clinical presentations, pathology, and outcomes were distinct. These findings demonstrate that TBX4 gene mutations are associated with neonatal respiratory failure and highlight the wide spectrum of clinicopathological outcomes that have implications for patient diagnosis and management.

https://ift.tt/2qApBmI

Child and Adolescent Suicidal Ideation and Suicide Attempts: Evidence from the Healthcare Cost and Utilization Project

To examine the trends associated with child and adolescent suicidal ideation and suicide attempts and to compare these trends to those among the adult population.

https://ift.tt/2F79l6Q

Thirteen-Year Outcomes in Very Preterm Children Associated with Diffuse Excessive High Signal Intensity on Neonatal Magnetic Resonance Imaging

To investigate the association between white matter diffuse excessive high signal intensity (DEHSI) on neonatal magnetic resonance imaging in very preterm infants and neurobehavioral outcomes at the age of 13 years.

https://ift.tt/2qADa5W

Kidney Transplantation in C3 Glomerulopathy: A Case Series

C3 glomerulopathy (C3G), a form of glomerulonephritis associated with dysregulation of the alternative complement pathway, occurs either as dense deposit disease (DDD) or C3 glomerulonephritis (C3GN). Few studies have reported outcomes of patients with C3G after transplantation since its formal classification and the advent of complement-targeting therapies such as eculizumab.

https://ift.tt/2Dt5Cim

Total Pancreatectomy for Presumed Intraductal Papillary Mucinous Neoplasms: A Multicentric Study of the French Surgical Association (AFC)

Objective: The aim of the current study was to assess the short and long-term outcome of total pancreatectomy (TP) for IPMN based on the largest series to date. Background: Literature data are scarce regarding TP for IPMN, though increasingly performed in this setting. Methods: Data of 888 IPMN patients operated between 2004 and 2013 were collected in a multicentric retrospective AFC database. Ninety-three patients (10.5%) who had TP entered this study. Patient demographics, indications, intraoperative data, 3-month morbi-mortality (Clavien), and long-term outcome were analyzed. Results: Most patients had mixed type IPMN (59%) and underwent upfront (56%) or intraoperatively-decided (33%) TP. Morbidity and mortality rates were 47.3% and 4.3%, respectively, with no lethal hypoglycemia; morbidity was higher for intraoperatively-decided TP. Misdiagnoses were frequent regarding main pancreatic duct involvement (12%), invasiveness (33%), or mural nodules (50%), resulting in 12 TPs (13%) performed for asymptomatic IPMN showing only low/moderate dysplasia (LMD). On histopathological examination, there were 54 (58%) invasive IPMN (mostly pT3/T4 (76%), N+ (60%), R0 (75%)), with a significantly worse 5-year survival (21.2%) compared to noninvasive group (85.7%; P

https://ift.tt/2yfnmto

Defective mitochondrial protein import contributes to complex I-induced mitochondrial dysfunction and neurodegeneration in Parkinson’s disease

Defective mitochondrial protein import contributes to complex I-induced mitochondrial dysfunction and neurodegeneration in Parkinson's disease

Defective mitochondrial protein import contributes to complex I-induced mitochondrial dysfunction and neurodegeneration in Parkinson's disease, Published online: 07 November 2018; doi:10.1038/s41419-018-1154-0

Defective mitochondrial protein import contributes to complex I-induced mitochondrial dysfunction and neurodegeneration in Parkinson's disease

https://ift.tt/2QsxNky

Aloe-emodin induces apoptosis in human oral squamous cell carcinoma SCC15 cells

Oral and pharyngeal cancer is the most common malignant human cancers. Chemotherapy is an effective approach for anti-oral cancer therapy, while the drug tolerance and resistance remain a problem for oral canc...

https://ift.tt/2PecDda

Detection of Low Copy Number Integrated Viral DNA Formed by In Vitro Hepatitis B Infection

We describe here the in vitro generation of HBV DNA via a Hepatitis B virus infection system and the highly sensitive detection of its (1–2 copies) integration using inverse nested PCR.

https://ift.tt/2QsJlUQ

Sandy Hook parent puts emphasis on compassion at trauma conference

Scarlett Lewis praised audience members for being the"heroes" of trauma response and discussed the importance of social-emotional learning

https://ift.tt/2Pi6dd6

Son’s death inspires father to become first responder

Dan Miller, an 11-year veteran firefighter-paramedic, became an EMT shortly after his 2-year-old son died of choking

https://ift.tt/2QsG0Fi

A High-throughput Platform for the Screening of Salmonella spp./Shigella spp.

Salmonella spp./Shigella spp. are common pathogens attributed to diarrhea. Here, we describe a high-throughput platform for the screening of Salmonella spp./Shigella spp. using real-time PCR combined with guided culture.

https://ift.tt/2D7BV5w

A case report of scrub typhus complicated with myocarditis and rhabdomyolysis

Scrub typhus is a zoonotic disease caused by Orientia tsutsugamushi, a gram-negative intracellular bacterium. Myocarditis and rhabdomyolysis are rare complications of scrub typhus.

https://ift.tt/2QoQQfq

Interprofessional palliative care education for pediatric oncology clinicians: an evidence-based practice review

Clinician education and expertise in palliative care varies widely across pediatric oncology programs. The purpose of this evidence-based practice review was to identify interprofessional palliative care educa...

https://ift.tt/2QnlNAJ

Issue Information

https://ift.tt/2Ds6CDB

Employing Pressurized Hot Water Extraction (PHWE) to Explore Natural Products Chemistry in the Undergraduate Laboratory

Here, we employ a pressurized hot water extraction (PHWE) method, which utilizes an unmodified household espresso machine to introduce undergraduates to natural products chemistry in the laboratory. Two experiments are presented: PHWE of eugenol and acetyleugenol from cloves and PHWE of seselin and (+)-epoxysuberosin from the Australian plant Correa reflexa.

https://ift.tt/2zAe8I1

Abx-Resistant Enterobacteriaceae Tied to Clinical Failure in UTI

WEDNESDAY, Nov. 7, 2018 -- Community-onset urinary tract infection (UTI) due to extended-spectrum cephalosporin-resistant (ESC-R) Enterobacteriaceae (EB) is significantly associated with clinical failure, according to a study published online Oct....

https://ift.tt/2F6cCDp

Excess Gestational Weight Gain Not Better for Child Bone Health

WEDNESDAY, Nov. 7, 2018 -- Among women who are under/normal weight, gestational weight gain (GWG) is associated with slightly increased bone measures in offspring at age 7 years, but there is no effect for overweight/obese mothers, according to a...

https://ift.tt/2qxfMpV

Happy Childhood Memories Associated With Better Health

WEDNESDAY, Nov. 7, 2018 -- Those with fond memories of childhood and strong relationships with their parents have better health throughout adulthood, according to a study published online Nov. 5 in Health Psychology. William J. Chopik, Ph.D., from...

https://ift.tt/2Fa8mmF

More Frequent Surveillance No Benefit After NSCLC Resection

WEDNESDAY, Nov. 7, 2018 -- For patients undergoing resection for non-small cell lung cancer (NSCLC), more frequent surveillance is not associated with improved survival, according to a study published in the October issue of the Annals of...

https://ift.tt/2qzZ2hA

Polygenic Risk Score Predicts Tx Response in Schizophrenia

WEDNESDAY, Nov. 7, 2018 -- A polygenic risk score (PRS) for schizophrenia can predict 12-week posttreatment symptom scores among patients with first-episode psychosis, according to a study published online Nov. 5 in the American Journal of...

https://ift.tt/2Fa8lPD

Peds Firearm-Related Injuries Lead to Clinical, Financial Burden

WEDNESDAY, Nov. 7, 2018 -- For pediatric patients, the clinical and financial burdens associated with firearm-related injuries are considerable, according to a research letter published online Oct. 29 in JAMA Pediatrics. Faiz Gani, M.B.B.S., and...

https://ift.tt/2qw3Kgo

Study IDs Early Life Factors Predictive of Myopia

WEDNESDAY, Nov. 7, 2018 -- Early life factors associated with myopia include maternal education, fertility treatment, summer birth, and hours spent playing computer games, according to a study published online Nov. 6 in the British Journal of...

https://ift.tt/2Fa8Nxj

Colectomy Appears to Increase Later Risk of Type 2 Diabetes

WEDNESDAY, Nov. 7, 2018 -- Patients who have the entire or left side of the colon removed show increased risk for developing type 2 diabetes in the 18 years following surgery, according to a study published online Oct. 30 in eLife. Anders B. Jensen,...

https://ift.tt/2qAfqPm

Nonadherence, Discontinuation of Statins High in 1st Year of Rx

WEDNESDAY, Nov. 7, 2018 -- First-year nonadherence and discontinuation are high among older adults prescribed statins, according to a study published online Nov. 7 in the British Journal of Clinical Pharmacology. Richard Ofori-Asenso, from Monash...

https://ift.tt/2Fa8hiR

Short Questionnaire IDs GI Disorders in Children With Autism

WEDNESDAY, Nov. 7, 2018 -- A short parent questionnaire may be able to identify gastrointestinal disorders in children with autism spectrum disorder (ASD), according to a study published online Oct. 22 in the Journal of Autism and Developmental...

https://ift.tt/2qzdg2f

Healthcare-associated infections in intensive care units in Taiwan, South Korea, and Japan: recent trends based on national surveillance reports

Sustainable systematic interventions are important for infection prevention and control (IPC). Data from surveillance of healthcare-associated infections (HAI) provides feedback for implementation of IPC progr...

https://ift.tt/2JKshac

Biochemical and Skeletal Outcomes of Parathyroidectomy for Normocalcemic (Incipient) Primary Hyperparathyroidism

Abstract

Background

Normocalcemic (incipient) primary hyperparathyroidism (PHPT) is characterized by inappropriately elevated parathyroid hormone (PTH) levels in the setting of normal serum calcium. The biochemical and skeletal outcomes after parathyroidectomy for normocalcemic PHPT are not well-described.

Methods

All patients who underwent parathyroidectomy for normocalcemic PHPT at a single institution were retrospectively reviewed (2006–2016). Pre- and postoperative calcium, PTH, and bone mineral density (BMD) were compared between patients with normalized versus persistently elevated PTH levels > 6 months after parathyroidectomy. Multivariable Cox regression was used to identify risk factors associated with persistently elevated PTH levels after parathyroidectomy.

Result

Parathyroidectomy was performed in 71 patients with normocalcemic PHPT, of whom 38 (53.5%) had multi-gland disease. No patients became hypercalcemic, with a median follow-up of 23.1 months. Persistently elevated PTH levels were noted in 33 (46.5%) patients. In multivariable analysis, preoperative PTH > 100 pg/mL was associated with persistently elevated PTH levels after parathyroidectomy. In 38 patients with available pre- and postoperative BMD measurements, the mean preoperative BMD improved + 5.6% (p < 0.01) in patients with normalized PTH, while no significant change was observed in patients with persistently elevated PTH levels (− 2.2%, p = 0.47).

Conclusions

Elevated PTH levels are common after parathyroidectomy for normocalcemic PHPT. Improvements in BMD may be predicated on long-term normalized PTH levels following surgery.

https://ift.tt/2JPjPH2

A53T Mutant Alpha-Synuclein Induces Tau-Dependent Postsynaptic Impairment Independently of Neurodegenerative Changes

Abnormalities in α-synuclein are implicated in the pathogenesis of Parkinson's disease (PD). Because α-synuclein is highly concentrated within presynaptic terminals, presynaptic dysfunction has been proposed as a potential pathogenic mechanism. Here, we report novel, tau-dependent, postsynaptic deficits caused by A53T mutant α-synuclein, which is linked to familial PD. We analyzed synaptic activity in hippocampal slices and cultured hippocampal neurons from transgenic mice of either sex expressing human WT, A53T, and A30P α-synuclein. Increased α-synuclein expression leads to decreased spontaneous synaptic vesicle release regardless of genotype. However, only those neurons expressing A53T α-synuclein exhibit postsynaptic dysfunction, including decreased miniature postsynaptic current amplitude and decreased AMPA to NMDA receptor current ratio. We also found that long-term potentiation and spatial learning were impaired by A53T α-synuclein expression. Mechanistically, postsynaptic dysfunction requires glycogen synthase kinase 3β-mediated tau phosphorylation, tau mislocalization to dendritic spines, and calcineurin-dependent AMPA receptor internalization. Previous studies reveal that human A53T α-synuclein has a high aggregation potential, which may explain the mutation's unique capacity to induce postsynaptic deficits. However, patients with sporadic PD with severe tau pathology are also more likely to have early onset cognitive decline. Our results here show a novel, functional role for tau: mediating the effects of α-synuclein on postsynaptic signaling. Therefore, the unraveled tau-mediated signaling cascade may contribute to the pathogenesis of dementia in A53T α-synuclein-linked familial PD cases, as well as some subgroups of PD cases with extensive tau pathology.

SIGNIFICANCE STATEMENT Here, we report mutation-specific postsynaptic deficits that are caused by A53T mutant α-synuclein, which is linked to familial Parkinson's disease (PD). The overexpression of WT, A53T, or A30P human α-synuclein leads to decreased spontaneous synaptic vesicle release. However, only those neurons expressing A53T α-synuclein exhibit tau phosphorylation-dependent postsynaptic dysfunction, which is characterized by decreased miniature postsynaptic current amplitude and decreased AMPA to NMDA receptor current ratio. The mutation-specific postsynaptic effects caused by human A53T α-synuclein will help us better understand the neurobiological basis of this specific form of familial PD. The differential effects of exogenous human WT, A53T, A30P, and E46K α-synuclein on glutamatergic synaptic responses will help to explain the clinical heterogeneity of sporadic and familial PD.

https://ift.tt/2Dpr8EI

The Subprimary Range of Firing Is Present in Both Cat and Mouse Spinal Motoneurons and Its Relationship to Force Development Is Similar for the Two Species

In the motor system, force gradation is achieved by recruitment of motoneurons and rate modulation of their firing frequency. Classical experiments investigating the relationship between injected current to the soma during intracellular recording and the firing frequency (the I–f relation) in cat spinal motoneurons identified two clear ranges: a primary range and a secondary range. Recent work in mice, however, has identified an additional range proposed to be exclusive to rodents, the subprimary range (SPR), due to the presence of mixed mode oscillations of the membrane potential. Surprisingly, fully summated tetanic contractions occurred in mice during SPR frequencies. With the mouse now one of the most popular models to investigate motor control, it is crucial that such discrepancies between observations in mice and basic principles that have been widely accepted in larger animals are resolved. To do this, we have reinvestigated the I–f relation using ramp current injections in spinal motoneurons in both barbiturate-anesthetized and decerebrate (nonanesthetized) cats and mice. We demonstrate the presence of the SPR and mixed mode oscillations in both species and show that the SPR is enhanced by barbiturate anesthetics. Our measurements of the I–f relation in both cats and mice support the classical opinion that firing frequencies in the higher end of the primary range are necessary to obtain a full summation. By systematically varying the leg oil pool temperature (from 37°C to room temperature), we found that only at lower temperatures can maximal summation occur at SPR frequencies due to prolongation of individual muscle twitches.

SIGNIFICANCE STATEMENT This work investigates recent revelations that mouse motoneurons behave in a fundamentally different way from motoneurons of larger animals with respect to the importance of rate modulation of motoneuron firing for force gradation. The current study systematically addresses the proposed discrepancies between mice and larger species (cats) and demonstrates that mouse motoneurons, in fact, use rate modulation as a mechanism of force modulation in a similar manner to the classical descriptions in larger animals.

https://ift.tt/2RJPZq5

Inhibitory Connectivity Dominates the Fan Cell Network in Layer II of Lateral Entorhinal Cortex

Fan cells in layer II of the lateral entorhinal cortex (LEC) form a main component of the projection to the dentate gyrus, CA3 and CA2 of the hippocampal formation. This projection has a counterpart originating from stellate cells in layer II of the medial entorhinal cortex (MEC). Available evidence suggests that the two pathways carry different information, exemplified by a difference in spatial tuning of cells in LEC and MEC. The grid cell, a prominent position-modulated cell type present in MEC, has been postulated to derive its characteristic hexagonal firing pattern from dominant disynaptic inhibitory connections between hippocampal-projecting stellate cells. Given that grid cells have not been described in LEC, we aim to describe the local synaptic connectivity of fan cells, to explore whether the network architecture is similar to that of the MEC stellate cell. Using a combination of in vitro multicell electrophysiological and optogenetic approaches in acute slices from rodents of either sex, we show that excitatory connectivity between fan cells is very sparse. Fan cells connect preferentially with two distinct types of inhibitory interneurons, suggesting disynaptic inhibitory coupling as the main form of communication among fan cells. These principles are similar to those reported for stellate cells in MEC, indicating an overall comparable local circuit architecture of the main hippocampal-projecting cell types in the lateral and medial entorhinal cortex.

SIGNIFICANCE STATEMENT Our data provide the first description of the synaptic microcircuit of hippocampal-projecting layer II cells in the lateral entorhinal cortex. We show that these cells make infrequent monosynaptic connections with each other, and that they preferentially communicate through a disynaptic inhibitory network. This is similar to the microcircuit of hippocampal-projecting stellate cells in layer II of the medial entorhinal cortex, but dissimilar to the connectivity observed in layer 2 of neocortex. In medial entorhinal cortex, the observed network structure has been proposed to underlie the firing pattern of grid cells. This opens the possibility that layer II cells in lateral entorhinal cortex exhibit regular firing patterns in an unexplored domain.

https://ift.tt/2RFrFFK

Feature-Specific Awake Reactivation in Human V1 after Visual Training

Brain activity patterns exhibited during task performance have been shown to spontaneously reemerge in the following restful awake state. Such "awake reactivation" has been observed across higher-order cortex for complex images or associations. However, it is still unclear whether the reactivation extends to primary sensory areas that encode simple stimulus features. To address this question, we trained human subjects from both sexes on a particular visual feature (Gabor orientation) and tested whether this feature will be reactivated immediately after training. We found robust reactivation in human V1 that lasted for at least 8 min after training offset. This effect was not present in higher retinotopic areas, such as V2, V3, V3A, or V4v. Further analyses suggested that the amount of awake reactivation was related to the amount of performance improvement on the visual task. These results demonstrate that awake reactivation extends beyond higher-order areas and also occurs in early sensory cortex.

SIGNIFICANCE STATEMENT How do we acquire new memories and skills? New information is known to be consolidated during offline periods of rest. Recent studies suggest that a critical process during this period of consolidation is the spontaneous reactivation of previously experienced patterns of neural activity. However, research in humans has mostly examined such reactivation processes in higher-order cortex. Here we show that awake reactivation occurs even in the primary visual cortex V1 and that this reactivation is related to the amount of behavioral learning. These results pinpoint awake reactivation as a process that likely occurs across the entire human brain and could play an integral role in memory consolidation.

https://ift.tt/2RGfFDT

Parkinson's Disease-Linked LRRK2-G2019S Mutation Alters Synaptic Plasticity and Promotes Resilience to Chronic Social Stress in Young Adulthood

The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a prevalent cause of late-onset Parkinson's disease, producing psychiatric and motor symptoms, including depression, that are indistinguishable from sporadic cases. Here we tested how this mutation impacts depression-related behaviors and associated synaptic responses and plasticity in mice expressing a Lrrk2-G2019S knock-in mutation. Young adult male G2019S knock-in and wild-type mice were subjected to chronic social defeat stress (CSDS), a validated depression model, and other tests of anhedonia, anxiety, and motor learning. We found that G2019S mice were highly resilient to CSDS, failing to exhibit social avoidance compared to wild-type mice, many of which exhibited prominent social avoidance and were thus susceptible to CSDS. In the absence of CSDS, no behavioral differences between genotypes were found. Whole-cell recordings of spiny projection neurons (SPNs) in the nucleus accumbens revealed that glutamatergic synapses in G2019S mice lacked functional calcium-permeable AMPARs, and following CSDS, failed to accumulate inwardly rectifying AMPAR responses characteristic of susceptible mice. Based on this abnormal AMPAR response profile, we asked whether long-term potentiation (LTP) of corticostriatal synaptic strength was affected. We found that both D₁ receptor (D₁R)- and D₂R-SPNs in G2019S mutants were unable to express LTP, with D₂R-SPNs abnormally expressing long-term depression following an LTP-induction protocol. Thus, G2019S promotes resilience to chronic social stress in young adulthood, likely reflecting synapses constrained in their ability to undergo experience-dependent plasticity. These unexpected findings may indicate early adaptive coping mechanisms imparted by the G2019S mutation.

SIGNIFICANCE STATEMENT The G2019S mutation in LRRK2 causes late-onset Parkinson's disease (PD). LRRK2 is highly expressed in striatal neurons throughout life, but it is unclear how mutant LRRK2 affects striatal neuron function and behaviors in young adulthood. We addressed this question using Lrrk2-G2019S knock-in mice. The data show that young adult G2019S mice were unusually resilient to a depression-like syndrome resulting from chronic social stress. Further, mutant striatal synapses were incapable of forms of synaptic plasticity normally accompanying depression-like behavior and important for supporting the full range of cognitive function. These data suggest that in humans, LRRK2 mutation may affect striatal circuit function in ways that alter normal responses to stress and could be relevant for treatment strategies for non-motor PD symptoms.

https://ift.tt/2DrOUAa

The Avian Basal Ganglia Are a Source of Rapid Behavioral Variation That Enables Vocal Motor Exploration

The basal ganglia (BG) participate in aspects of reinforcement learning that require evaluation and selection of motor programs associated with improved performance. However, whether the BG additionally contribute to behavioral variation ("motor exploration") that forms the substrate for such learning remains unclear. In songbirds, a tractable system for studying BG-dependent skill learning, a role for the BG in generating exploratory variability, has been challenged by the finding that lesions of Area X, the song-specific component of the BG, have no lasting effects on several forms of vocal variability that have been studied. Here we demonstrate that lesions of Area X in adult male zebra finches (Taeniopygia gutatta) permanently eliminate rapid within-syllable variation in fundamental frequency (FF), which can act as motor exploration to enable reinforcement-driven song learning. In addition, we found that this within-syllable variation is elevated in juveniles and in adults singing alone, conditions that have been linked to enhanced song plasticity and elevated neural variability in Area X. Consistent with a model that variability is relayed from Area X, via its cortical target, the lateral magnocellular nucleus of the anterior nidopallium (LMAN), to influence song motor circuitry, we found that lesions of LMAN also eliminate within-syllable variability. Moreover, we found that electrical perturbation of LMAN can drive fluctuations in FF that mimic naturally occurring within-syllable variability. Together, these results demonstrate that the BG are a central source of rapid behavioral variation that can serve as motor exploration for vocal learning.

SIGNIFICANCE STATEMENT Many complex motor skills, such as speech, are not innately programmed but are learned gradually through trial and error. Learning involves generating exploratory variability in action ("motor exploration") and evaluating subsequent performance to acquire motor programs that lead to improved performance. Although it is well established that the basal ganglia (BG) process signals relating to action evaluation and selection, whether and how the BG promote exploratory motor variability remain unclear. We investigated this question in songbirds, which learn to produce complex vocalizations through trial and error. In contrast with previous studies that did not find effects of BG lesions on vocal motor variability, we demonstrate that the BG are an essential source of rapid behavioral variation linked to vocal learning.

https://ift.tt/2Ds0ISQ

Pathway-Specific Asymmetries between ON and OFF Visual Signals

Visual processing is largely organized into ON and OFF pathways that signal stimulus increments and decrements, respectively. These pathways exhibit natural pairings based on morphological and physiological similarities, such as ON and OFF α-ganglion cells in the mammalian retina. Several studies have noted asymmetries in the properties of ON and OFF pathways. For example, the spatial receptive fields (RFs) of OFF α-cells are systematically smaller than ON α-cells. Analysis of natural scenes suggests that these asymmetries are optimal for visual encoding. To test the generality of ON/OFF asymmetries, we measured the spatiotemporal RF properties of multiple RGC types in rat retina. Through a quantitative and serial classification, we identified three functional pairs of ON and OFF RGCs. We analyzed the structure of their RFs and compared spatial integration, temporal integration, and gain across ON and OFF pairs. Similar to previous results from the cat and primate, RGC types with larger spatial RFs exhibited briefer temporal integration and higher gain. However, each pair of ON and OFF RGC types exhibited distinct asymmetric relationships between RF properties, some of which were opposite to the findings of previous reports. These results reveal the functional organization of six RGC types in the rodent retina and indicate that ON/OFF asymmetries are pathway specific.

SIGNIFICANCE STATEMENT Circuits that process sensory input frequently process increments separately from decrements, so-called ON and OFF responses. Theoretical studies indicate that this separation, and associated asymmetries in ON and OFF pathways, may be beneficial for encoding natural stimuli. However, the generality of ON and OFF pathway asymmetries has not been tested. Here we compare the functional properties of three distinct pairs of ON and OFF pathways in the rodent retina and show that their asymmetries are pathway specific. These results provide a new view on the partitioning of vision across diverse ON and OFF signaling pathways.

https://ift.tt/2Dvtdz4

Corrigendum

Corrigendum to: "Patterns of Fish Reproduction at the Interface between Air and Water" by Atsushi Ishimatsu et al. Integrative & Comparative Biology 2018; doi: 10.1093/icb/icy108.

https://ift.tt/2QqOkVY

The nature of the human T cell response to the cancer antigen 5T4 is determined by the balance of regulatory and inflammatory T cells of the same antigen-specificity: implications for vaccine design

Abstract

The oncofoetal antigen 5T4 is a promising T cell target in the context of colorectal cancer, as demonstrated by a recent clinical study where 5T4-specific T cell responses, induced by vaccination or cyclophosphamide, were associated with a significantly prolonged survival of patients with metastatic disease. Whilst Th1-type (IFN-γ⁺) responses specific to 5T4, and other oncofoetal antigens, are often readily detectable in early stage CRC patients and healthy donors, their activity is suppressed as the cancer progresses by CD4⁺CD25^hiFoxp3⁺ regulatory T cells (Treg) which contribute to the immunosuppressive environment conducive to tumour growth. This study mapped the fine specificity of Th1 and Treg cell responses to the 5T4 protein. Surprisingly, both immunogenic peptides and those recognised by Tregs clustered in the same HLA-DR transcending epitope-rich hotspots within the 5T4 protein. Similarly, regions of low Th1-cell immunogenicity also did not contain peptides capable of stimulating Tregs, further supporting the notion that Treg and Th1 cells recognise the same peptides. Understanding the rules which govern the balance of Th1 and Treg cells responding to a given peptide specificity is, therefore, of fundamental importance to designing strategies for manipulating the balance in favour of Th1 cells, and thus the most effective anti-cancer T cell responses.

https://ift.tt/2PIuhFv

Increased center of pressure trajectory of the finger during precision grip task in stroke patients

Abstract

The aim of this study was to assess the spatial stability of stroke patients while holding a freely movable object. Twenty-two acute stroke patients with mild hand impairment performed a grip and lift task using the thumb and index finger. The displacement of the center of pressure (COP) trajectory, the grip force (GF) and several clinical parameters were monitored. Although the GF was not different between paretic and nonparetic hands, the COP trajectory of the paretic index finger was increased. Moreover, the COP trajectories of the thumb and index finger in hemorrhagic patients were longer than those in ischemic patients. These discrepancies between kinetic parameters suggest that different aspects of grip force control may be considered in patients with mild stroke.

https://ift.tt/2Ox2rYf

The nature of the human T cell response to the cancer antigen 5T4 is determined by the balance of regulatory and inflammatory T cells of the same antigen-specificity: implications for vaccine design

Abstract

The oncofoetal antigen 5T4 is a promising T cell target in the context of colorectal cancer, as demonstrated by a recent clinical study where 5T4-specific T cell responses, induced by vaccination or cyclophosphamide, were associated with a significantly prolonged survival of patients with metastatic disease. Whilst Th1-type (IFN-γ⁺) responses specific to 5T4, and other oncofoetal antigens, are often readily detectable in early stage CRC patients and healthy donors, their activity is suppressed as the cancer progresses by CD4⁺CD25^hiFoxp3⁺ regulatory T cells (Treg) which contribute to the immunosuppressive environment conducive to tumour growth. This study mapped the fine specificity of Th1 and Treg cell responses to the 5T4 protein. Surprisingly, both immunogenic peptides and those recognised by Tregs clustered in the same HLA-DR transcending epitope-rich hotspots within the 5T4 protein. Similarly, regions of low Th1-cell immunogenicity also did not contain peptides capable of stimulating Tregs, further supporting the notion that Treg and Th1 cells recognise the same peptides. Understanding the rules which govern the balance of Th1 and Treg cells responding to a given peptide specificity is, therefore, of fundamental importance to designing strategies for manipulating the balance in favour of Th1 cells, and thus the most effective anti-cancer T cell responses.

https://ift.tt/2PIuhFv