Effect of Lead on Human Middle Ear Epithelial Cells

Lead is a ubiquitous metal in the environment, but no studies have examined lead toxicity on the middle ear. Here, we investigated lead toxicity and its mechanism in human middle ear epithelial cells (HMEECs). Moreover, we investigated the protective effects of amniotic membrane extract (AME) and chorionic membrane extract (CME) against lead toxicity in HMEECs. Cell viability was analyzed using the cell counting kit, and reactive oxygen species (ROS) activity was measured using a cellular ROS detection kit. After lead(II) acetate trihydrate treatment, mRNA levels of various genes were assessed by semiquantitative real-time polymerase chain reaction. Following treatment with AME or CME after lead exposure, the changes in cell viability, ROS activity, and gene expression were analyzed. Exposure to >100 μg/mL of lead(II) acetate trihydrate caused a significant decrease in cell viability and increased ROS production in HMEECs. Lead exposure significantly increased the mRNA expression of genes encoding inflammatory cytokines and mucins. Administration of AME or CME restored cell viability, reduced ROS activity, and ameliorated mRNA levels. Our findings suggest that environmental lead exposure is related to the development of otitis media, and AME and CME may have antioxidative and anti-inflammatory effects against lead toxicity.

http://ift.tt/2I5gbaz

Proton pump inhibitor use and risk of hip fractures among community-dwelling persons with Alzheimer's disease—a nested case-control study

Summary

Background

Hip fractures are a major health concern among older persons with Alzheimer's disease, who usually use many concomitant drugs for several diseases. Evidence of the association between proton pump inhibitor use and risk of hip fracture is contradictory.

Aim

To investigate whether the long-term use of proton pump inhibitor is associated with risk of hip fractures among community-dwelling persons with Alzheimer's disease.

Methods

In this nested case-control study, the nationwide MEDALZ data were utilised. Community-dwelling persons with Alzheimer's disease who encountered incident hip fracture (N = 4818; mean age 84.1) were included as cases. Four controls were matched for each case at the date of hip fracture (N = 19 235; mean age 84.0). The association between hip fracture and duration of current PPI use (ongoing use during 0-30 days before the index date), and cumulative duration of use during 10 years before was investigated with conditional logistic regression.

Results

Long-term or cumulative proton pump inhibitor use was not associated with an increased risk of hip fracture. Current proton pump inhibitor use was associated with an increased risk of hip fracture (adjusted OR 1.12, 95% CI 1.03-1.22). The risk was increased in short-term current use (<1 year) (adjusted OR 1.23, 95% CI 1.10-1.37).

Conclusions

The increased risk of hip fracture was evident only in short-term proton pump inhibitor use, but no association was found for long-term or cumulative use. Thus, our findings do not support previous assumptions that long-term proton pump inhibitor use would be associated with an increased risk of hip fractures.

http://ift.tt/2I65VPd

On the Electron-Transfer Mechanism in the Contact-Electrification Effect

Abstract

A long debate on the charge identity and the associated mechanisms occurring in contact-electrification (CE) (or triboelectrification) has persisted for many decades, while a conclusive model has not yet been reached for explaining this phenomenon known for more than 2600 years! Here, a new method is reported to quantitatively investigate real-time charge transfer in CE via triboelectric nanogenerator as a function of temperature, which reveals that electron transfer is the dominant process for CE between two inorganic solids. A study on the surface charge density evolution with time at various high temperatures is consistent with the electron thermionic emission theory for triboelectric pairs composed of Ti–SiO₂ and Ti–Al₂O₃. Moreover, it is found that a potential barrier exists at the surface that prevents the charges generated by CE from flowing back to the solid where they are escaping from the surface after the contacting. This pinpoints the main reason why the charges generated in CE are readily retained by the material as electrostatic charges for hours at room temperature. Furthermore, an electron-cloud–potential-well model is proposed based on the electron-emission-dominatedcharge-transfer mechanism, which can be generally applied to explain all types of CE in conventional materials.

Real-time charge transfer in contact electrification (CE) is investigated quantitatively as a function of temperature via a triboelectric nanogenerator, revealing that electron transfer is the dominant process for CE between two inorganic solids. An electron-cloud–potential-well model is proposed for understanding all types of CE in conventional materials.

http://ift.tt/2FvqXIO

Learning dynamic control of body yaw orientation

Abstract

To investigate the role of gravitational cues in the learning of a dynamic balancing task, we placed blindfolded subjects in a device programmed with inverted pendulum dynamics about the yaw axis. Subjects used a joystick to try and maintain a stable orientation at the direction of balance during 20 100 s-long trials. They pressed a trigger button on the joystick to indicate whenever they felt at the direction of balance. Three groups of ten subjects each participated. One group balanced with their body and the yaw axis vertical, and thus did not have gravitational cues to help them to determine their angular position. They showed minimal learning, inaccurate indications of the direction of balance, and a characteristic pattern of positional drifting away from the balance point. A second group balanced with the yaw axis pitched 45° from the gravitational vertical and had gravity relevant position cues. The third group balanced with their yaw axis horizontal where they had gravity-dependent cues about body position in yaw. Groups 2 and 3 showed better initial balancing performance and more learning across trials than Group 1. These results indicate that in the absence of vision, the integration of transient semicircular canal and somatosensory signals about angular acceleration is insufficient for determining angular position during dynamic balancing; direct position-dependent gravity cues are necessary.

http://ift.tt/2tkHLgz

Systematic review: adrenal insufficiency secondary to swallowed topical corticosteroids in eosinophilic oesophagitis

Summary

Background

Swallowed topical corticosteroids are prescribed for eosinophilic oesophagitis (EoE), but there is a theoretical risk of adrenal insufficiency from their use.

Aims

To determine if the use of topical corticosteroids to treat EoE is associated with the development of adrenal insufficiency.

Method

We conducted a systematic review of the published literature from January 1, 1950 to April 1, 2017 using Pubmed, Embase, Web of Science and Cochrane Central. Studies and meeting abstracts were included that described patients with EoE who received swallowed topical corticosteroids and any investigation for adrenal insufficiency.

Results

The search revealed 1610 unique publications, and 17 met inclusion criteria. There were 7 randomised controlled trials (RCTs), 6 prospective observational studies, 3 retrospective observational studies, and 1 case report. Cortisol measurements were performed on 596 individuals with EoE who received topical corticosteroids. Adrenal testing was abnormal, as defined by each study, in 94/596 patients (crude rate of 15.8%). Only 2 studies were considered to have a low risk of bias, being randomised controlled trials that estimated adrenal insufficiency in the active treatment and placebo groups, before and after treatment. None of the seven randomised controlled trials demonstrated statistically significantly different rates of adrenal insufficiency between topical corticosteroid and placebo over treatment intervals of 2-12 weeks.

Conclusion

Topical corticosteroids were associated with adrenal insufficiency in a minority of patients. Most cases came from uncontrolled observational studies, with widely varying definitions of adrenal insufficiency. Longer follow-up and larger controlled studies are needed to quantify the risk of adrenal insufficiency with maintenance topical corticosteroid therapy in EoE.

http://ift.tt/2D1Z9q6

Faecal calprotectin effectively excludes inflammatory bowel disease in 789 symptomatic young adults with/without alarm symptoms: a prospective UK primary care cohort study

Summary

Background

Primary care faecal calprotectin testing distinguishes inflammatory bowel disease (IBD) from functional gut disorder in young patients presenting with abdominal symptoms; however, previous evaluations have excluded patients with alarm symptoms.

Aims

We sought to evaluate the diagnostic accuracy of calprotectin to distinguish IBD from functional gut disorder in young adults in whom general practitioners (GPs) suspected IBD; including patients reporting gastrointestinal alarm symptoms. We hypothesised that calprotectin would reduce secondary care referrals and healthcare costs.

Methods

We undertook a prospective cohort study of 789 young adults (18-46 years old) presenting with gastrointestinal symptoms to 49 local general practices that had undergone calprotectin testing (1053 tests: between Jan 2014 and May 2016) because of suspected IBD. We considered calprotectin levels of ≥100 μg/g positive. Primary and secondary care records over 12 months from the point of calprotectin testing were used as the reference standard.

Results

Overall, 39% (308/789) patients reported gastrointestinal alarm symptoms and 6% (50/789) tested patients were diagnosed with IBD. The positive and negative predictive values of calprotectin testing for distinguishing IBD from functional gut disorder in patients with gastrointestinal alarm symptoms were 50% (95% CI 36%-64%) and 98% (96%-100%): and in patients without gastrointestinal alarm symptoms were 27% (16%-41%) and 99% (98%-100%), respectively. We estimate savings of 279 referrals and £160 per patient.

Conclusions

Calprotectin testing of young adults with suspected IBD in primary care accurately distinguishes IBD from functional gut disorder, even in patients with gastrointestinal alarm symptoms and reduces secondary care referrals and diagnostic healthcare costs.

http://ift.tt/2FXSGQ6

Current Treatment Options: Headache Related to Menopause—Diagnosis and Management

Abstract

Purpose of review

Menopause is a life-changing event in numerous ways. Many women with migraine hold hope that the transition to the climacteric state will coincide with a cessation or improvement of migraine. This assumption is based mainly on common lay perceptions as well as assertions from many in the healthcare community. Unfortunately, evidence suggests this is far from the rule. Many women turn to a general practitioner or a headache specialist for prognosis and management. A natural instinct is to manipulate the offending agent, but in some cases, this approach backfires, or the concern for adverse events outweighs the desire for a therapeutic trial, and other strategies must be pursued. Our aim was to review the frequency and type of headache syndromes associated with menopause, to review the evidence for specific treatments for headache associated with menopause, and to provide management recommendations and prognostic guidance.

Recent findings

We reviewed both clinic- and population-based studies assessing headache associated with menopause. Headache in menopause is less common than headache at earlier ages but can present a unique challenge. Migraine phenotype predominates, but presentations can vary or be due to secondary causes. Other headache types, such as tension-type headache (TTH) and cluster headache (CH) may also be linked to or altered by hormonal changes. There is a lack of well-defined diagnostic criteria for headache syndromes associated with menopause. Women with surgical menopause often experience a worse course of disease status than those with natural menopause. Hormonal replacement therapy (HRT) often results in worsening of migraine and carries potential for increased cardiovascular and ischemic stroke risk. Estrogen replacement therapy (ERT) in patients with migraine with aura (MA) may increase the risk of ischemic stroke; however, the effect is likely dose-dependent. Some medications used in the prophylaxis of migraine may be useful in ameliorating the vasomotor and mood effects of menopause, including venlafaxine, escitalopram, paroxetine, and gabapentin. Other non-medication strategies such as acupuncture, vitamin E, black cohosh, aerobic exercise, and yoga may also be helpful in reducing headache and/or vasomotor symptoms associated with menopause.

Summary

The frequency and type of headache associated with menopause is variable, though migraine and TTH are most common. Women may experience a worsening, an improvement, or no change in headache during the menopausal transition. Treatment may be limited by vascular risks or other medical and psychiatric factors. We recommend using medications with dual benefit for migraine and vasomotor symptoms including venlafaxine, escitalopram, paroxetine, and gabapentin, as well as non-medication strategies such as acupuncture, vitamin E, black cohosh, aerobic exercise, and yoga.

If HRT is pursued, continuous (rather than cyclical) physiological doses should be used, transdermal route of administration is recommended, and the patient should be counseled on the potential for increased risk of adverse events (AEs). Concomitant use of a progestogen decreases the risk of endometrial hyperplasia with ERT. Biological mechanisms are incompletely understood, and there is a lack of consensus on how to define and classify headache in menopause. Further research to focus on pathophysiology and nuanced management is desired.

http://ift.tt/2FdYR5A

Model-based Dosage Individualization of Ganciclovir in Neonates and Young Infants with Congenital Cytomegalovirus Infection: A Pilot Study [PublishAheadOfPrint]

Background: Newborns with congenital cytomegalovirus (CMV) infection are at high risk for developing permanent sequelae. Intravenous ganciclovir therapy is frequently used for the treatment of congenital CMV infection. Target area under the concentration versus time curve (AUC_0–24) of 40-50 μg·h/mL is recommended. The standard dose resulted in a large variability in ganciclovir exposure in newborns, indicating the unmet need of dosage individualization in this vulnerable population, but the implementation of this strategy remains challenging in clinical practice. We aim to evaluate the clinical utility of model-based dosage individualization of ganciclovir in newborns using an opportunistic sampling approach.

Methods: The predictive performance of a published ganciclovir population pharmacokinetic model was evaluated using an independent patient cohort. The individual dose was adjusted based on the target AUC_0-24 to ensure the efficacy.

Results: A total of 26 newborns with congenital CMV infection were included in the present study. Only 11 (42.3%) patients achieved the target AUC_0-24 after giving the standard dose. For all the subtherapeutic (below 80% target AUC) patients (n=5), model-based dosage adjustment was performed using Bayesian estimation method combined with the opportunistic sampling strategy. The adjusted doses were increased 28.6% - 60.0% in these five patients and all adapted AUC_0–24 achieved the target (range: 48.6-66.1 μg·h/mL).

Conclusion: The clinical utility of model-based dosing individualization of ganciclovir was demonstrated in newborns with congenital CMV infection. Population pharmacokinetic model combined with the opportunistic sampling strategy provides a clinical feasible method to adapt ganciclovir dose in neonatal clinical practice.

http://ift.tt/2D273Qr

Relebactam (MK-7655) in combination with imipenem: Exploring the pharmacokinetic/pharmacodynamic relationship with a hollow fiber infection model [PublishAheadOfPrint]

Resistance to antibiotics among bacterial pathogens is rapidly spreading and therapeutic options against multidrug-resistant bacteria are limited. There is an urgent need for new drugs, especially those that can circumvent the broad array of resistance pathways that bacteria have evolved. In this study, we assessed the pharmacokinetic/pharmacodynamic relationship of the novel β-lactamase inhibitor relebactam (MK-7655; REL) in a hollow fiber infection model. REL is intended for use with the carbapenem β-lactam antibiotic imipenem for the treatment of Gram-negative bacterial infections. In this study, we used an in vitro hollow fiber infection model to confirm the efficacy of human exposures associated with the Phase 2 doses (imipenem 500 mg + REL 125 or 250 mg administered intravenously every 6 hours as a 30-minute infusion) against imipenem-resistant strains of Pseudomonas aeruginosa and Klebsiella pneumoniae. Dose fractionation experiments confirmed that the pharmacokinetic parameter best correlated with REL activity is the area under the concentration-time curve, consistent with findings in a murine pharmacokinetic/pharmacodynamic model. Determination of the pharmacokinetic/pharmacodynamic relationship between β-lactam antibiotics and β-lactamase inhibitors is complex as there is an interdependence between their respective exposure-response relationships. Here, we show that this interdependence could be captured by treating the minimum inhibitory concentration (MIC) of imipenem as dynamic: it changes with time and this change is directly related to REL levels. For the strains tested, the percentage of time above dynamic MIC for imipenem was maintained at the carbapenem target of 30-40%, required for maximum efficacy, for imipenem 500 mg plus REL 250 mg.

http://ift.tt/2FXC8aP

Native human monoclonal antibodies with potent cross-lineage neutralization of influenza B viruses [PublishAheadOfPrint]

Although antibodies that effectively neutralize a broad set of influenza viruses exist in the human antibody repertoire, they are rare. We used a single cell screening technology to identify rare monoclonal antibodies (mAbs) that recognized a broad set of influenza B viruses (IBV). The screen yielded 23 mAbs with diverse germ line origins that recognized hemagglutinins (HAs) derived from influenza strains of both the Yamagata and Victoria lineages of IBV. Of the 23 mAbs, three exhibited low expression in a transient transfection system, four were neutralizers that bound to the HA head region, eleven were stalk-binding non-neutralizers, and five were stalk-binding neutralizers with four of these five representing unique antibody sequences. Of these four unique stalk-binding neutralizing mAbs, all were broadly reactive and neutralizing against a panel of multiple strains spanning both IBV lineages as well as highly effective in treating lethal IBV infections in mice at both 24 and 72 hours post-infection. The mAbs in this group were thermostable and bound different epitopes in the highly conserved HA stalk region. These characteristics suggest these mAbs are suitable for consideration as candidates for clinical studies to address effectiveness in treating of IBV infected patients.

http://ift.tt/2D3Ffeg

P174E substitution in GES-1 and GES-5 {beta}-lactamases improves catalytic efficiency towards carbapenems [PublishAheadOfPrint]

GES-type β-lactamases are a group of enzymes that have evolved their hydrolytic activity towards carbapenems. In this study the role of residue 174 inside the -loop of GES-1 and GES-5 was investigated. GES-1^P174E and GES-5^P174Emutants, selected by site-saturation mutagenesis, were purified and kinetically characterized. Comparing with GES-1 and GES-5 wild-type enzymes, GES-1^P174E and GES-5^P174E mutants exhibited lower k_cat and k_cat/K_m values for cephalosporins and penicillins. Concerning carbapenems, the two mutants shared higher k_cat values but lower K_m values respect to those calculated for GES-1 and GES-5. The GES-1^P174E and GES-5^P174E showed high hydrolytic efficiency for imipenem with k_cat/K_m values 100- and 660-fold higher than GES-1. Clavulanic acid and tazobactam are good inhibitors for both GES-1^P174E and GES-5^P174E. Molecular dynamic simulations (MDs) carried out for GES-1, GES-5, GES-1^P174E and GES-5^P174E complexed with imipenem and meropenem have shown that mutation at position 174 induces a drastic increase of enzymes flexibility, in particular in the -loop. The CD spectroscopy spectra of the four enzymes indicates that substitution P174E in GES-1 and GES-5 does not affect the secondary structural content of the enzymes.

http://ift.tt/2FVPKn2

Elevated MIC values to imidazole drugs among Aspergillus fumigatus isolates with TR34/L98H/S297T/F495I mutation [PublishAheadOfPrint]

Use of azole fungicides in agriculture is believed to be one of the main reasons for the emergence of azole resistance in Aspergillus fumigatus. Although widely used in agriculture, imidazole fungicides have not been linked to resistance in A. fumigatus. This study showed that elevated MIC values to imidazole drugs were observed among A. fumigatus isolates with TR₃₄/L98H/S297T/F495I mutation, but not among isolates with TR₃₄/L98H mutation. The STR typing analysis of 580 A. fumigatus isolates from 20 countries suggested that the majority of TR₃₄/L98H/S297T/F495I strains from China were genetically different from the predominated major clade consisted of most of the azole resistant strains and the strains with the same mutation from the Netherlands and Denmark. Alignments of sterol 14α-demethylase sequences implicated that F495I in A. fumigatus was orthologous to F506I in Penicillium digitatum and F489L in Pyrenophora teres, which have been reported to be associated with imidazole resistance. The in vitro antifungal susceptibility testing of different recombinants of cyp51A mutations further confirms the association of F495I mutation with imidazole resistance. In conclusion, this study suggested that environmental use of imidazole fungicides might confer selection pressure for the emergence of azole resistance in A. fumigatus.

http://ift.tt/2D3F7LO

Heavy metal resistance genes are associated with blaNDM-1 and blaCTX-M-15-Enterobacteriaceae [PublishAheadOfPrint]

The occurrence of heavy metal resistance genes in multi-resistant Enterobacteriaceae possessing bla_NDM-1 or bla_CTX-M-15 genes were examined by PCR and S1-PFGE. When compared with clinical susceptible isolates (10.0-30.0%), the pcoA, merA, silC and arsA genes occurred with higher frequencies in bla_NDM-1 (48.8-71.8%) and bla_CTX-M-15 (19.4-52.8%) positive isolates, and they are mostly located on plasmids. Given the high association of metal resistance genes with multidrug resistant Enterobacteriaceae, the use of heavy metals in hospitals and the environment needs increased vigilance.

http://ift.tt/2FXGIGa

Population pharmacokinetics of piperacillin in septic patients - should alternative dosing strategies be considered? [PublishAheadOfPrint]

Sufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin/tazobactam is often used for empiric treatment but due to the pharmacokinetic (PK) variability seen in septic patients, optimal dosing may be a challenge. We determined the PK profile for piperacillin 4g every 8h in 22 septic patients admitted to a medical ward. Piperacillin concentrations were compared to clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/L) and the following PK/PD targets were evaluated: 50% f T>MIC and 100% f T>MIC. A two-compartment population PK model described the data well, with clearance divided into renal and non-renal components. The renal component was proportional to the estimated creatinine clearance (eCL_Cr), and constituted 74% of the total clearance in a typical individual (eCL_Cr of 83.9 mL/min). Patients with high eCL_Cr (>130 mL/min) were at risk of sub-therapeutic concentrations for the current regimen, with 90% PTA reached at MICs of 2.0 (50% f T>MIC) and 0.125 mg/L (100% f T>MIC). Simulations of alternative dosing regimens and modes of administration showed that dose increment and prolonged infusion increased the chance of achieving pre-defined PK/PD targets. Alternative dosing strategies may therefore be needed to optimize piperacillin exposure in septic patients.

http://ift.tt/2FVQ3OI

Spread of Plasmid-Encoded NDM-1 and GES-5 Carbapenemases among Extensively Drug-Resistant and Pandrug-Resistant Clinical Enterobacteriaceae in Durban, South Africa [PublishAheadOfPrint]

Whole-genome sequence analyses revealed the presence of bla_NDM-1 (n=31), bla_GES-5 (n=8), bla_OXA-232 (n=1), or bla_NDM-5 (n=1) in extensively drug-resistant and pandrug-resistant Enterobacteriaceae isolated from in-patients in 10 private hospitals (2012-2013) in Durban, South Africa. Two novel NDM-1 encoding plasmids from Klebsiella pneumoniae were closed by PacBio sequencing. In p19-10_01 (IncFIB(K), 223.434 bp) bla_NDM-1 was part of a Tn1548-like structure (16.276 bp) delineated by IS26. The multireplicon plasmid p18-43_01 (IncR_1/IncFIB(pB171)/IncFII(Yp); 212.326 bp) shared an 80-kb region with p19-10_01, not including the bla_NDM-1 containing region. The two plasmids were used as references for tracing NDM-1 encoding plasmids in the other genome assemblies. The p19-10_01 sequence was detected in K. pneumonia (n=7) only. Whereas p18-43_01 was tracked to K. pneumoniae (n=4), Klebsiella michiganensis (n=1), Serratia marcescens (n=11), Enterobacter spp. (n=7), and Citrobacter freundii (n=1), revealing horizontal spread of this bla_NDM-1-bearing plasmid structure. Global phylogeny showed clustering of the K. pneumoniae (18/20) isolates together with closely related carbapenemase-negative ST101 isolates from other geographical origin. The South African isolates divided into three phylogenetic sub-branches, where each group had distinct resistance and replicon profile, and Fig. carrying either p19-10_01, p18-10_01 or pCHE-A1 (8201 bp). The latter carrying bla_GES-5 and aacA4 within an integron mobilization unit. Our findings imply independent plasmid acquisition followed by local dissemination. Additionally, we detected bla_OXA-232 carried by pPKPN4 in K. pneumoniae (ST14) and bla_NDM-5 contained by a pNDM-MGR194-like genetic structure in Escherichia coli (ST167), adding even more complexity to the multilayer molecular mechanisms behind nosocomial spread of CRE in Durban, South Africa.

http://ift.tt/2FW2yK6

Pneumonia and renal replacement therapy are risk factors for ceftazidime-avibactam treatment failures and resistance among patients with carbapenem-resistant Enterobacteriaceae infections [PublishAheadOfPrint]

Ceftazidime-avibactam was used to treat 77 patients with carbapenem-resistant Enterobacteriaceae (CRE) infections at our center. Thirty- and 90-day survival rates were 81% and 69%, respectively; rates were higher than predicted by SAPS II and SOFA scores at the onset of infection. Clinical success was achieved in 55% of patients, but varied by site of infection. Success rates were lowest for pneumonia (36%) and higher for bacteremia (75%) and urinary tract infections (88%). By multivariate analysis, pneumonia (P=0.045) and receipt of renal replacement therapy (RRT; P=0.046) were associated with clinical failure. Microbiologic failures occurred in 32% of patients, and occurred more commonly among patients infected with KPC-3-producing than KPC-2-producing CRE (P=0.002). Pneumonia was an independent predictor of microbiologic failures (P=0.007). Ceftazidime-avibactam resistance emerged in 10% of patients, including 14% infected with Klebsiella pneumoniae and 32% with microbiologic failures. RRT was an independent predictor for the development of resistance (P=0.009). Resistance was identified exclusively among K. pneumoniae harboring variant KPC-3 enzymes. Upon phylogenetic analysis of whole genome sequences, resistant isolates from 87.5% (7/8) of patients clustered within a previously defined sequence type (ST)258, clade II sub-lineage; resistant isolates from one patient clustered independently from other ST258, clade II isolates. In conclusion, our report offers new insights into the utility and limitations of ceftazidime-avibactam across CRE infection types. Immediate priorities are to identify ceftazidime-avibactam dosing and therapeutic regimens that improve upon the poor outcomes among patients with pneumonia, and in those receiving RRT.

http://ift.tt/2FgDvQY

Blocking the ART2.2/P2 × 7-system is essential to avoid a detrimental bias in functional CD4 T cell studies

http://ift.tt/2oSg4GI

Charting the Future of Cancer Health Disparities Research—Letter

http://ift.tt/2oRXXR3

The Molecular Chaperone HSP90 Promotes Notch Signaling in the Germline of Caenorhabditis elegans

In a genetic screen to identify genes that promote GLP-1/Notch signaling in Caenorhabditis elegans germline stem cells, we found a single mutation, om40, defining a gene called ego-3. ego-3(om40) causes several defects in the soma and the germline, including paralysis during larval development, sterility, delayed proliferation of germline stem cells, and ectopic germline stem cell proliferation. Whole genome sequencing identified om40 as an allele of hsp-90, previously known as daf-21, which encodes the C. elegans ortholog of the cytosolic form of HSP90. This protein is a molecular chaperone with a central position in the protein homeostasis network, which is responsible for proper folding, structural maintenance, and degradation of proteins. In addition to its essential role in cellular function, HSP90 plays an important role in stem cell maintenance and renewal. Complementation analysis using a deletion allele of hsp-90 confirmed that ego-3 is the same gene. hsp-90(om40) is an I->N conservative missense mutation of a highly conserved residue in the middle domain of HSP-90. RNA interference-mediated knockdown of hsp-90 expression partially phenocopied hsp-90(om40), confirming the loss-of-function nature of hsp-90(om40). Furthermore, reduced HSP-90 activity enhanced the effect of reduced function of both the GLP-1 receptor and the downstream LAG-1 transcription factor. Taken together, our results provide the first experimental evidence of an essential role for HSP90 in Notch signaling in development.

http://ift.tt/2FhCJHh

Effectiveness of Various Isometric Exercises at Improving Bone Strength in Cortical Regions Prone to Distal Tibial Stress Fractures

Abstract

A computational model was used to compare the local bone strengthening effectiveness of various isometric exercises that may reduce the likelihood of distal tibial stress fractures. The developed model predicts local endosteal and periosteal cortical accretion and resorption based on relative local and global measures of the tibial stress state and its surface variation. Using a multisegment three-dimensional leg model, tibia shape adaptations due to thirty-three combinations of hip, knee, and ankle joint angles and the direction of a single or sequential series of generated isometric resultant forces were predicted. The maximum stress at a common fracture prone region in each optimized geometry was compared under likely stress fracture-inducing midstance jogging conditions. No direct correlations were found between stress reductions over an initially uniform circular hollow cylindrical geometry under these critical design conditions and the exercise-based sets of active muscles, joint angles, or individual muscle force and local stress magnitudes. Additionally, typically favorable increases in cross-sectional geometric measures did not guarantee stress decreases at these locations. Instead, tibial stress distributions under the exercise conditions best predicted strengthening ability. Exercises producing larger anterior distal stresses created optimized tibia shapes that better resisted the high midstance jogging bending stresses. Bent leg configurations generating anteriorly-directed or inferiorly-directed resultant forces created favorable adaptations. None of the studied loads produced by a straight leg was significantly advantageous. These predictions and the insight gained can provide preliminary guidance in the screening and development of targeted bone strengthening techniques for those susceptible to distal tibial stress fractures.

http://ift.tt/2FfUuGY

A phase II trial to evaluate the efficacy of panitumumab combined with fluorouracil-based chemotherapy for metastatic colorectal cancer: the PF trial

Abstract

Purpose

Fluorouracil monotherapy, instead of the FOLFOX or FOLFIRI regimen, is administered to patients intolerant to oxaliplatin or irinotecan because of their adverse effects. A prospective clinical trial was designed to evaluate the efficacy and safety of fluorouracil monotherapy combined with panitumumab administered to patients with KRAS wild-type (WT) metastatic colorectal cancer (mCRC) intolerant to oxaliplatin and irinotecan. Screening for potential serum biomarkers to predict early therapeutic responses was conducted.

Methods

This single-arm, open-label multicenter phase II trial recruited patients with KRAS WT mCRC from 16 institutes between January 2012 and October 2014. Panitumumab (6 mg/kg) was intravenously administered every 2 weeks, combined with fluorouracil monotherapy, in 2-week cycles. The primary objective was overall response rate, and secondary endpoints included disease-control rate, progression-free survival, overall survival, toxicity, and blood-test data.

Results

Forty patients (male, 65.0%; median age, 74 years; colon cancer, 72.5%) met eligibility criteria and received 7 cycles (median) of fluorouracil chemotherapy combined with panitumumab. There were no treatment-related deaths. Median time to treatment failure was 3.2 months. 23 (57.5%) patients experienced at least one adverse effect ≥ grade 3. The response rate was 10.0% (95% confidence interval 2.8–23.7%). Median progression-free survival and overall survival were 4.3 and 11.3 months, respectively. Total lactase dehydrogenase (LDH) levels and those of LDH-4 and LDH-5, quickly changed with disease reduction or progression.

Conclusions

Fluorouracil monotherapy combined with panitumumab was safely administered to patients with KRAS WT mCRC intolerant to oxaliplatin and irinotecan. Serum LDH levels may predict early responses.

http://ift.tt/2Fh6uEc

The importance of body mass normalisation for ultrasound measurements of the morphology of oblique abdominis muscles: the effect of age, gender, and sport practice

Some studies have not considered body mass as a confounder in analysis of oblique abdominis muscles (OAM) (including the oblique externus [OE] and oblique internus [OI]), which may have led to improper interpretation of results. To assess the differences in the effect of age, gender, and physical activity between normalised for body mass and actual values of the OAM as well as to establish the effect of age, gender, and physical activity on normalised for body mass OAM thicknesses in adolescents. A real-time ultrasound was used to obtain images of the OAM. Body mass normalisation for OAM thicknesses was performed with allometric scaling and the following equations: Allometric-scaled OE = OE thickness/body mass0.88; Allometric-scaled OI = OI thickness/body mass0.72. Analysis showed that boys have significantly thicker OAM than girls, and those who practise sports have thicker OAM than non-active individuals. For allometric-scaled OAM, there was only a significant gender effect, where boys have thicker allometric-scaled OAM than girls. There was a significant correlation between participants' age and the actual value of the OAM. The correlations between age and allometric-scaled OAM were insignificant. An analysis of OAM without body mass normalisation can lead to improper interpretation of study results. Thus, future studies should analyse OE and OI thickness measurements after normalisation rather than actual values. In the adolescent population, there is no effect of age and physical activity on allometric-scaled OAM; males have thicker allometric-scaled OAM than females. (Folia Morphol 2018; 77, 1: 123–130)

http://ift.tt/2Fggfq2

The impact of pelvicalyceal anatomy on the stone formation in patients with lower pole renal stones

Background: The aim of our study was to determine whether various anatomic factors constitute a predisposition to a lower pole renal stones.

Materials and methods: We analysed the computed tomography (CT) urography of 75 patients with a single lower pole stone. Measurements were taken of the infundibulopelvic angle (IPA), infundibular width (IW), infundibular length (IL) and calyceopelvic height (CPH).

Results: The mean patient age was 50 years (range 17–79 years). The mean stone size was 11.9 mm. The mean IPA using Sampaio method in affected kidney was 113.4 ± 15.3o (range 80–139o), 59.5 ± 17.3o using Elbahnasy method. The values of IPA on the contralateral kidney were 119.86 ± 15.37o (range 79–141o; p = = 0.001) using Sampaio method of measurement and 59.78 ± 12o (range 34–90 o; p = 0.465) using the method described by Elbahnasy. We reported statistically significant differences between stone-bearing kidney and contralateral kidney in measurement IPA using only Sampaio method. The mean infundibular width was 4.22 ± 1.81 mm on the affected kidney and 3.72 ± 2.5 mm on the contralateral side (p = 0.164). The mean infundibular length was 15.37 ± 4.57 mm on the affected kidney and 14.66 ± 4.35 mm on the unaffected side (p = 0.329). The CPH was 10.19 ± 4.05 mm on the affected kidney and 10.44 ± 3.83 mm on the normal side (p = 0.688).

Conclusions: Pelvicalyceal morphology of the kidney is one of the factors that determine the risk of developing kidney stones. Out of the analysed morphological parameters of kidney IPA is a statistically significant risk factor to form lower pole kidney stones. Other anatomic parameters did not seem to have a significant role in predisposing to form lower pole kidney stone. (Folia Morphol 2018; 77, 1: 16–21)  

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Protective effect of garlic extract against maternal and foetal cerebellar damage induced by lead administration during pregnancy in rats

Background: In spite of its industrial usefulness and varied daily uses, lead (Pb) pollution is a widespread ecological problem that faces the humans in the 21th century. Pb was found to produces a wide range of toxic effects including neurotoxicity especially to the developing and young offspring. Recently, the utilisation of herbal plants has received a significant attention where there has been rising awareness in their therapeutic use; among these is the garlic. In light of the above, the current study is designed experimentally in female pregnant rats in order to investigate the beneficial role of garlic extract in the protection from the maternal and foetal cerebellar damage produced by administration of different doses of Pb during pregnancy.

Materials and methods: Positively pregnant female rats were divided into five groups; one control group, two Pb-treated groups (exposed to 160 and 320 mg/kg b.w. of Pb, respectively) and two groups treated with both Pb and garlic (exposed to Pb as previous groups together with 250 mg/kg b.w./day of garlic extract). Treatments started from day 1 to day 20 of pregnancy, where the mother rats of different experimental groups were sacrificed to obtain the foetuses. Pb level in the maternal and foetal blood and cerebellum was estimated by spectrophotometry. Specimens of the cerebellum of different mother and foetal groups were processed to histological and immunohistochemical staining for microscopic examination.

Results: The results showed that administration of Pb to pregnant rats resulted in a dose-dependent toxicity for both mothers and foetuses in the form of decrease in maternal weight gain, placental and foetal weights, brain weight and diminished foetal growth parameters, which were prominent in rat's group treated with larger dose of Pb. In Pb-treated rats, Pb level in blood and cerebellum was high when compared with the control group. The histopathological examination of the cerebellum of treated dams and foetuses showed marked alterations mainly in the form of Purkinje cell degeneration and lack of development of foetal cerebellum. Co-treatment of garlic extract along with Pb resulted in a significant decrease in Pb levels as compared with those treated with Pb alone with improvement of the histopathological changes.

Conclusions: This study was useful in evaluating the hazardous effects of uncontrolled use of Pb in general and in assessing the developmental and neurotoxicity of foetuses due to exposure during pregnancy in particular. Co-administration of garlic has beneficial effects in amelioration of Pb-induced neurotoxicity and reversing the histopathological changes of the cerebellum of mother rats and foetuses. (Folia Morphol 2018; 77, 1: 1–15)

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The effect of anatomic differences on the relationship between renal artery and diaphragmatic crus

Background: The aim of this study is to investigate the effect of anatomic differences on the relationship between renal artery and diaphragmatic crus via the touch of two structures. Materials and methods: The study included dynamic computed tomography (CT) scans of 308 patients performed mainly for characterisation of liver and renal masses. Anatomic differences including the thickness of the diaphragmatic crus, the localisation of renal artery ostium at the wall of aorta, the level of renal artery origin with respect to superior mesenteric artery were evaluated. Statistical relationships between renal artery-diaphragmatic crus contact and the anatomic differences were assessed.

Results: Thickness of the diaphragmatic crus at the level of renal artery origin exhibited a statistically significant relationship to renal artery-diaphragmatic crus contact at the left (p < 0.001) and right side (p < 0.001). There was a statistically significant relationship between high renal artery origin and renal artery- -diaphragmatic crus contact at the left (p < 0.001) and right side (p = 0.01). The localisation of renal artery ostium at the wall of aorta (right side, p = 0.436, left side, p = 0.681) did not demonstrate a relationship to renal artery-diaphragmatic crus contact.

Conclusions: Thickness of the diaphragmatic crus and high renal artery origin with respect to superior mesenteric artery are crucial anatomic differences determining the relationship of renal artery and diaphragmatic crus. (Folia Morphol 2018; 77, 1: 22–28)  

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Co-existence of the double inferior vena cava with complex interiliac venous communication and aberrant common hepatic artery arising from superior mesenteric artery: a case report

Variations of the arterial and venous system of the abdomen and pelvis have important clinical significance in hepatobiliary surgery, abdominal laparoscopy, and radiological intervention. A case of double inferior vena cava (IVC) with complex interiliac communication and variation of the common hepatic artery (CHA) arising from superior mesenteric artery (SMA) in a 79-year-old male cadaver is presented. Both IVCs ascended on either side of the abdominal aorta. The left-sided IVC crossed anterior to the aorta at the level of the left renal vein. The union of both IVCs was at the level just above the right renal vein. The diameter of right-sided IVC, left-sided IVC and the common IVC were 16.73 mm, 21.57 mm and 28.75 mm, respectively. In the pelvic cavity, the right common iliac vein was formed by a union of right external and internal iliac veins while the formation of left common iliac vein was from the external iliac vein and two internal iliac veins. An interiliac vein ran from right internal iliac vein to left common iliac vein with an additional communicating vein running from the middle of this interiliac vein to the right common iliac vein. Another co-existence variation in this case was the origin of the CHA arising from the SMA with a suprapancreatic retroportal course. Clinical importance of double IVC are observed in retroperitoneal surgery, whole organ transplantation or radical nephrectomy, surgical ligation of the IVC or the placement of an IVC filter for thromboembolic disease. The variation of CHA has an important clinical significance in liver transplantation, abdominal laparoscopy and radiological abdominal intervention. (Folia Morphol 2018; 77, 1: 151–155)

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The supreme turbinate and the drainage of the posterior ethmoids: a computed tomographic study

Background: It is generally acknowledged that the posterior ethmoidal cells drain under the superior nasal turbinate (SorNT) or, rarely, under the supreme nasal turbinate (SmeNT), and the sphenoid ostium (SO) opens to the sphenoethmoidal recess. However, detailed relations between these structures are variable, complex and still not clear. There is no reliable data on the prevalence of SmeNT and drainage of the posterior ethmoidal cells under this structure. The aim of this study was to re-evaluate the anatomy of the aforementioned region.

Materials and methods: Multiplanar and three-dimensional reconstruction analysis of 100 thin slice paranasal sinus computed tomography scans.

Results: SmeNT was identified in 77 subjects (136 sides). It formed the ostium to the posterior ethmoidal cell adjacent to the skull base or orbit in 58 subjects (91 sides). This cell drained independently from the remaining posterior ethmoidal cells. The sphenoethmoidal (Onodi) cell drained to supreme meatus in 41 subjects (54 sides), and to superior meatus in 37 subjects (49 sides). SO was always located medial to the posteroinferior attachment of SmeNT, or SorNT (in absence of SmeNT).

Conclusions: Patients with divergent drainage of the posterior ethmoids (with posterior ethmoidal cell draining to the supreme meatus) may require more extensive surgery to avoid persistence or recurrence of inflammatory disease. SmeNT is more common than thought, but due to its posterior and superior location to SorNT, it is rarely seen intraoperatively. If SmeNT is present, SO is always located medial to its posteroinferior attachment. (Folia Morphol 2018; 77, 1: 110–115)

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Volumetric evaluation of temporal bone structures in the cases with bilateral tinnitus: clinical and morphometrical study

Background: Tinnitus is the recognition of sound in the absence of any external auditory stimulus to the noise of ringing in the ears. Middle ear aeration carries important role for ossicular coupling and normal hearing. There is restricted morphometric data on the cases with bilateral tinnitus.

Materials and methods: In this study we evaluated hearing findings of 18 cases with subjective nonpulsatile bilateral tinnitus and also morphometry and volumetry of temporal bone substructures on the computed tomography images using stereological method compared with the gender and age matched 12 healthy subjects. Duration of tinnitus, exposing acoustic trauma or/and high level noise levels, evaluation of middle ear volume, jugular bulb levels, distances between jugular bulb and both oval window and middle ear were evaluated.

Results: Both males and females with tinnitus showed worse hearing thresholds through bone and air conductions than healthy subjects but it was not statistically significant. Pure tone thresholds through bone and air conductions were not statistically different in both sexes with bilateral tinnitus. Right middle ear volume of the cases with bilateral tinnitus was mean 5.57 cm3 for males and 5.64 cm3 for females; and also the left middle ear volume of the cases with bilateral tinnitus was mean 5.87 cm3 for males and 5.65 cm3 for females. There were no significant differences between the cases with bilateral tinnitus and the control subjects according to the side of the body.

Conclusions: The data on the hearing findings and morphometrical evaluation of the cases with bilateral tinnitus may be important for anatomists and clinicians. (Folia Morphol 2018; 77, 1: 57–64)  

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Assessment of the orbit morphometry on West Anatolian dry skulls

The orbit is very frequently damaged by traumas which result in not only bone deficits, but also functional deformities if reconstruction is not appropriate. Anatomical exposure of the bony orbit is of importance for both anatomists and surgeons who perform operation on this area. The current study evaluated the group of morphometrical parameters on 74 adult West Anatolian dry skulls and stereological surface area on the dry skull orbits while describing the clinical importance. Surface areas on the orbital base of the skulls were also evaluated using stereological method, bilaterally. Anthropological assessment of orbital base (in terms of width and height) revealed no significant difference between right and left sides. Both width and height of the optic foramen were significantly higher on the right side compared to left. The distances between the margins (medial, lateral, superior, inferior) of the orbital base and the optic foramen were longer on the right side compared to left, except the distances between the lateral margins. There was no significant difference among the subjects between right and left sides with respect to the orbital base in terms of stereological area calculation. The results are significant because there are no recorded anatomical data on West Anatolian skulls at previous researches. (Folia Morphol 2018; 77, 1: 105–109)

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The value of dual-source multidetector-row computed tomography in determining pulmonary blood supply in patients with pulmonary atresia with ventricular septal defect

Background: Primary evaluation of patients with pulmonary atresia with ventricular septal defect (PA-VSD) traditionally relies upon echocardiography and conventional cardiac angiography (CCA). Cardiac angiography is considered the gold standard for delineation of anatomy in children with PA-VSD. Data comparing CCA and dual-source multidetector-row computed tomography angiography (MDCT) in PA-VSD patients is limited. The objective of this study was to test the hypothesis that MDCT is equivalent to CCA for anatomic delineation in these patients.

Materials and methods: Twenty-eight patients with PA-VSD underwent CCA and MDCT in close proximity to each other without interval therapy. A retrospective review of these 28 patients was performed. All MDCT data of pulmonary artery morphology, major aortopulmonary collateral arteries (MAPCAs) and type of blood supply (dual vs. single supply) were evaluated by blinded experts and results were compared with CCA.

Results: Twenty-eight patients had adequate size right and left pulmonary arteries (21 confluent and 7 non-confluent). Seven patients had complete absence of native pulmonary artery and 3 patients had stenosis of distal branches of pulmonary arteries; all had MAPCAs from descending thoracic aorta and/or subclavian arteries. Sensitivity, specificity, positive and negative predictive value of MDCT for detecting confluent of pulmonary arteries, absence of native pulmonary artery and stenosis of pulmonary arteries were all 100%. Moreover, accuracy of detecting MAPCAs was excellent.

Conclusions: These results suggest that MDCT and CCA are equivalent in their ability to delineate pulmonary artery anatomy and MAPCAs. Dual source MDCT provides high diagnostic accuracy in evaluation of pulmonary blood supply in patients with PA-VSD and allows precise characterisation of the condition of pulmonary arteries and MAPCAs which is of paramount importance in managing patients with PA-VSD. (Folia Morphol 2018; 77, 1: 116–122)  

 

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Cone beam computed tomography evaluation of ponticulus posticus in patients with cleft lip and palate: a retrospective radio-anatomic study

Background: Ponticulus posticus (PP) is an abnormal bony bridge on the atlas. It plays a significant role in patients undergoing C1 lateral mass screw procedure. Patients with cleft lip and palate (CLP) have higher risk than patients in general population for the appearance of cervical vertebral anomalies. The purpose of the this study was twofold: to determine the prevalence and characteristics of PP in patients with CLP, and to compare the findings with patients in general population using cone beam computed tomography.

Materials and methods: Cone beam computed tomography images from 54 individuals who had undergone surgical repair of cleft lip and/or palate were analysed as the study group. For comparison purposes a control group was randomly selected from 108 patients and matched with the CLP subjects.

Results: Although 12 of the 54 (22.3%) patients with surgically repaired cleft lip and/or palate in the study group were identified to have PP, only 10 of the 108 (9.2%) patients in the control group had PP. The distribution of the presence of PP between the groups was statistically significant.

Conclusions: Ponticulus posticus is an important anomaly and the presence of PP is important for patients. PP can have clinical significance in cervical spine surgery as this study has indicated that the likelihood of encountering PP is higher in patients with CLP. We suggest that PP should be taken into account prior to cervical vertebral surgery in patients with CLP. (Folia Morphol 2018; 77, 1: 72–78)  

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Distal root curvatures in mandibular molars: analysis using digital panoramic X-rays

Background: The aim of this study was to describe the degree of curvature in distal roots in the first and second permanent mandibular molars in a Chilean patient sample. A cross-sectional descriptive study was conducted in which digital panoramic X-rays were analysed.

Materials and methods: Examinations of patients under 18 years, with signs of distortion or alteration in the contrast or the presence of pathologies that affected visualisation of the roots and pulp-chamber floor of the teeth to be analysed were excluded. Using the AutoCad software, an angle was drawn to represent the curve of the root in its different thirds, drawing lines inside the root canal from the pulp-chamber floor to the dental apex. Using the classic definition of dilaceration (root curvature > 90°), its prevalence was established. 412 teeth and roots were analysed, finding a dilaceration prevalence of 0.73% (n = 3). 84.72% of the roots presented some type of curvature.

Results: The middle third had the highest percentage of curvatures and the greatest average of angular curvature, whereas the cervical third was the straightest. No significant differences were found between the degree of curvature and the gender of the subjects, except for the apical third of tooth 3.6. The analysis of curvature by root third offers to the clinician a better perspective of the directional change of the roots and does not limit it to just the presence of curves in the apical third.

Conclusions: The report of the angular degree of the curvatures, in addition to the prevalence of dilacerations, informs to the clinicians about the likelihood of finding difficulties when treating root canals. (Folia Morphol 2018; 77, 1: 131–137)

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Morphological assessment of the stylohyoid complex variations with cone beam computed tomography in a Turkish population

Background: The aim of this investigation was to evaluate the length, thickness, sagittal and transverse angulations and the morphological variations of the stylohyoid complex (SHC), to assess their probable associations with age and gender, and to investigate the prevalence of it in a wide range of a Turkish sub-population by using cone beam computed tomography (CBCT).

Materials and methods: The CBCT images of the 1000 patients were evaluated retrospectively. The length, thickness, sagittal and transverse angulations, morphological variations and ossification degrees of SHC were evaluated on multiplanar reconstructions (MPR) adnd three-dimensional (3D) volume rendering (3DVR) images. The data were analysed statistically by using nonparametric tests, Pearson's correlation coefficient, Student's t test, c2 test and one-way ANOVA. Statistical significance was considered at p < 0.05.

Results: It was determined that 684 (34.2%) of all 2000 SHCs were elongated (> 35 mm). The mean sagittal angle value was measured to be 72.24° and the mean transverse angle value was 70.81°. Scalariform shape, elongated type and nodular calcification pattern have the highest mean age values between the morphological groups, respectively. Calcified outline was the most prevalent calcification pattern in males. There was no correlation between length and the calcification pattern groups while scalariform shape and pseudoarticular type were the longest variations.

Conclusions: We observed that as the anterior sagittal angle gets wider, SHC tends to get longer. The most observed morphological variations were linear shape, elongated type and calcified outline pattern. Detailed studies on the classification will contribute to the literature. (Folia Morphol 2018; 77, 1: 79–89)  

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Foetal development of the human gluteus maximus muscle with special reference to its fascial insertion

The human gluteus maximus muscle (GMX) is characterised by its insertion to the iliotibial tract (a lateral thick fascia of the thigh beneath the fascia lata), which plays a critical role in lateral stabilisation of the hip joint during walking. In contrast, in non-human primates, the GMX and biceps femoris muscle provide a flexor complex. According to our observations of 15 human embryos and 11 foetuses at 7–10 weeks of gestation (21–55 mm), the GMX anlage was divided into 1) a superior part that developed earlier and 2) a small inferior part that developed later. The latter was adjacent to, or even continuous with, the biceps femoris. At 8 weeks, both parts inserted into the femur, possibly the future gluteal tuberosity. However, depending on traction by the developing inferior part as well as pressure from the developing major trochanter of the femur, most of the original femoral insertion of the GMX appeared to be detached from the femur. Therefore, at 9–10 weeks, the GMX had a digastric muscle-like appearance with an intermediate band connecting the major superior part to the small inferior mass. This band, most likely corresponding to the initial iliotibial tract, extended laterally and distally far from the muscle fibres. The fascia lata was still thin and the tensor fasciae latae seemed to develop much later. It seems likely that the evolutionary transition from quadripedality to bipedality and a permanently upright posture would require the development of a new GMX complex with the iliotibial tract that differs from that in non-human primates. (Folia Morphol 2018; 77, 1: 144–150)

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Hydromorphone HCL Injection USP by Hospira: Recall - Potential For Empty Or Cracked Glass Vials

Audience: Pharmacy, Risk Manager [Posted 03/05/2018] ISSUE: Hospira is voluntarily recalling three lots of Hydromorphone HCl Injection, USP CII 10 mg/mL, 1 mL in 2 mL Single Dose Vials lot numbers 71330DD (NDC 0409-2634-01), and 691853F and 700753F...

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Baicalein Accelerates Tendon-Bone Healing via Activation of Wnt/β-Catenin Signaling Pathway in Rats

Background. Tendon-bone healing is a reconstructive procedure which requires a tendon graft healing to a bone tunnel or to the surface of bone after the junction injury between tendon, ligament, and bone. The surgical reattachment of tendon to bone often fails due to regeneration failure of the specialized tendon-bone junction. Materials and Methods. An extra-articular tendon-bone healing rat model was established to discuss the effect of the baicalein 10 mg/(kg·d) in accelerating tendon-bone healing progress. Also, tendon-derived stem cells (TDSCs) were treated with various concentrations of baicalein or dickkopf-1 (DKK-1) to stimulate differentiation for 14 days. Results. In vivo, tendon-bone healing strength of experiment group was obviously stronger than the control group in 3 weeks as well as in 6 weeks. And there were more mature fibroblasts, more Sharpey fibers, and larger new bone formation area treated intragastrically with baicalein compared with rats that were treated with vehicle for 3 weeks and 6 weeks. In vitro, after induction for 14 days, the expressions of osteoblast differentiation markers, that is, alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), osteocalcin (OCN), osterix (OSX), and collagen I, were upregulated and Wnt/β-catenin signaling pathway was enhanced in TDSCs. The effect of DKK-1 significantly reduced the effect of baicalein on the osteogenic differentiation. Conclusion. These data suggest that baicalein may stimulate TDSCs osteogenic differentiation via activation of Wnt/β-catenin signaling pathway to accelerate tendon-bone healing.

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Effect of powdered shells treatment of the snail Megalobulimus lopesi on wounds of diabetic rats

Abstract Purpose: To analyzed the healing effect of the powdered shell of the Megalobulimus lopesi snail on wounds of diabetic rats, since in non-diabetic rats the powdered shell presented healing potential. Methods: Seventy-two Wistar rats (Rattus norvegicus albinus) were divided into three groups: Control group (GC.diab), no therapeutic intervention on the wound; Vehicle's Control group, topical via, in diabetic rats (GCvt.diab): Powder Shell Group (PC) applied topically (GPCvt.diab): Experimental group was administered topically shortly after wound dressing and once a day during the experimental period (3, 7, 14 and 21 days) the composition containing the powdered shell of the snail. The following variables related to the healing potential were analyzed: macroscopic one, where the capacity of reduction of the wound area was evaluated; histological analysis in HE, angiogenic activity, morphometric analysis (re-epithelization), leukocyte inflammatory infiltrate; leukocyte count and also differentiation in peripheral blood. Results: The topical application in wounds of diabetic rats presented healing activity, accelerating wound closure, stimulating angiogenesis and being pro-inflammatory in the early and anti-inflammatory stages in the final times of the healing process. Conclusion: The topical administration of the powdered shell on wounds of diabetic patients becomes a therapeutic option of low cost, with ease in the administration and access as well.

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Comparative study of polyglactin 910 and simple catgut in the formation of intraperitoneal adhesions

Abstract Purpose: To compare polyglactin 910 and simple catgut sutures for the incidence of intraperitoneal adhesions. Methods: Twenty female Wistar rats were placed into two groups. Group 1 received ischemic sutures and Group 2 received polyglactin 910. Five sutures inductive of adhesions in each rat were made. After 14 days, the rats were euthanized with an assessment of the presence of adhesions, the number of sutures involved and classification according to the Granat et al. scale described by Ozel et al17. Results: In total, 19 of the 20 rats presented adhesions, with nine from Group 1 and ten from Group 2. There was a smaller number of affected sutures in Group 1, while in Group 2 the majority of the sutures formed adhesions (p=0.0197). According to the Granat et al. scale, Group 1 predominately developed fine, filamentous adhesions or thickening in a restricted area. Group 2 mainly presented extensive, thick adhesions with the involvement of the viscera (p=0.0055). Conclusion: Polyglactin 910 sutures formed more adhesions that were more extensive and thicker than the simple catgut sutures.

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Effects of thymoquinone and curcumin on the regeneration of rat livers subject to 70% hepatectomy

Abstract Purpose: To investigate thymoquinone, curcumin and a combination of these two drugs were effective or not at the growth of liver. Methods: Forty female Wistar-Albino rats distributed into five groups of eight rats each, control, thymoquinone, curcumin, and thymoquinone/curcumin groups. Pathological specimens were studied using the Ki-67 Proliferation Index(PI); and arginase(Arg), tissue plasminogen activator(tPA), ceruloplasmin(Cer) and nitric oxide(NO) were studied in biochemical analysis. Results: Our results showed that Ki-67 proliferation index was low in Groups 1. The proliferation coefficient was significantly higher in the Group 2 and Group 4 than in the Group 1 and Group 3.(P < 0.001 between Groups 1 and 2, 1 and 4, and 3 and 4). There was no difference between Groups 2 and 4 (P = 1). The results of the biochemical Arg, tPA and Cer test showed statistically between the Group 1 and Group 2. NO showed significant differences Group 1 and 3. Conclusions: Thymoquinone and curcumin both have known positive effects on the organism. Histological and biochemical tests showed that thymoquinone is more effective than curcumin.

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Efficacy of phosphocreatine pre-administration on XIAP and Smac in ischemic penumbra of rats with focal cerebral ischemia reperfusion injury

Abstract Purpose: To observe the efficacy of phosphocreatine pre-administration (PCr-PA) on X-linked inhibitor of apoptosis protein (XIAP), the second mitochondia-derived activator of caspase (Smac) and apoptosis in the ischemic penumbra of rats with focal cerebral ischemia-reperfusion injury (CIRI). Methods: A total of 60 healthy male Sprague Dawley (SD) rats were randomly divided into three groups (n=20): group A (the sham operation group), group B <intraperitoneally injected with 20 mg/kg (10 mg/ml) of saline before preparing the ischemia-reperfusion (IR) model>, and group C <intraperitoneally injected with 20 mg/kg (10 mg/ml) of PCr immediately before preparing the IR model>. After 24 h for reperfusion, the neurological function was evaluated and the tissue was sampled to detect expression of XIAP, Smac and caspase-3 positive cells in the ischemic penumbra so as to observe the apoptosis. Results: Compared with group B, neurological deficit scores, numbers of apoptotic cells, expression of Smac,caspase-9 and the numbers of Caspase-3 positive cells were decreased while expression of XIAP were increased in the ischemic penumbra of group C. Conclusions: Phosphocreatine pre-administration may elicit neuroprotective effects in the brain by increasing expression of X-linked inhibitor of apoptosis protein, reducing expression of second mitochondia-derived activator of caspase, and inhibiting the apoptosis in the ischemic penumbra.

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Investigation of the antioxidant effects of pheniramine maleate and nebivolol on testicular damage in rats with experimentally induced testis torsion

Abstract Purpose: To investigate the biochemical, histopathologic, and spermatogenetic changes in the detorsionated testicle after experimental torsion and to study the antioxidant effects of pheniramine maleate and nebivolol. Methods: Twenty-four Sprague-Dawley male rats were divided into 4 groups: Group 1: Sham; Group 2: Torsion/Detorsion (T/D); Group 3: T/D + Pheniramine maleate (PM); Group 4: T/D + Nebivolol (NB) group. Paroxanase (PON), total antioxidant status (TAS), total oxidant status (TOS), and oxidative stres index (OSI) were measured, and spermatogenetic and histopathologic evaluation was performed in tissue and blood samples. Results: The evaluation of tissue TAS indicated no statistically significant difference in Group 3 compared to Group 2. A statistically significant increase was detected in Group 4 compared to Group 2. Serum PON levels revealed a statistically significant increase in Groups 3 and 4 compared to Groups 1 and 2. The Johnsen testicular biopsy score decreased in Groups 3 and 4, but the decrease was not statistically significant. Conclusions: Pheniramine maleate and nebivolol have antioxidant effects against ischemia-reperfusion damage. They also support tissue recovery, which is more significantly observed by nebivolol.

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The effect of pycnogenol on lymphatic nodes and adhesion during in a peritoneal adhesion model in rats

Abstract Purpose: To investigate the effects of pycnogenol on peritoneal adhesions and additionally to investigate the immunohistochemical effects of free oxygen radicals and reactive lymph nodes detected in the adhesive tissue that was sampled surrounding the cecum on intra-abdominal adhesions. Methods: Twenty-seven Wistar Albino rats were divided into three groups. In group 1 (sham), laparotomy was performed and stitched up. In group 2 (control), after laparotomy was performed, punctate hemorrhage was induced by cecal abrasion in the cecum and each rat was intraperitoneally administered 2 cc of saline. In group 3 (experimental), after laparotomy was performed, punctate hemorrhage was induced by cecal abrasion in the cecum and each rat was intraperitoneally administered a sterile Pycnogenol derivative. The rats in all groups were re-laparotomized on postoperative day 7; samples were obtained from the peritoneal tissue surrounding the cecum, and the rats were sacrificed. Results: In group 3, there was a statistically significant difference in terms of inflammation, lymph node size, and free oxygen radicals; these parameters tended to increase. In terms of fibrosis evaluated using H&E and MT, there was no significant difference between groups 2 and 3. Conclusions: No positive outcomes indicating that pycnogenol reduces intra-abdominal adhesions were obtained. However, it caused severe inflammation in the tissue. Moreover, a significant increase in lymph node size was detected secondary to inflammation. Additionally, in immunohistochemical analyses conducted to detect oxidative stress, pycnogenol increased the production of free oxygen radicals in the tissue.

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Effects of the application of the amniotic membrane in the healing process of skin wounds in rats

Abstract Purpose: To evaluate the efficacy of the application of the human amniotic membrane (HAM) on the inflammatory process, fibroblast proliferation, formation of collagenand reduction of skin wound areas in rats. Methods: Thirty six rats were submitted to a surgical injury induction and divided into two groups (n = 18): group C (control) and T (treated with the HAM). The macroscopic evolution in the wound area and the histological characteristics of the skin samples were evaluated. Results: The regression of the wound area was greater in group T. The histological analysis revealed a significant reduction (p < 0.05) in the inflammatory infiltrate in group T at all experimental periods compared with that in the control group. Furthermore, the group T presented a significant increase in the proliferation of fibroblasts at 14 and 21 days compared with group C (p < 0.05). Regarding the deposition of mature collagen fibers, there was an increase in the replacement of type III collagen by type I collagen in group T (p < 0.05). Conclusion: Treatment with the HAM reduced the healing time as well as the inflammatory responses, increased the proliferation of fibroblasts, and induced a higher concentration of mature collagen fibers.

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Transforming growth factor beta1 (TGF-ß1) levels in a rat model of induced pleural empyema

Abstract Purpose: To evaluate the concentration of transforming growth factor beta 1 (TGFB1) levels in a rat pleural effusion obtained by inoculation of intrapleural bacteria or turpentine through thoracentesis. Methods: Thirty-Nine Wistar rats were divided into three groups: Staphylococcus aureus (SA, n = 17); Streptococcus pneumoniae (SP, n = 12); and turpentine (control, n = 10). Pleural fluid was collected through ultrasound-guided thoracentesis 12 h, 24 h, and 36 h after instillation of bacteria or turpentine. Levels of TGFB1 were measured in pleural fluid. Results: At 12 h, mean TGFB1concentrations were 5.3450 pg/mL in the SA group, 5.3449 pg/mL in the SP group, and 5.3450 pg/mL in controls. At 24 h, they were 4.6700 pg/mL in the SA group, 4.6700 pg/mL in the SP group, and 4.6700 pg/mL in controls. At 36 h, they were 4.6699 pg/mL in the SA group and in control. No difference was observed among the groups in mean TGFB1concentration (p = 0.12); however, a significant intragroup reduction in mean TGFB1 was observed between 12 and 24 h (p < 0.01). Conclusion: The transforming growth factor beta 1 concentrations were not useful as a diagnostic tool or an early marker of infected pleural effusion.

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Effect of a new cross-linked hyaluronan gel on the staple line after sleeve gastrectomy in a rat model

Abstract Purpose: To evaluate the effect of a new cross-linked hyaluronan (NCHA) gel on healing of the staple line in an experimental sleeve gastrectomy. Methods: Eighteen rats were randomly divided into three groups. The control group (n = 6) received no medication. In the saline group (n = 6) and NCHA gel group (n = 6), saline and NCHA gel were respectively administered onto the staple line and intraperitoneally into the abdominal cavity after the standard stapling procedure. Results: The fibroblast activity and collagen deposition were significantly higher in the NCHA gel group than in the control group (p = 0.00, p = 0.017) and saline group (p = 0.004, p = 0.015). The tissue hydroxyproline protein level was significantly higher in the NCHA gel group than in the control group (p = 0.041). Adhesion formation was significantly lower in the NCHA gel group than in the control and saline groups (p = 0.015, p = 0.041). Conclusions: New cross-linked hyaluronan gel could be an effective approach to improve staple line wound healing and prevent potential leakage after sleeve gastrectomy. Moreover, NCHA gel helps to prevent adhesion formation without compromising healing of the staple line.

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Effects of aquaporin 4 and inward rectifier potassium channel 4.1 on medullospinal edema after methylprednisolone treatment to suppress acute spinal cord injury in rats

Abstract Purpose: To investigate the effects of aquaporin 4 (AQP4) and inward rectifier potassium channel 4.1 (Kir4.1) on medullospinal edema after treatment with methylprednisolone (MP) to suppress acute spinal cord injury (ASCI) in rats. Methods: Sprague Dawley rats were randomly divided into control, sham, ASCI, and MP-treated ASCI groups. After the induction of ASCI, we injected 30 mg/kg MP via the tail vein at various time points. The Tarlov scoring method was applied to evaluate neurological symptoms, and the wet-dry weights method was applied to measure the water content of the spinal cord. Results: The motor function score of the ASCI group was significantly lower than that of the sham group, and the spinal water content was significantly increased. In addition, the levels of AQP4 and Kir4.1 were significantly increased, as was their degree of coexpression. Compared with that in the ASCI group, the motor function score and the water content were significantly increased in the MP group; in addition, the expression and coexpression of AQP4 and Kir4.1 were significantly reduced. Conclusion: Methylprednisolone inhibited medullospinal edema in rats with acute spinal cord injury, possibly by reducing the coexpression of aquaporin 4 and Kir4.1 in medullospinal tissues.

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Erratum

Abstract Purpose: To analyzed the healing effect of the powdered shell of the Megalobulimus lopesi snail on wounds of diabetic rats, since in non-diabetic rats the powdered shell presented healing potential. Methods: Seventy-two Wistar rats (Rattus norvegicus albinus) were divided into three groups: Control group (GC.diab), no therapeutic intervention on the wound; Vehicle's Control group, topical via, in diabetic rats (GCvt.diab): Powder Shell Group (PC) applied topically (GPCvt.diab): Experimental group was administered topically shortly after wound dressing and once a day during the experimental period (3, 7, 14 and 21 days) the composition containing the powdered shell of the snail. The following variables related to the healing potential were analyzed: macroscopic one, where the capacity of reduction of the wound area was evaluated; histological analysis in HE, angiogenic activity, morphometric analysis (re-epithelization), leukocyte inflammatory infiltrate; leukocyte count and also differentiation in peripheral blood. Results: The topical application in wounds of diabetic rats presented healing activity, accelerating wound closure, stimulating angiogenesis and being pro-inflammatory in the early and anti-inflammatory stages in the final times of the healing process. Conclusion: The topical administration of the powdered shell on wounds of diabetic patients becomes a therapeutic option of low cost, with ease in the administration and access as well.

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Emblic Leafflower (Phyllanthus emblica L.) Fruits Ameliorate Vascular Smooth Muscle Cell Dysfunction in Hyperglycemia: An Underlying Mechanism Involved in Ellagitannin Metabolite Urolithin A

Ellagitannins in Phyllanthus emblica L. (emblic leafflower fruits) have been thought of as the beneficial constituents for ameliorating endocrinal and metabolic diseases including diabetes. However, the effect of emblic leafflower fruits on diabetic vascular complications involved in ellagitannin-derived urolithin metabolites is still rare. In this study, acetylcholine-induced endothelium-independent relaxation in aortas was facilitated upon emblic leafflower fruit consumption in the single dose streptozotocin-induced hyperglycemic rats. Emblic leafflower fruit consumption also suppressed the phosphorylation of Akt (Thr308) in the hyperglycemic aortas. More importantly, urolithin A (UroA) and its derived phase II metabolites were identified as the metabolites upon emblic leafflower fruit consumption by HPLC-ESI-Q-TOF-MS. Moreover, UroA reduced the protein expressions of phosphor-Akt (Thr308) and β-catenin in a high glucose-induced A7r5 vascular smooth muscle cell proliferation model. Furthermore, accumulation of β-catenin protein and activation of Wnt signaling in LiCl-triggered A7r5 cells were also ameliorated by UroA treatment. In conclusion, our data demonstrate that emblic leafflower fruit consumption facilitates the vascular function in hyperglycemic rats by regulating Akt/β-catenin signaling, and the effects are potentially mediated by the ellagitannin metabolite urolithin A.

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Magic mirror on the wall: Which is the best biomarker for HCC?

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Reply ‘Magic mirror on the wall: Which is the best biomarker for HCC'

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Dual Role for Inositol-requiring Enzyme 1α in Promoting the Development of Hepatocellular Carcinoma during Diet-induced Obesity

Abstract

Obesity is associated with both endoplasmic reticulum (ER) stress and chronic metabolic inflammation. ER stress activates the unfolded protein response (UPR) and has been implicated in a variety of cancers, including hepatocellular carcinoma (HCC). It is unclear whether individual UPR pathways are mechanistically linked to HCC development, however. Here we report a dual role for inositol-requiring enzyme 1α (IRE1α), the ER-localized UPR signal transducer, in obesity-promoted HCC development. We found that genetic ablation of IRE1α in hepatocytes not only markedly reduced the occurrence of diethylnitrosamine (DEN)-induced HCC in LKO mice when fed a normal chow (NC) diet, but also protected against the acceleration of HCC progression during high-fat diet (HFD) feeding. Irrespective of their adiposity states, LKO mice showed decreased hepatocyte proliferation and STAT3 activation, even in the face of increased hepatic apoptosis. Furthermore, IRE1α abrogation blunted obesity-associated activation of hepatic IKKβ-NF-κB pathway, leading to reduced production of the tumor-promoting inflammatory cytokines TNF and IL-6. Importantly, higher IRE1α expression along with elevated STAT3 phosphorylation was also observed in the tumor tissues from human HCC patients, correlating with their poorer survival rate. Conclusion: These results demonstrate that IRE1α acts in a feed-forward loop during obesity-induced metabolic inflammation to promote HCC development through STAT3-mediated hepatocyte proliferation. This article is protected by copyright. All rights reserved.

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Reply (to LTE HEP-18-0257)

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MicroRNA Signatures Discriminate Between Uterine and Ovarian Serous Carcinomas

Synchronous endometrial and ovarian malignancies occur in 5% of women presenting with endometrial cancer and 10% of patients presenting with ovarian malignancy. When a high-grade serous carcinoma concurrently involves both ovary and endometrium, pathological determination of whether they are synchronous primaries or metastatic tumors from one primary site can be challenging. MicroRNAs (miRNA) are 22-nucleotide noncoding RNAs that are aberrantly expressed in cancer cells and may inherit their cellular linage characteristics.

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The Utility of the Total Neuropathy Score as an Instrument to Assess Neuropathy Severity in Chronic Kidney Disease: A Validation Study

To demonstrate construct validity of the Total Neuropathy Score (TNS) in assessing peripheral neuropathy in subjects with chronic kidney disease (CKD).

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Precision of perceived direction of gravity in partial bilateral vestibulopathy correlates with residual utricular function

Bilateral-vestibular deficiency (BVD) results from functional impairment of both vestibular organs, leading to gait unsteadiness in almost all patients (Zingler et al., 2007) and oscillopsia (illusionary movement of the visual surroundings during head movements) (Hain et al., 2013), which is found less consistently (from 44% (Zingler et al., 2007) to 97% (Black et al., 2004)). These complaints have been linked to a reduced angular vestibulo-ocular reflex (aVOR), which normally stabilizes gaze during head movements, and to impairment of the otolith organs (utriculus, sacculus), which are key for sensing linear acceleration and gravity (Schoene, 1964; Hain et al., 2013).

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Hemoglobin A 1c Targets for Nonpregnant Adults With Type 2 Diabetes Mellitus

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Hemoglobin A 1c Targets for Glycemic Control With Pharmacologic Therapy for Nonpregnant Adults With Type 2 Diabetes Mellitus: A Guidance Statement Update From the American College of Physicians

Description:

The American College of Physicians developed this guidance statement to guide clinicians in selecting targets for pharmacologic treatment of type 2 diabetes.

Methods:

The National Guideline Clearinghouse and the Guidelines International Network library were searched (May 2017) for national guidelines, published in English, that addressed hemoglobin A_1c (HbA_1c) targets for treating type 2 diabetes in nonpregnant outpatient adults. The authors identified guidelines from the National Institute for Health and Care Excellence and the Institute for Clinical Systems Improvement. In addition, 4 commonly used guidelines were reviewed, from the American Association of Clinical Endocrinologists and American College of Endocrinology, the American Diabetes Association, the Scottish Intercollegiate Guidelines Network, and the U.S. Department of Veterans Affairs and Department of Defense. The AGREE II (Appraisal of Guidelines for Research and Evaluation II) instrument was used to evaluate the guidelines.

Guidance Statement 1:

Clinicians should personalize goals for glycemic control in patients with type 2 diabetes on the basis of a discussion of benefits and harms of pharmacotherapy, patients' preferences, patients' general health and life expectancy, treatment burden, and costs of care.

Guidance Statement 2:

Clinicians should aim to achieve an HbA1c level between 7% and 8% in most patients with type 2 diabetes.

Guidance Statement 3:

Clinicians should consider deintensifying pharmacologic therapy in patients with type 2 diabetes who achieve HbA1c levels less than 6.5%.

Guidance Statement 4:

Clinicians should treat patients with type 2 diabetes to minimize symptoms related to hyperglycemia and avoid targeting an HbA1c level in patients with a life expectancy less than 10 years due to advanced age (80 years or older), residence in a nursing home, or chronic conditions (such as dementia, cancer, end-stage kidney disease, or severe chronic obstructive pulmonary disease or congestive heart failure) because the harms outweigh the benefits in this population.

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Technology and Transparency: Empowering Patients and Clinicians to Improve Health Care Value

With patients and clinicians confronting daunting uncertainties in health care, arguments rage about quality, costs, and how to improve the lives of both those who seek and those who provide care. In light of rapidly evolving health information technologies, the authors anticipate that widespread societal movement toward greater transparency will spur important advances.

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Direct-Acting Antiviral Prophylaxis in Kidney Transplantation From Hepatitis C Virus–Infected Donors to Noninfected Recipients An Open-Label Nonrandomized Trial

Background:

Given the high mortality rate for patients with end-stage kidney disease receiving dialysis and the efficacy and safety of hepatitis C virus (HCV) treatments, discarded kidneys from HCV-infected donors may be a neglected public health resource.

Objective:

To determine the tolerability and feasibility of using direct-acting antivirals (DAAs) as prophylaxis before and after kidney transplantation from HCV-infected donors to non–HCV-infected recipients (that is, HCV D⁺/R⁻ transplantation).

Design:

Open-label nonrandomized trial. (ClinicalTrials.gov: NCT02781649)

Setting:

Single center.

Participants:

10 HCV D⁺/R⁻ kidney transplant candidates older than 50 years with no available living donors.

Intervention:

Transplantation of kidneys from deceased donors aged 13 to 50 years with positive HCV RNA and HCV antibody test results. All recipients received a dose of grazoprevir (GZR), 100 mg, and elbasvir (EBR), 50 mg, immediately before transplantation. Recipients of kidneys from donors with genotype 1 infection continued receiving GZR–EBR for 12 weeks after transplantation; those receiving organs from donors with genotype 2 or 3 infection had sofosbuvir, 400 mg, added to GZR–EBR for 12 weeks of triple therapy.

Measurements:

The primary safety outcome was the incidence of adverse events related to GZR–EBR treatment. The primary efficacy outcome was the proportion of recipients with an HCV RNA level below the lower limit of quantification 12 weeks after prophylaxis.

Results:

Among 10 HCV D⁺/R⁻ transplant recipients, no treatment-related adverse events occurred, and HCV RNA was not detected in any recipient 12 weeks after treatment.

Limitation:

Nonrandomized study design and a small number of patients.

Conclusion:

Pre- and posttransplantation HCV treatment was safe and prevented chronic HCV infection in HCV D⁺/R^– kidney transplant recipients. If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection.

Primary Funding Source:

Merck Sharp & Dohme Corp.

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Prolonged Persistence of Adalimumab Transferred From Mother to Infant During Pregnancy

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Effect of Physical Activity on Frailty Secondary Analysis of a Randomized Controlled Trial

Background:

Limited evidence suggests that physical activity may prevent frailty and associated negative outcomes in older adults. Definitive data from large long-term randomized trials are lacking.

Objective:

To determine whether a long-term, structured, moderate-intensity physical activity program is associated with a lower risk for frailty and whether frailty status alters the effect of physical activity on the reduction in major mobility disability (MMD) risk.

Design:

Multicenter, single-blind, randomized trial.

Setting:

8 centers in the United States.

Participants:

1635 community-dwelling adults, aged 70 to 89 years, with functional limitations.

Intervention:

A structured, moderate-intensity physical activity program incorporating aerobic, resistance, and flexibility activities or a health education program consisting of workshops and stretching exercises.

Measurements:

Frailty, as defined by the SOF (Study of Osteoporotic Fractures) index, at baseline and 6, 12, and 24 months, and MMD, defined as the inability to walk 400 m, for up to 3.5 years.

Results:

Over 24 months of follow-up, the risk for frailty (n = 1623) was not statistically significantly different in the physical activity versus the health education group (adjusted prevalence difference, −0.021 [95% CI, −0.049 to 0.007]). Among the 3 criteria of the SOF index, the physical activity intervention was associated with improvement in the inability to rise from a chair (adjusted prevalence difference, −0.050 [CI, −0.081 to −0.020]). Baseline frailty status did not modify the effect of physical activity on reducing incident MMD (P for interaction = 0.91).

Limitation:

Frailty status was neither an entry criterion nor a randomization stratum.

Conclusion:

A structured, moderate-intensity physical activity program was not associated with a reduced risk for frailty over 2 years among sedentary, community-dwelling older adults. The beneficial effect of physical activity on the incidence of MMD did not differ between frail and nonfrail participants.

Primary Funding Source:

National Institute on Aging, National Institutes of Health.

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Death Is a Small Thing

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Risk for Arterial and Venous Thrombosis in Patients With Myeloproliferative Neoplasms A Population-Based Cohort Study

Background:

Patients with myeloproliferative neoplasms (MPNs) are reported to be at increased risk for thrombotic events. However, no population-based study has estimated this excess risk compared with matched control participants.

Objective:

To assess risk for arterial and venous thrombosis in patients with MPNs compared with matched control participants.

Design:

Matched cohort study.

Setting:

Population-based setting in Sweden from 1987 to 2009, with follow-up to 2010.

Patients:

9429 patients with MPNs and 35 820 matched control participants.

Measurements:

The primary outcomes were rates of arterial and venous thrombosis. Flexible parametric models were used to calculate hazard ratios (HRs) and cumulative incidence with 95% CIs.

Results:

The HRs for arterial thrombosis among patients with MPNs compared with control participants at 3 months, 1 year, and 5 years were 3.0 (95% CI, 2.7 to 3.4), 2.0 (CI, 1.8 to 2.2), and 1.5 (CI, 1.4 to 1.6), respectively. The corresponding HRs for venous thrombosis were 9.7 (CI, 7.8 to 12.0), 4.7 (CI, 4.0 to 5.4), and 3.2 (CI, 2.9 to 3.6). The rate was significantly elevated across all age groups and was similar among MPN subtypes. The 5-year cumulative incidence of thrombosis in patients with MPNs showed an initial rapid increase followed by gentler increases during follow-up. The HR for venous thrombosis decreased during more recent calendar periods.

Limitation:

No information on individual laboratory results or treatment.

Conclusion:

Patients with MPNs across all age groups have a significantly increased rate of arterial and venous thrombosis compared with matched control participants, with the highest rates at and shortly after diagnosis. Decreases in the rate of venous thrombosis over time likely reflect advances in clinical management.

Primary Funding Source:

The Cancer Research Foundations of Radiumhemmet, Blodcancerfonden, the Swedish Research Council, the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet, the Adolf H. Lundin Charitable Foundation, and Memorial Sloan Kettering Cancer Center.

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Statin Denial: An Internet-Driven Cult With Deadly Consequences

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White Blood Cell BRCA1 Promoter Methylation Status and Ovarian Cancer Risk

Background:

The role of normal tissue gene promoter methylation in cancer risk is poorly understood.

Objective:

To assess associations between normal tissue BRCA1 methylation and ovarian cancer risk.

Design:

2 case–control (initial and validation) studies.

Setting:

2 hospitals in Norway (patients) and a population-based study (control participants).

Participants:

934 patients and 1698 control participants in the initial study; 607 patients and 1984 control participants in the validation study.

Measurements:

All patients had their blood sampled before chemotherapy. White blood cell (WBC) BRCA1 promoter methylation was determined by using methylation-specific quantitative polymerase chain reaction, and the percentage of methylation-positive samples was compared between population control participants and patients with ovarian cancer, including the subgroup with high-grade serous ovarian cancer (HGSOC).

Results:

In the initial study, BRCA1 methylation was more frequent in patients with ovarian cancer than control participants (6.4% vs. 4.2%; age-adjusted odds ratio [OR], 1.83 [95% CI, 1.27 to 2.63]). Elevated methylation, however, was restricted to patients with HGSOC (9.6%; OR, 2.91 [CI, 1.85 to 4.56]), in contrast to 5.1% and 4.0% of patients with nonserous and low-grade serous ovarian cancer (LGSOC), respectively. These findings were replicated in the validation study (methylation-positive status in 9.1% of patients with HGSOC vs. 4.3% of control participants—OR, 2.22 [CI 1.40 to 3.52]—4.1% of patients with nonserous ovarian cancer, and 2.7% of those with LGSOC). The results were not influenced by tumor burden, storage time, or WBC subfractions. In separate analyses of young women and newborns, BRCA1 methylation was detected in 4.1% (CI, 1.8% to 6.4%) and 7.0% (CI, 5.0% to 9.1%), respectively.

Limitations:

Patients with ovarian cancer were recruited at the time of diagnosis in a hospital setting.

Conclusion:

Constitutively normal tissue BRCA1 promoter methylation is positively associated with risk for HGSOC.

Primary Funding Source:

Norwegian Cancer Society.

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Annals Graphic Medicine - Is This What Depression Looks Like?

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Device Closure Versus Medical Therapy Alone for Patent Foramen Ovale in Patients With Cryptogenic Stroke A Systematic Review and Meta-analysis

Background:

The optimal strategy for preventing recurrent stroke in patients with cryptogenic stroke and patent foramen ovale (PFO) is unknown.

Purpose:

To compare transcatheter PFO closure with medical therapy alone for prevention of recurrent stroke in patients with PFO and cryptogenic stroke.

Data Sources:

PubMed and the Cochrane Library (without language restrictions) from inception to October 2017, reference lists, and abstracts from cardiology meetings.

Study Selection:

Randomized trials enrolling adults with PFO and cryptogenic stroke that compared stroke outcomes (main outcome) and potential harms in those receiving transcatheter device closure versus medical therapy alone.

Data Extraction:

Two investigators independently extracted study data and rated risk of bias.

Data Synthesis:

Of 5 trials, 1 was excluded because it used a device that is no longer available due to high rates of complications and failure. Four high-quality trials enrolling 2892 patients showed that PFO closure decreased the absolute risk for recurrent stroke by 3.2% (risk difference, −0.032 [95% CI, −0.050 to −0.014]) compared with medical therapy. The treatment strategies did not differ in rates of transient ischemic attack or major bleeding. Closure of PFOs was associated with higher rates of new-onset atrial fibrillation (AF) than medical therapy alone in all trials, but this outcome had marked between-trial heterogeneity (I² = 82.5%), and high event rates in some groups resulted in extreme values for CIs.

Limitation:

Heterogeneity of device type and antithrombotic therapy across trials, small numbers for some outcomes, and heterogeneous and inconclusive AF results.

Conclusion:

In patients with PFO and cryptogenic stroke, transcatheter device closure decreases risk for recurrent stroke compared with medical therapy alone. Because recurrent stroke rates are low even with medical therapy alone and PFO closure might affect AF risk, shared decision making is crucial for this treatment.

Primary Funding Source:

None.

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Percutaneous Closure Versus Medical Treatment in Stroke Patients With Patent Foramen Ovale A Systematic Review and Meta-analysis

Background:

New evidence emerged recently regarding the percutaneous closure of patent foramen ovale (PFO) to prevent recurrent stroke in patients with cryptogenic stroke.

Purpose:

To compare risks for recurrent cerebrovascular events in adults with PFO and cryptogenic stroke who underwent PFO closure versus those who received medical therapy alone.

Data Sources:

PubMed, Scopus, and Google Scholar from 1 December 2004 through 14 September 2017; references of eligible studies; relevant scientific session abstracts; and cardiology Web sites.

Study Selection:

Randomized controlled trials, published in English, that compared PFO closure using a currently available device with medical treatment alone and that reported, at minimum, the rates of stroke or transient ischemic attack (TIA) or of new-onset atrial fibrillation (AF) or atrial flutter (AFL).

Data Extraction:

2 investigators independently extracted study data and assessed study quality.

Data Synthesis:

4 of 5 trials comparing PFO closure with medical therapy used commercially available devices. These 4 trials, involving 2531 patients, found that PFO closure reduced the risk for the main outcome of stroke or TIA (risk difference [RD], −0.029 [95% CI, −0.050 to −0.007]) and increased the risk for new-onset AF or AFL (RD, 0.033 [CI, 0.012 to 0.054]). The beneficial effect of PFO closure was associated with larger interatrial shunts (P = 0.034).

Limitation:

Trials were not double-blind, and inclusion criteria were heterogeneous.

Conclusion:

Compared with medical treatment, PFO closure prevents recurrent stroke and TIA but increases the incidence of AF or AFL in PFO carriers with cryptogenic stroke.

Primary Funding Source:

Italian Ministry of Education, University and Research (MIUR). (PROSPERO: CRD42017074686)

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Prescription Opioid Use, Misuse, and Use Disorders in U.S. Adults

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Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Synopsis of the 2017 American College of Cardiology/American Heart Association Hypertension Guideline

Description:

In November 2017, the American College of Cardiology (ACC) and the American Heart Association (AHA) released a clinical practice guideline for the prevention, detection, evaluation, and treatment of high blood pressure (BP) in adults. This article summarizes the major recommendations.

Methods:

In 2014, the ACC and the AHA appointed a multidisciplinary committee to update previous reports of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The committee reviewed literature and commissioned systematic reviews and meta-analyses on out-of-office BP monitoring, the optimal target for BP lowering, the comparative benefits and harms of different classes of antihypertensive agents, and the comparative benefits and harms of initiating therapy with a single antihypertensive agent or a combination of 2 agents.

Recommendations:

This article summarizes key recommendations in the following areas: BP classification, BP measurement, screening for secondary hypertension, nonpharmacologic therapy, BP thresholds and cardiac risk estimation to guide drug treatment, treatment goals (general and for patients with diabetes mellitus, chronic kidney disease, and advanced age), choice of initial drug therapy, resistant hypertension, and strategies to improve hypertension control.

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Annals for Educators - 6 March 2018

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The 2017 American College of Cardiology/American Heart Association Hypertension Guideline: A Resource for Practicing Clinicians

The 2017 ACC/AHA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults is the first comprehensive clinical practice guideline for hypertension since the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) in 2003. This commentary discusses the 4 ACC/AHA recommendations that differ substantially from those in JNC 7.

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