A mechanical theory of competition between plant root growth and soil pressure reveals a potential mechanism of root penetration.
Root penetration into the soil is essential for plants to access water and nutrients, as well as to mechanically support aboveground structures. This requires a combination of healthy plant growth, adequate soil mechanical properties, and compatible plant-soil interactions. Despite the current knowledge of the static rheology driving the interactions at the root-soil interface, few theoretical approaches have attempted to describe root penetration with dynamic rheology. In this work, we experimentally showed that radish roots in contact with soil of specific density during a specific growth stage fail to penetrate the soil. To explore the mechanism of root penetration into the soil, we constructed a theoretical model to explore the relevant conditions amenable to root entry into the soil. The theory indicates that dimensionless parameters such as root growth anisotropy, static root-soil competition, and dynamic root-soil competition are important for root penetration. The consequent theoretical expectations were supported by finite element analysis, and a potential mechanism of root penetration into the soil is discussed.


Normal range and variation of the zona pellucida-induced acrosome reaction in fertile men.
To investigate the normal range of the zona pellucida (ZP)-induced acrosome reaction (AR) in fertile men. A study of normative data. Academic research and teaching tertiary hospital.None.Fertile men (n = 111) who had children or whose female partner was currently pregnant. MAIN OUTCOME MEASURE (S): Semen analysis, sperm-ZP binding, and the ZP-induced AR. There was wide range for the ZP-induced AR: 20%-98% with a mean of 48%. The ZP-induced AR was significantly correlated with sperm concentration and normal morphology. The ZP-induced AR was significantly lower in men with sperm concentration <or=60 x 10(6)/mL than those with sperm concentration >60 x 10(6)/mL. Similarly, men with normal sperm morphology >or=15% had significantly higher ZP-induced AR than men with normal morphology <15%. There is a wide range of the ZP-induced AR in fertile men that is correlated with sperm concentration and normal morphology.


Environmental level of the antidepressant venlafaxine induces behavioral disorders through cortisol in zebrafish larvae (Danio rerio).
Psychoactive drugs discharged into the environment have different effects on the behavior of vertebrates. The objective of this study was to evaluate the effect of venlafaxine on the behavior of zebrafish, and whether melatonin could reverse the induction of venlafaxine. In this study, a series of venlafaxine concentrations (1 μg/L, 10 μg/L, 100 μg/L) was used to treat zebrafish embryos from 2 hours post-fertilization (hpf) to 5dpf. We found that venlafaxine (1 μg/L) can stimulate the growth of the head area, eye area, and body length of zebrafish. The light-dark test showed that venlafaxine (1 μg/L) could increase the activity of zebrafish larvae. What's more, venlafaxine (1 μg/L) upregulated the expression of steroid regulatory factors including steroidogenic acute regulatory protein (star), cytochrome P450 family member 11A1 (cyp11a1) and 11 β hydroxylase (cyp11b1) by cAMP-pCREB pathway, affecting the function of the steroidogenic cells, which might be involved in the increased cortisol levels in zebrafish larvae. Whereas, melatonin (230 μg/L) restored the altered locomotion behavior induced by venlafaxine and recovered the altered gene expression. Our results demonstrate that venlafaxine at levels detected in the aquatic environment impacts behavior and may compromise the adaptive responses to the environment in zebrafish larvae.


Cellular composition and interferon-gamma expression of the local inflammatory response in feline infectious peritonitis (FIP).
Feline infectious peritonitis (FIP) is one of the most important viral diseases of cats. International studies estimate that approximately 80% of all purebred cats are infected with the causative agent, feline coronavirus (FCoV). Out of these, 5-12% develop clinical symptoms of FIP. The pathogenesis of the disease is complex with many unresolved issues relating to the role of the immune system. The aim of the present study was to determine the proportions of various inflammatory cell types in FIP lesions by using a panel of cat specific, thoroughly validated, monoclonal antibodies. In addition, the expression of interferon-gamma within the inflammatory lesions was examined by RT-PCR. Our results confirm the mixed nature of the inflammatory reaction in FIP, involving B cells and plasma cells as well as CD4+ and CD8+ T cells. However, one cell type stands out as being the key element in both the "wet" and "dry" forms of FIP: the macrophage. Upregulation of IFN-gamma expression within the inflammatory lesions suggests a local activation of macrophages, which might result in increased viral replication.


Environmental filtering triggers community assembly of forest understorey plants in Central European pine stands.
Habitat filtering models predict ecologically similar plant species to jointly colonize sites due to comparable environmental characteristics leading to an aggregated pattern of species spatial occurrence. Models focused on interspecific competition expect species with similar ecological requirements to be spatially segregated. While both models are corroborated by field work, few empirical studies have tried to infer under which habitat conditions these patterns of co-occurrence prevail. Here we use an exceptional data set on central European pine forest understorey plant communities to assess the change in community structure along gradients of soil productivity and heterogeneity. We found all understorey communities to be significantly nested. The degree of segregation increased with increasing soil Ca and Mg content, as well as with increasing pH, nutrient availability, and moisture. However, variability in soil characteristics did not significantly influence the pattern of species co-occurrence. We also found an intimate link between productivity, species richness, and species segregation making any causal inference challenging. These results point to possible misinterpretations and pitfalls in studies on community assembly. Finally our results demonstrate that managed forests provide a natural experiment of understorey community assembly under controlled conditions, an experiment that deserves further attention.


The Increasing Value of Biomass: Moving From C6 Carbohydrates to Multifunctionalized Building Blocks via 5-(hydroxymethyl)furfural.
Recent decades have been marked by enormous progress in the field of synthesis and chemistry of 5-(hydroxymethyl)furfural (HMF), an important platform chemical widely recognized as the "sleeping giant" of sustainable chemistry. This multifunctional furanic compound is viewed as a strong link for the transition from the current fossil-based industry to a sustainable one. However, the low chemical stability of HMF significantly undermines its synthetic potential. A possible solution to this problem is synthetic diversification of HMF by modifying it into more stable multifunctional building blocks for further synthetic purposes.


Degradation of malachite green on Pd/WO3 photocatalysts under simulated solar light.
The photocatalytic degradation of malachite green (MG) dye molecules in aqueous solution was investigated by using palladium (Pd) modified tungsten trioxide (WO(3)) under simulated solar light. The optimum values for Pd content vs. WO(3) and catalyst concentration in solution for MG (5.0 μmol L(-1)) degradation were 0.5 wt.% and 150 mg L(-1), respectively. The MG concentration change followed the pseudo first order kinetics of the Langmuir-Hinshelwood model. Since MG was also degraded under visible light (λ>470 nm), which was not absorbed by WO(3), the mechanism involved both the photocatalytic degradation and self-sensitized degradation of MG. Pd modified WO(3) would be useful as an efficient tool for the decolorization of wastewater under solar light.


Profiles of Intimate Partner Violence Victimization, Substance Misuse, and Depression Among Female Caregivers Involved with Child Protective Services.
Intimate partner violence (IPV) victimization, substance misuse, and depression are highly prevalent among female caregivers involved with child protective services (CPS). Understanding heterogeneity in the occurrence of these problems is essential to improving pathways to intervention for women in this population. Latent class analysis was employed to determine whether there exist homogeneous subgroups of female caregivers who experience different patterns of IPV victimization, substance misuse, and depression. A restricted three-class solution best fit the data, suggesting high risk, moderate risk, and no risk subgroups. A substantial number of female caregivers comprise the high-risk subgroup (33%) in which caregivers reported very high rates of IPV victimization, substance misuse, and depression. Only a very small proportion comprised the no-risk subgroup (9%). Findings emphasize the heterogeneity among subgroups of female caregivers based on these risk factors, which may have implications for practitioners, such as CPS caseworkers, and researchers alike.


Greater occipital nerve MR tractography: Feasibility and anatomical considerations.
To assess the feasibility of greater occipital nerve (GON) tractography using a fully automated tractography technique on the whole-neck volume, in comparison with anatomical knowledge. Healthy subjects were consecutively included in this study if they had no history or symptoms of headache or brain disorder. A 3T MRI scanner with a 32 channel head coil was used. The following parameters for Diffusion Weighed (DWI) were used: b value of 1000 s/mm2, 32 directions, acquired voxel size: 2 mm isotropic. High-Order tractography with the Constrained Spherical Deconvolution (CSD) model was generated. Track-Weighted Imaging (TWI) maps were generated with MRTrix. Two radiologists performed blind evaluations of the GON pathways on TWI maps. A total of 20 healthy subjects were included (12 males and eight females, mean age 53.8 years old). In comparison with anatomical atlas, GON complete visualization (from C1-C2 origin to muscular emergence) was possible in 18 out of 20 healthy subjects. In two cases, GON was not visible in the cervical spine foramen. Tractography through TWI is a feasible technique to accurately depict GON. This technique may appear as a promising technique for therapeutic management of patients with occipital neuralgia.


Effect of NO2 and SO2 inhalation on benzo(a)pyrene metabolism in rat lung.
Male Wistar rats were continuously exposed to NO2 (14.4 ppm), SO2 (46.5 ppm) and to a mixture of both gases and their effect on lung microsomal aryl hydrocarbon (benzo(a)pyrene) hydroxylase (AHH) activity was determined. The pre-exposed animals were administered methylcholanthrene (MC) to investigate the exposure effect on enzyme inducibility and pattern of B(a)P metabolites. NO2 significantly increased AHH activity but no marked change was noted with SO2. Induction of AHH by MC was markedly inhibited by SO2, only slightly by mixture of NO2-SO2 but not with NO2 alone.


Nursing supervision for care comprehensiveness.
To reflect on nursing supervision as a management tool for care comprehensiveness by nurses, considering its potential and limits in the current scenario. A reflective study based on discourse about nursing supervision, presenting theoretical and practical concepts and approaches. Limits on the exercise of supervision are related to the organization of healthcare services based on the functional and clinical model of care, in addition to possible gaps in the nurse training process and work overload. Regarding the potential, researchers emphasize that supervision is a tool for coordinating care and management actions, which may favor care comprehensiveness, and stimulate positive attitudes toward cooperation and contribution within teams, co-responsibility, and educational development at work. Nursing supervision may help enhance care comprehensiveness by implying continuous reflection on including the dynamics of the healthcare work process and user needs in care networks. refletir a supervisão de enfermagem como instrumento gerencial do enfermeiro para integralidade do cuidado, considerando suas potencialidades e limitações no cenário atual. estudo reflexivo baseado na formulação discursiva sobre a supervisão de enfermagem, apresentando conceitos e enfoques teóricos e/ou práticos. limitações no exercício da supervisão estão relacionadas à organização dos serviços de saúde embasada no modelo funcional e clínico de atenção, assim como possíveis lacunas no processo de formação do enfermeiro e sobrecarga de trabalho. Quanto às potencialidades, destaca-se a supervisão como instrumento de articulação de ações assistenciais e gerenciais, que pode favorecer integralidade da atenção, estimular atitudes de cooperação e colaboração em equipe, além da corresponsabilização e promoção da educação no trabalho. supervisão de enfermagem pode contribuir para fortalecimento da integralidade do cuidado, pressupondo reflexão contínua, para contemplar a dinamicidade do processo de trabalho em saúde e necessidades dos usuários nas redes de atenção.


Thermoplastic custom trays for making regional facial impressions.
A facial impression technique that uses a thermoplastic splint material as a custom tray has been described. The use of this technique simplifies a time-consuming and cumbersome procedure for both the patient and the dentist.


Imaging features of the PI-RADS for predicting extraprostatic extension of prostate cancer: systematic review and meta-analysis.
To systematically determine the diagnostic performance of each MRI feature of the PI-RADS for predicting extraprostatic extension (EPE) in prostate cancer. A literature search in the MEDLINE and EMBASE databases was conducted to identify original studies reporting the accuracy of each feature on MRI for the dichotomous diagnosis of EPE. The meta-analytic pooled diagnostic odds ratio (DOR), sensitivity, specificity, and their 95% confidence intervals (CIs) were obtained using a bivariate random-effects model. After screening 1955 studies, 17 studies with a total of 3062 men were included. All six imaging features, i.e., bulging prostatic contour, irregular or spiculated margin, asymmetry or invasion of neurovascular bundle, obliteration of rectoprostatic angle, tumor-capsule interface > 10 mm, and breach of the capsule with evidence of direct tumor extension, were significantly associated with EPE. Breach of the capsule with direct tumor extension demonstrated the highest pooled DOR (15.6, 95% CI [7.7-31.5]) followed by tumor-capsule interface > 10 mm (10.5 [5.4-20.2]), asymmetry or invasion of neurovascular bundle (7.6 [3.8-15.2]), and obliteration of rectoprostatic angle (6.1 [3.8-9.8]). Irregular or spiculated margin showed the lowest pooled DOR (2.3 [1.3-4.2]). Breach of the capsule with direct tumor extension and tumor-capsule interface > 10 mm showed the highest pooled specificity (98.0% [96.2-99.0]) and sensitivity (86.3% [70.0-94.4]), respectively. Among the six MRI features of prostate cancer, breach of the capsule with direct tumor extension and tumor-capsule interface > 10 mm were the most predictive of EPE with the highest specificity and sensitivity, respectively.


[Incidental high blood pressure in family practice: due to hypertension and/or left ventricular hypertrophy in more than half of the patients].
To determine if patients with incidentally high blood pressure actually have hypertension and if these patients have an increased left ventricular mass. Cross-sectional study. Two family practices with 8 general practitioners in Leiden and Noordwijk, the Netherlands. From the Family Practice Network in the Leiden area 133 (67%) out of 200 patients with incidental high blood pressure, who did not receive antihypertensive medication, participated in the study. Their blood pressure was measured 6 times with a mercury manometer, an automatic, non-invasive ambulatory blood pressure monitoring during 24 hours was performed once and their left ventricular mass was measured by means of echocardiography. Of the 133 selected patients 46% had a mean diastolic blood pressure > 95 mmHg measured with the mercury manometer and 64% had a mean 24-hr diastolic blood pressure > 90 mmHg measured with the ambulatory blood pressure monitor. The correlation between both blood pressure measurements was moderate (correlation coefficient 0.73). Left ventricular hypertrophy was found in 53% of the patients, irrespective of their blood pressures. In this investigation 45-65% of patients with an incidentally high blood pressure had a mean diastolic pressure > 95 mmHg as measured with a mercury manometer and (or) a mean 24-hr diastolic blood pressure > 90 mmHg as measured with the ambulatory blood pressure monitor; 53% had left ventricular hypertrophy.


Expression and phosphorylation of protein kinase C isoforms in Abeta(1-42) activated T lymphocytes from Alzheimers disease.
The protein kinase C (PKC) family of enzymes is a regulator of transmembrane signal transduction. There is evidence demonstrating altered activity of some PKC isoforms (PKC-alpha, PKC-delta and PKC-zeta) in the neurons of brains of Alzheimers Disease (AD) sufferers, but little is known about their involvement in the intracellular machinery of amyloid beta protein-reactive T lymphocytes in AD. By applying a modified, split-well culture system, for Abeta(1-42) reactivity, we carried out flow cytometry analysis and biochemical investigations on the possible involvement of PKC-alpha, PKC-delta and PKC-zeta in the signalling system activated in Abeta-reactive T cells purified from peripheral blood mononucleate cells (PBMC) from healthy subjects and patients with AD. Flow cytometry analysis of Abeta(1-42) activated T lymphocytes in the majority of AD patients highlighted a distinct cellular cluster highly expressing phospho-PKC-delta (P-PKC-delta), while most full-blown AD patients highly expressed two distinct P-PKC-delta and phospho-PKC-zeta (P-PKC-zeta) bright sub-populations. The same investigation performed in freshly purified peripheral T lymphocytes, did not highlight any subpopulation, suggesting that the detection of P-PKC-delta and P-PKC-zeta bright subpopulations is specifically linked to Abeta(1-42) activated T lymphocytes. The data presented here, therefore, suggest possible novel hallmarks to discriminate between healthy elderly subjects and beginning or full-blown Alzheimers Disease patients.


Biological variation of the natriuretic peptides and their role in monitoring patients with heart failure.
B-type natriuretic peptide (BNP) and the inactive metabolite NT-proBNP are proven tests for diagnosis and staging of severity for patients with heart failure. However, the utility of these biomarkers for monitoring the success of drug therapy remains to be determined. Results of longitudinal studies on serial blood testing must be linked to overall patient morbidity and mortality outcomes. We previously determined the 8-week biological variability (BV) of BNP and NT-proBNP assays in healthy subjects and the 1-day BV for BNP alone in patients with compensated and stable heart failure. From these studies, the percent statistical change in serial samples of approximately 100% difference was estimated (95% confidence). We applied the biological variability concepts to the serial results of BNP and NT-proBNP collected from patients with heart failure and compared the performance of these two markers. While there are minor differences in the results between the assays from one time period to another, the overall interpretation of results are essentially identical. Moreover, the majority of individual serial time points are not significantly different from the previous value. Frequent testing (e.g. daily) for BNP and NT-proBNP to monitor therapy for patients with CHF is not indicated, as overall changes require several days to become evident.


Sensitizing brain metastases to stereotactic radiosurgery using hyperbaric oxygen: A proof-of-principle study.
Increased oxygen levels may enhance the radiosensitivity of brain metastases treated with stereotactic radiosurgery (SRS). This project administered hyperbaric oxygen (HBO) prior to SRS to assess feasibility, safety, and response. 38 patients were studied, 19 with 25 brain metastases treated with HBO prior to SRS, and 19 historical controls with 27 metastases, matched for histology, GPA, resection status, and lesion size. Outcomes included time from HBO to SRS, quality-of-life (QOL) measures, local control, distant (brain) metastases, radionecrosis, and overall survival. The average time from HBO chamber to SRS beam-on was 8.3 ± 1.7 minutes. Solicited adverse events (AEs) were comparable between HBO and control patients; no grade III or IV serious AEs were observed. Radionecrosis-free survival (RNFS), radionecrosis-free survival before whole-brain radiation therapy (WBRT) (RNBWFS), local recurrence-free survival before WBRT (LRBWFS), distant recurrence-free survival before WBRT (DRBWFS), and overall survival (OS) were not significantly different for HBO patients and controls on Kaplan-Meier analysis, though at 1-year estimated survival rates trended in favor of SRS + HBO: RNFS - 83% vs 60%; RNBWFS - 78% vs 60%; LRBWFS - 95% vs 78%; DRBWFS - 61% vs 57%; and OS - 73% vs 56%. Multivariate Cox models indicated no significant association between HBO treatment and hazards of RN, local or distant recurrence, or mortality; however, these did show statistically significant associations (p < 0.05) for: local recurrence with higher volume, radionecrosis with tumor resection, overall survival with resection, and overall survival with higher GPA. Addition of HBO to SRS for brain metastases is feasible without evident decrement in radiation necrosis and other clinical outcomes.


Home intravenous versus oral antibiotics following appendectomy for perforated appendicitis in children: a randomized controlled trial.
To compare the effect of home intravenous (IV) versus oral antibiotic therapy on complication rates and resource utilization following appendectomy for perforated appendicitis. This was a randomized controlled trial of patients aged 4-17 with surgically treated perforated appendicitis from January 2011 to November 2013. Perforation was defined intraoperatively and divided into three grades: I-contained perforation, II-localized contamination to right gutter/pelvis, and III-diffuse contamination. Patients were randomized to complete a ten-day course of home antibiotic therapy with either IV ertapenem or oral amoxicillin-clavulanate. Thirty-day postoperative complication rates including abscess, readmission, wound infection, and charges were compared. Eighty-two patients were enrolled. Forty four (54%) were randomized to the IV group and 38 (46%) to the oral group. IV patients were older (12.3 ± 3.6 versus 10.1 ± 3.6, p < 0.05) with higher BMI (20.9 ± 5.8 versus 17.9 ± 3.5, p < 0.05). There were no differences in gender, comorbidities, or perforation grade (I-20.4% vs. 26.3%, II-36.4% vs. 34.2%, III-43.2% vs. 39.5%, all p > 0.05). Comparing IV to oral, there was no difference in length of stay (4.4 ± 1.5 versus 4.4 ± 2.0 days, p > 0.05), postoperative abscess rate (11.6% vs. 8.1%, p > 0.05), or readmission rate (14.0% vs. 16.2%, p > 0.05). Hospital and outpatient charges were higher in the IV group (p < 0.0001). Oral antibiotics had equivalent outcomes and incurred fewer charges than IV antibiotics following appendectomy for perforated appendicitis.


When ERCP Fails: EUS-Guided Access to Biliary and Pancreatic Ducts.
Pancreaticobiliary (PB) endotherapy continues to progress in the era of therapeutic endosonography. Endoscopic retrograde cholangiopancreatography (ERCP) remains the primary method for PB access in native and altered anatomy. In altered anatomy, PB access can be obtained via enteroscopy-assisted ERCP (e-ERCP) or laparoscopy-assisted ERCP; however, both approaches have significant limitations. Endoscopic ultrasound-guided biliary and pancreatic duct drainage (EUS-BPD) are increasingly becoming the preferred alternative when ERCP fails, with advantages over percutaneous drainage. EUS-BPD continues to evolve with better feasibility, safety and efficacy as dedicated procedural equipment continues to improve. In this article, we discuss the role of endoscopic ultrasound (EUS) when ERCP fails and their indications, technique, and outcomes.


Vascular density and phenotype around ductal carcinoma in situ (DCIS) of the breast.
Up to 50% of recurrences of ductal carcinoma in situ of the breast are associated with invasive carcinoma but no pathological or molecular features have yet been found to predict for the development of invasive disease. For a tumour to invade, it requires the formation of new blood vessels. Previous studies have described a vascular rim around ducts involved by ductal carcinoma in situ, raising the possibility that the characteristics of periductal vascularisation may be important in determining transformation from in situ to invasive disease. Periductal vascular density and phenotype were determined using morphometry and a panel of anti-endothelial antibodies (von Willebrand factor, CD31, CD141 and CD34) and related to the presence of invasive carcinoma and other histological features. Compared to normal lobules, pure ductal carcinoma in situ exhibited a greater density of CD34+ and CD31+ vessels but a decrease in those that were immunopositive for vWF, indicating a difference in phenotype and in density. Ductal carcinoma in situ associated with invasive carcinoma showed a profile of vascular immunostaining similar to that of pure ductal carcinoma in situ but there were significantly greater numbers of CD34+ and CD141+ vessels and fewer staining for vWF. There was a significant negative correlation between vascular density and both the cross-sectional areas of the ducts involved and the extent of the necrosis of the tumour they contained. A correlation between vascular density and nuclear grade was also noted, being highest in the intermediate grade. The greater density of CD34+ and CD141+ vessels around ductal carcinoma in situ associated with invasive carcinoma could reflect a greater predisposition to invade but a direct effect of co-existent invasive carcinoma cannot entirely be ruled out in the present study. The relationship between vascular density, grade, duct size and nuclear grade suggests that periductal angiogenesis increases with tumour growth rate but is unable to keep pace with the most rapidly growing lesions.


Randomized, placebo-controlled, pilot study evaluating aprepitant single dose plus palonosetron and dexamethasone for the prevention of acute and delayed chemotherapy-induced nausea and vomiting.
The combination of palonosetron and aprepitant is safe and effective in the prevention of chemotherapy-induced emesis (CIE). The purpose of this pilot study was to ascertain the effectiveness of 1-day versus 3-day aprepitant in the prevention of acute and delayed nausea and vomiting in patients who were receiving highly emetogenic chemotherapy. This study was institutional review board-approved and informed consent was obtained before this study was begun. This was a pilot, single-institution, randomized, double-blind, placebo-controlled trial that evaluated 3 different treatment arms. All groups received palonosetron 0.25 mg intravenously on Day 1 and dexamethasone on Days 1-4. Arm A received aprepitant 125 mg orally on Day 1 followed by 80 mg on Days 2-3. Arm B received aprepitant 125 mg orally on Day 1 and placebo on Days 2-3. Arm C received placebos on Days 1-3. The primary endpoint was to evaluate the proportion of patients with acute and delayed emesis within each group. Seventy-five patients were included in the analysis. The study commenced with 3 groups; however, an interim analysis displayed unacceptable emesis events in Arm C, and this group was terminated. There were no significant differences between Arms A and B for emesis, nausea, or the use of breakthrough antiemetics. In Arms A and B, 93% of patients were emesis-free from Days 1-5 compared with only 50% in Arm C. From this pilot study of patients who were receiving palonosetron, aprepitant, and dexamethasone for highly emetogenic chemotherapy, a single dose of aprepitant displayed similar effectiveness compared with 3-day aprepitant.


Novel processes invaginate the pre-synaptic terminal of retinal bipolar cells.
Mixed-rod cone bipolar (Mb) cells of goldfish retina have large synaptic terminals (10 microm in diameter) that make 60-90 ribbon synapses mostly onto amacrine cells and rarely onto ganglion cells and, in return, receive 300-400 synapses from gamma-aminobutyric acid (GABA)-ergic amacrine cells. Tissue viewed by electron microscopy revealed the presence of double-membrane-bound processes deep within Mb terminals. No membrane specializations were apparent on these invaginating processes, although rare vesicular fusion was observed. These invaginating dendrites were termed "InDents". Mb bipolar cells were identified by their immunoreactivity for protein kinase C. Double-label immunofluorescence with other cell-type-specific labels eliminated Müller cells, efferent fibers, other Mb bipolar cells, dopaminergic interplexiform cells, and somatostatin amacrine cells as a source of the InDents. Confocal analysis of double-labeled tissue clearly showed dendrites of GABA amacrine cells, backfilled ganglion cells, and dendrites containing PanNa immunoreactivity extending into and passing through Mb terminals. Nearly all Mb terminals showed evidence for the presence of InDents, indicating their common presence in goldfish retina. No PanNa immunoreactivity was found on GABA or ganglion cell InDents, suggesting that a subtype of glycine amacrine cell contained voltage-gated Na channels. Thus, potassium and calcium voltage-gated channels might be present on the InDents and on the Mb terminal membrane opposed to the InDents. In addition to synaptic signaling at ribbon and conventional synapses, Mb bipolar cells may exchange information with InDents by an alternative signaling mechanism.


Radiologic findings in anorectal gonorrhea.
Gonorrhea is the most prevalent communicable disease in the United States and the incidence of anorectal involvement is high. Anorectal gonorrhea may be clinically elusive making the radiologic findings crucial in suggesting the diagnosis. Edematous rectal mucosa with limited distensibility and small ulcerations are the prominent radiologic findings.


A new acridine derivative induces cell cycle arrest and antiangiogenic effect on Ehrlich ascites carcinoma model.
Acridine derivatives, including amsacrine, have antitumor activity. However, side effects, development of resistance and their low bioavailability, have limited their use. Herein, we described the synthesis, and evaluated the toxicity and antitumor activity of a new amsacrine analogous, the N'-(2-chloro-6-methoxy-acridin-9-yl)-2-cyano-3-(4-dimethylaminophenyl)-acrilohidrazida (ACS-AZ10). The compound was obtained in a linear pathway where the ASC-Az intermediate was obtained by coupling of 6,9-dichloro-3-methoxy-acridine and 2-ciany-acethohidrazide followed by condensation with the corresponding aldehyde. The toxicity of ACS-AZ10 was evaluated in mice using acute toxicity and micronucleus assays. Ehrlich ascites carcinoma model was used to investigate the antitumor activity and toxicity of ACS-AZ10 (7.5, 15 or 30mg/kg, i.p.), after nine days of treatment. Cell cycle and angiogenesis were also evaluated. The ASC-AZ10 was obtained with satisfactory yields and its structure was confirmed by spectroscopic and spectrometric techniques. On acute toxicity study, ACS-AZ10 (2000mg/kg, i.p.) induced transient depressant effects on central nervous system. The LD50 was approximately 2500mg/kg. ACS-AZ10 (15 or 30mg/kg) displayed significant antitumor activity considering the tumor weight and volume, cell viability, and total Ehrlich cell count. ACS-AZ10 (7.5mg/kg) induced an increase in sub-G1 peak, suggesting apoptosis. At 15mg/kg ACS-AZ10 induced cell cycle arrest in G2/M phase and a reduction in the percentage of cells in G0/G1 and S phases, suggesting a pre-mitotic blockade. ACS-AZ10 reduced the microvessel density, indicating an antiangiogenic effect. Weak hematological, biochemical and histopathological toxicity were observed. The compound doesn't show genotoxicity in micronucleus assay. ACS-AZ10 has potent antitumor activity in vivo along with low toxicity.


Kinetics of zinc status and zinc deficiency in Berardinelli-Seip syndrome.
Berardinelli-Seip syndrome (BSS) is a very rare disorder characterized by near-complete absence of adipose tissue from birth or early infancy, hypoleptinemia, hypertriglyceridemia, insulin resistance, diabetes mellitus, and other clinical signals. It is caused by mutations in AGPAT2 or Gng3lg. We evaluated 10 BSS patients and 10 healthy subjects. A single dose of 382.43 μmol zinc was administered intravenously before and after 3 months of oral zinc supplementation. Blood samples were collected from the contralateral arm at 0, 30, 60, 90, and 120 min after zinc injection. Plasma and serum were obtained to measure hematological and biochemical parameters. Urine was collected to measure creatinine, protein, and zinc. Basal serum zinc levels were similar in controls and BSS patients. However, serum zinc profiles were significant reduced in BSS patients in comparison with controls. The change in total-body zinc clearance was more significant in BSS patients, indicating that these patients had suboptimum zinc deficiency.


Modulation of fluoropyrimidine metabolism in L1210 cells by L-alanosine.
L-Alanosine, an analogue of aspartic acid which inhibits the conversion of inosine monophosphate to adenosine monophosphate (AMP), was evaluated in L1210 cells as a modulator of 5-fluorouracil (FUra) and 5-fluorouridine (FUrd) metabolism. L-Alanosine resulted in increased intra-cellular levels of 5-phosphoribosyl-1-pyrophosphate (PRPP), enhanced FUra metabolism to ribonucleotide derivatives, and resulted in more FUra residues incorporated into RNA. Sequential addition of L-alanosine and FUra also resulted in synergistic cytotoxicity as determined by soft agar cloning. Adenine antagonized these biochemical and biological effects of L-alanosine. L-Alanosine also augmented the rate at which FUrd was metabolized and was also associated with a greater incorporation of the FUra residues into RNA. Cytotoxicity after sequential L-alanosine and FUrd was also synergistic. The mechanism by which L-alanosine altered the metabolism of FUrd, however, was different from the way in which it enhanced FUra metabolism in that aspartic acid and not adenine was able to reverse the effects of L-alanosine on FUrd metabolism and cytotoxicity. L-Alanosine appeared to augment the RNA-directed activity of FUra and FUrd in that there was no correlation between the enhanced metabolism and cytotoxicity of these two fluoropyrimidines and either levels of fluorodeoxyuridylate (FdUMP) which inhibits thymidylate (TMP) synthetase or inhibition of the ability of cells to incorporate deoxyuridylate into acid-precipitable material.


Factors influencing bereaved families' decisions about organ donation: an integrative literature review.
This article reports on the process and outcomes of a systematic integrative literature review, designed to enhance understanding of the factors influencing bereaved families' decisions to agree or decline the donation of their deceased relative's organs for transplantation. Research originating from eight Western countries (N = 20 studies) provided an international perspective to the review. Thematic analysis and synthesis of textual data culminated in the development of three global themes (past, present, and future) that captured the temporal dimensions of family decision making. The review findings provide valuable insight into ways of increasing the rate of consent to organ donation through the development family-centered care interventions that reflect the needs of the bereaved. Further research to explore the pathway of donation after circulatory death and the experiences of bereaved families who decline organ donation is essential to providing a more complete understanding of the factors affecting donation decisions.


[Metrological and operating characteristics of thermoluminescent and photographic film dosimeters for the centralized individual dosimetric monitoring of medical personnel].
Characteristics of a TLD thermoluminescent kit with LiF detectors of TLD and DTG-4 types (diameters 3.5 and 5 mm) and TLD-400 were compared with those of a kit of IFKU-1 individual photographic film badges. Individual thermoluminescent dosimeters record a total dose of occupational and background irradiation, and film badges--a dose of occupational irradiation only. It should be taken into account in radiation-hygienic interpretation of individual dosimetric control readings.


The FUS::DDIT3 fusion oncoprotein inhibits BAF complex targeting and activity in myxoid liposarcoma.
Mammalian SWI/SNF (mSWI/SNF or BAF) ATP-dependent chromatin remodeling complexes play critical roles in governing genomic architecture and gene expression and are frequently perturbed in human cancers. Transcription factors (TFs), including fusion oncoproteins, can bind to BAF complex surfaces to direct chromatin targeting and accessibility, often activating oncogenic gene loci. Here, we demonstrate that the FUS::DDIT3 fusion oncoprotein hallmark to myxoid liposarcoma (MLPS) inhibits BAF complex-mediated remodeling of adipogenic enhancer sites via sequestration of the adipogenic TF, CEBPB, from the genome. In mesenchymal stem cells, small-molecule inhibition of BAF complex ATPase activity attenuates adipogenesis via failure of BAF-mediated DNA accessibility and gene activation at CEBPB target sites. BAF chromatin occupancy and gene expression profiles of FUS::DDIT3-expressing cell lines and primary tumors exhibit similarity to SMARCB1-deficient tumor types. These data present a mechanism by which a fusion oncoprotein generates a BAF complex loss-of-function phenotype, independent of deleterious subunit mutations.


Antimalarial evaluation and docking studies of hybrid phenylthiazolyl-1,3,5-triazine derivatives: a novel and potential antifolate lead for Pf-DHFR-TS inhibition.
Present communication deals with the docking study of hybrid phenyl thiazolyl-1,3,5-triazine analogues (1a-36d) on three selected different binding site viz., α, β and γ of wild type Pf-DFHR-TS. In admiration of excellent H-bond scoring, with regard to cycloguanil and to a large extent similar scoring with WR99210, compound 4a, 12b, 21c, 23c, 28d, 29d, 34d, and 35d were selected for in vitro antimalarial activity against 3D7 strain of Plasmodium falciparum. Findings from the study disclose that a significant correlation was exist between in vitro results and in silico prediction (r(2)=0.543). Furthermore, investigation of structure-activity relationships elucidate crucial structural requirement for site specific binding of ligands.


Applications of imaging flow cytometry in the diagnostic assessment of red cell membrane disorders.
Red cell membranopathies refers to phenotypically and morphologically heterogeneous disorders. High throughput imaging flow cytometry (IFC) combines the speed, sensitivity, and phenotyping abilities of flow cytometry with the detailed imagery and functional insights of microscopy to produce high content image analysis with quantitative analysis. We have evaluated the applications of IFC to examine both the morphology as well as fluorescence signal intensity in red cell membranopathies. Fluorescence intensity of eosin-5-maleimide (EMA) labeled red cells was measured for diagnosis of RBC membrane protein defect on Amnis ImageStreamX followed by Image analysis on IDEAS software to study features such as circularity and shape ratio. The hereditary spherocytosis (HS) group showed significantly decreased MFI (52,800 ± 9,100) than normal controls (81,100 ± 4,700) (p < .05) whereas non-HS showed 78,300 ± 9,900. The shape ratio of hereditary elliptocytosis (HE) was significantly higher (43.8%) than normal controls (14.6%). The circularity score is higher in HS (64.15%) than the normal controls (44.3%) whereas the circularity score was very less in HE (10%) due to the presence of elliptocytes. The advantages of the IFC over standard flow cytometry is its ability to provide high-content image analysis and measurement of parameters such as circularity and shape ratio allow discriminating red cell membranopathies (HS and HE) due to variations in shape and size. It could be a single, effective, and rapid IFC test for detection and differentiation of red cell membrane disorders in hematology laboratories where an IFC is available.


Cost-effectiveness of routine screening for Lynch syndrome in colorectal cancer patients up to 70 years of age.
To assess the cost-effectiveness of routine Lynch syndrome (LS) screening among colorectal cancer (CRC) patients ≤70 years of age. A population-based series of CRC patients ≤70 years of age was routinely screened for LS. We calculated life years gained (LYG) and incremental cost-effectiveness ratios (ICERs) for different age cutoffs and comparing age-targeted screening with the revised Bethesda guidelines. Screening 1,117 CRC patients identified 23 LS patients, of whom 7 were ≤50 years of age, 7 were 51-60, and 9 were 61-70. Additionally, 70 LS carriers were identified among relatives (14, 42, and 14 per age category). Screening amounted to 205.9 LYG or 43.6, 118.0, and 44.3 LYG per age category. ICERs were [euro ]4.226/LYG for screening CRC patients ≤60 years of age compared with those ≤50 years and [euro ]7.051/LYG for screening CRC patients ≤70 years compared with those ≤60 years. The revised Bethesda guidelines identified 70 of 93 (75%) LS carriers. The ICER for LS screening in CRC patients ≤70 years of age compared with the revised Bethesda guidelines was [euro ]7.341/LYG. All ICERs remained less than [euro ]13.000/LYG in one-way sensitivity analyses. Routine LS screening by analysis of microsatellite instability, immunohistochemistry, and MLH1 hypermethylation in CRC patients ≤70 years of age is a cost-effective strategy with important clinical benefits for CRC patients and their relatives.Genet Med 18 10, 966-973.


On the Sr1-xBaxFeO₂F Oxyfluoride Perovskites: Structure and Magnetism from Neutron Diffraction and Mössbauer Spectroscopy.
Four oxyfluorides of the title series (x = 0.00, 0.25, 0.50, 0.75) have been stabilized by topotactic treatment of perovskite precursors Sr1-xBaxFeO3-δ prepared by soft-chemistry procedures, yielding reactive materials that can easily incorporate a substantial amount of F atoms at moderate temperatures, thus avoiding the stabilization of competitive SrF₂ and BaF₂ parasitic phases. XRD and Neutron Powder Diffraction (NPD) measurements assess the phase purity and yield distinct features concerning the unit cell parameters' variation, the Sr and Ba distribution, the stoichiometry of the anionic sublattice and the anisotropic displacement factors for O and F atoms. The four oxyfluorides are confirmed to be cubic in all of the compositional range, the unit cell parameters displaying Vergard's law. All of the samples are magnetically ordered above room temperature; the magnetic structure is always G-type antiferromagnetic, as shown from NPD data. The ordered magnetic moments are substantially high, around 3.5 μB, even at room temperature (RT). Temperature-dependent Mössbauer data allow identifying Fe3+ in all of the samples, thus confirming the Sr1-xBaxFeO₂F stoichiometry. The fit of the magnetic hyperfine field vs. temperature curve yields magnetic ordering TN temperatures between 740 K (x = 0.00) and 683 K (x = 0.75). These temperatures are substantially higher than those reported before for some of the samples, assessing for stronger Fe-Fe superexchange interactions for these specimens prepared by fluorination of citrate precursors in mild conditions.


Ferritins in Chordata: Potential evolutionary trajectory marked by discrete selective pressures: History and reclassification of ferritins in chordates and geological events' influence on their evolution and radiation.
Ferritins (FTs) are iron storage proteins that are involved in managing iron-oxygen balance. In our work, we present a hypothesis on the putative effect of geological changes that have affected the evolution and radiation of ferritin proteins. Based on sequence analysis and phylogeny reconstruction, we hypothesize that two significant factors have been involved in the evolution of ferritin proteins: fluctuations of atmospheric oxygen concentrations, altering redox potential, and changing availability of water rich in bioavailable ferric ions. Fish, ancient amphibians, reptiles, and placental mammals developed the broadest repertoire of singular FTs, attributable to embryonic growth in aquatic environments containing low oxygen levels and abundant forms of soluble iron. In contrast, oviparous land vertebrates, like reptiles and birds, that have developed in high oxygen levels and limited levels of environmental Fe2+ exhibit a lower diversity of singular FTs, but display a broad repertoire of subfamilies, particularly notable in early reptiles.


Imaging of enzyme activity by scanning electrochemical microscope equipped with a feedback control for substrate-probe distance.
The enzymatic activity of diaphorase (Dp) immobilized on a solid substrate was characterized using a scanning electrochemical microscope (SECM) with shear force feedback to control the substrate-probe distance. The shear force between the substrate and the probe was monitored with a tuning fork-type quartz crystal and used as the feedback control to set the microelectrode probe close to the substrate surface. The sensitivity and the contrast of the SECM image were improved in the constant distance mode (distance, 50 nm) with the shear force feedback compared to the image in the constant height mode without the feedback. By using this system, the SECM and topographic images of the immobilized diaphorase were simultaneously measured. The microelectrode tip used in this study was ground aslant like a syringe needle in order to obtain the shaper topographic images. This shape was also effective for avoiding the interference during the diffusion of the enzyme substrates.


Synergistic effect of metformin on sorafenib in in vitro study using hepatocellular carcinoma cell lines.
Hepatocellular carcinoma (HCC) recurrence remains a great concern following hepatic resection and liver transplantation. We investigated the metformin-induced cytotoxic effects on sorafenib in an in vitro study using HCC cell lines. This research was conducted through an in vitro study using one HepG2.2.15 liver tumor and two patient-derived graft HCC cell lines. An in vitro study revealed noticeable cytotoxic effects of metformin as well as noticeable synergistic cytotoxic effects of metformin and sorafenib on cell viability. Assays for the mechanisms of action of antitumor effects revealed that alpha-fetoprotein expression was suppressed by both metformin and sorafenib, but no synergistic effect was observed. LC3-I and LC3-II assays revealed the synergistic upregulation of autophagy and assays for IL-1β, IL-6, p53, and TNF-α revealed the synergistic upregulation of cell damage and apoptosis. In contrast, metformin did not affect HBx expression, thus no noticeable synergistic effect was considered to be present. Our in vitro study demonstrated cytotoxic effects of metformin and synergistic antitumor effects of sorafenib. These results should be verified in further clinical studies with patients of advanced HCC.


Towards crucial post-modification in biosynthesis of terpenoids and steroids: C3 oxidase and acetyltransferase.
Terpenoids and steroids are two large families of natural products with diverse biological activities. C3 oxidase and acetyltransferase are the key enzymes in the post-modification of terpenoids and steroids, while their discovery is of great importance for the efficient bioproduction and wide application of these natural products. In this review, we first explain the reaction mechanism of typical enzymes. Next, we summarize the current state-of-art strategies in the discovery of C3 oxidase and acetyltransferase, and discuss rational engineering of these enzymes with novel catalytic functions. Finally, we propose how to obtain an excellent biocatalyst of C3 oxidase and acetyltransferase by exploiting the discovery strategy and the reaction mechanism.


Chlamydia trachomatis cervical infection in women seeking routine gynecologic care: criteria for selective testing.
Chlamydia trachomatis infection is one of the most common sexually transmitted diseases. Developing methods to identify patients who are at higher risk would enable clinicians to perform selective testing for C. trachomatis infection, which may reduce morbidity, sequelae, and overall costs. Risk factors for C. trachomatis infection of the cervix in women seen for routine gynecologic care were therefore analyzed. Extensive clinical data and cervical cultures were obtained from 1,141 women between the ages of 18 and 50. Multivariate techniques were used to develop and prospectively test a model to predict infection. In the model development series of 530 patients seen in a hospital-based practice, 24 (4.5%) had a positive culture result. In the validation series of 611 patients seen in private practice, 17 (2.8%) had positive culture results. The majority of infected patients (61%) were asymptomatic. For sexually active women 18 to 35 years of age, the optimal predictive model was based on three factors: level of education (high school or less), a sex partner with other partners during the prior three months, and endocervical bleeding induced by the initial swab. In the validation series, the prevalence of infection for women with one or more of these factors was 5.8% (95% confidence interval, 4.0 to 8.6) compared with 0.9% in patients without these factors (p = 0.005). Clinical information can be used in a low-prevalence population to predict a patient's risk for C. trachomatis infection and to select patients for testing.


Calcium- and voltage-dependent potassium channel in the rat retinal amacrine cells identified in vitro using a cell type-specific monoclonal antibody.
Single-channel currents were studied from identified amacrine cells of rat retinal monolayer cultures. Cells were immunohistochemically identified using an amacrine cell-specific monoclonal antibody, HPC-1. Single-channel currents with the following properties were observed. (1) The mean opening duration was voltage dependent, tending to increase on hyperpolarization. (2) The reversal potential was almost identical to the calculated EK derived from the potassium concentration gradient. (3) The conductance was 110 pS at a low extracellular potassium concentration. (4) Currents were blocked by TEA. (5) Mean opening duration was also dependent on the calcium concentration of the intracellular side. These properties were consistent with the voltage and calcium-dependent potassium channels of a large conductance. Our results also demonstrated that cell-type-specific monoclonal antibodies together with electrophysiological recordings offer a very useful method to investigate the physiological properties of distinct neuronal types in mixed cell cultures.


Overexpression of EphB6 and EphrinB2 controls soma spacing of cortical neurons in a mutual inhibitory way.
To establish functional circuitry, neurons settle down in a particular spatial domain by spacing their cell bodies, which requires proper positioning of the soma and establishing of a zone with unique connections. Deficits in this process are implicated in neurodevelopmental diseases. In this study, we examined the function of EphB6 in the development of cerebral cortex. Overexpression of EphB6 via in utero electroporation results in clumping of cortical neurons, while reducing its expression has no effect. In addition, overexpression of EphrinB2, a ligand of EphB6, also induces soma clumping in the cortex. Unexpectedly, the soma clumping phenotypes disappear when both of them are overexpressed in cortical neurons. The mutual inhibitory effect of EphB6/ EphrinB2 on preventing soma clumping is likely to be achieved via interaction of their specific domains. Thus, our results reveal a combinational role of EphrinB2/EphB6 overexpression in controlling soma spacing in cortical development.


My mind is as clear as it used to be: A pilot study illustrating the difficulties of employing a single-item subjective screen to detect cognitive impairment in outpatients with cancer.
Oncology patients often complain that their "mind does not seem to be clear." This subjective perception, sometimes referred to as "chemo brain," may be due to situational stressors, psychological disorders, organic factors, or effects of neurotoxic medications. Cognitive decline cannot only diminish quality of life, but can also interfere with a patient's ability to make decisions regarding complex treatment issues. The current study investigated the utility of using item 11 of the Zung Self-Rating Depression Screen (ZSDS) as a cognitive screen. A sample of 61 ambulatory cancer patients completed this study. Participants were recruited from four sites of Community Cancer Care, Inc., in Indiana. A battery of cognitive instruments and psychosocial inventories was administered in a standardized order. The sample had a mean age of 58.6 years and comprised 57.4% (n=35) women and 42.6% (n=26) men. Item 11 of the ZSDS was not significantly correlated to the cognitive measures. Correlates of the perception of cognitive impairment were the Dementia Rating Scale (DRS) Attention Scale (r=-0.26, P<0.05) and the ZSDS total score (r=-0.29, P<0.05). Patients' perceptions of having a cognitive impairment determined by item 11 of the ZSDS was predicted by total score on the ZSDS (F=42.5, P<0.001), age (F=26.0, P<0.001), and score on the Stroop test (F=19.8, P<0.001). Analysis of sensitivity and specificity indicated that the single-item screen used in this study is not an accurate means for identifying oncology patients with actual cognitive impairment. We conclude that while the perception of cognitive impairment is common in cancer patients, there may be problems in interpreting the nature of these complaints, particularly in separating them from depressive preoccupation.


Normal glymphatic system function in patients with new daily persistent headache using diffusion tensor image analysis along the perivascular space.
To investigate the glymphatic function in patients with new daily persistent headache (NDPH) using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method. NDPH, a rare and treatment-refractory primary headache disorder, is poorly understood. There is limited evidence to suggest that headaches are associated with glymphatic dysfunction. Thus far, no studies have evaluated glymphatic function in patients with NDPH. In this cross-sectional study conducted in the Headache Center of Beijing Tiantan Hospital, patients with NDPH and healthy controls were enrolled. All participants underwent brain magnetic resonance imaging examinations. Clinical characteristics and neuropsychological evaluation were examined in patients with NDPH. ALPS indexes for both hemispheres were measured to determine the glymphatic system function in patients with NDPH and healthy controls. In total, 27 patients with NDPH (14 males, 13 females; age [mean ± standard deviation (SD)]: 36.6 ± 20.6) and 33 healthy controls (15 males, 18 females; age [mean ± SD]: 36.0 ± 10.8) were included in the analysis. No significant differences between groups were observed in the left ALPS index (1.583 ± 0.182 vs. 1.586 ± 0.175, mean difference = 0.003, 95% confidence interval [CI] of difference = -0.089 to 0.096, p = 0.942), or right ALPS index (1.578 ± 0.230 vs. 1.559 ± 0.206, mean difference = -0.027, 95% CI of difference = -0.132 to 0.094, p = 0.738). Additionally, ALPS indexes were not correlated with clinical characteristics or neuropsychiatric scores. No glymphatic dysfunction was detected in patients with NDPH by means of the ALPS method. Additional studies with larger samples are needed to confirm these preliminary findings and improve the understanding of glymphatic function in NDPH.


The price of COVID-19 risk in a public university.
We study the allocation of and compensation for occupational COVID-19 risk at Auburn University, a large public university in the U.S. In Spring 2021, approximately half of the face-to-face classes had enrollments above the legal capacity allowed by a public health order, which followed CDC's social distancing guidelines. We find lower-ranked graduate student teaching assistants and adjunct instructors were more likely to deliver riskier classes. Using an IV strategy in which teaching risk is shifted by classroom features (geometry and furniture), we show instructors who taught at least one risky class earned $7,400 more than those who did not.


Treating Coronary Artery Disease: Beyond Statins, Ezetimibe, and PCSK9 Inhibition.
Statins, ezetimibe, and PCSK9 inhibitors are currently the standard of care for the prevention and treatment of coronary artery disease. Despite their widespread use, coronary artery disease remains the leading cause of death worldwide, a fact that pleads for the development of new protective therapies. In no small part due to advances in the field of human genetics, many new therapies targeting various lipid traits or inflammation have recently received approval from regulatory agencies such as the US Food and Drug Administration or fared favorably in clinical trials. This wave of new therapies promises to transform the care of patients at risk for life-threatening coronary events.


Acetabular reinforcement ring in primary total hip arthroplasty: a minimum 10-year follow-up.
We report the results of a titanium acetabular reinforcement ring with a hook (ARRH) in primary total hip arthroplasty (THA), which was introduced in 1987 and continues to be used routinely in our center. The favorable results of this device in arthroplasty for developmental dysplasia and difficult revisions motivated its use in primary THA. With this implant only minimal acetabular reaming is necessary, anatomic positioning is achieved by placing the hook around the teardrop and a homogenous base for cementing the polyethylene cup is provided. Between April 1987 and December 1991, 241 THAs with insertion of an ARRH were performed in 178 unselected, consecutive patients (average age 58 years; range 30-84 years) with a secondary osteoarthrosis in 41% of the cases. At the time of the latest follow-up, 33 patients (39 hips) had died and 17 cases had been lost to follow-up. The median follow-up was 122 months with a minimum of 10 years. Eight hips had been revised, leaving 177 hips in 120 living patients without revision. Six cups were revised because of aseptic loosening. Two hips were revised for sepsis. The mean Merle d'Aubigné score for the remaining hips was 16 (range 7-18) at the latest follow-up. For aseptic loosening, the probability of survival of the cup was 0.97 (95% confidence interval, 0.94-0.99). However, analysis of radiographs implied loosening in seven other cups without clinical symptoms. The results of primary THA using an acetabular reinforcement ring parallel the excellent results of these implants often observed in difficult primary and revision arthroplasty at a minimum of 10 years. Survivorship is comparable to modern cementless implants. Medial migration that occurs with loosening of the acetabular component seems to be prevented with this implant. Radiographic loosening signs can exist without clinical symptoms.


Genetic polymorphisms in tumour necrosis factor receptors (TNFRSF1A/1B) illustrate differential treatment response to TNFα inhibitors in patients with Crohn's disease.
Monoclonal antibodies inhibiting tumour necrosis factor-α (TNFα) signalling pathway (anti-TNFα) have been widely used in Crohn's disease (CD). However, treatment response varies among patients with CD and the clinical outcome is dependent on single nucleotide polymorphisms (SNP) in TNFα receptor superfamily 1A and 1B (TNFRSF1A/1B). We tested nine SNPs in TNFα, TNFRSF1A and TNFRSF1B by TaqMan genotyping from peripheral blood samples of 104 subjects. Additionally, we quantified the effects of these SNPs on their corresponding gene expression by RT-PCR and susceptibility to Mycobacterium avium subsp paratuberculosis (MAP) infection by IS900 nested PCR. Four SNPs (TNFα:rs1800629, TNFRSF1A:rs767455, TNFRSF1B:rs1061624 and TNFRSF1B:rs3397) were over-represented significantly (p<0.05) among patients with CD compared with healthy controls. The TNFRSF1A:rs767455 GG genotype was found in 15/54 patients with CD (28%), while it was only found in 2/50 healthy controls (4%) (OR 9.2, 95% CI 1.98 to 42.83). The TNFRSF1B:rs3397 TT genotype was found in 15/54 patients with CD (28%) compared with (4/50) healthy controls (8%) (OR 4.4, 95% CI 1.36 to 14.14). Furthermore, the SNPs TNFRSF1A:rs767455 and TNFRSF1B:rs3397 were associated with downregulating their corresponding genes significantly (p<0.05). MAP infection was predominantly found among patients with CD in comparison to healthy controls (57% vs 8%, respectively), which was also dependent on the SNPs TNFRSF1A:rs767455 and TNFRSF1B:rs3397. Our SNP haplotype analysis of TNFRSF1A:rs767455 and TNFRSF1B:rs3397 indicates that the G-T haplotype is significantly distributed among patients with CD (46%) and MAP infection susceptibility is also associated with this specific haplotype (31%). The SNPs TNFRSF1A:rs767455 and TNFRSF1B:rs3397, which are known to affect anti-TNFα clinical outcome in CD, were associated with lower corresponding gene expression and higher MAP infection susceptibility.


Screening of antimicrobial synergism between phenolic acids derivatives and UV-A light radiation.
The objective of this study was to investigate synergistic antibacterial activity based on a combination of UV-A light and three classes of food grade compounds: benzoic acid derivatives, cinnamic acid derivatives, and gallates. By using Escherichia coli O157:H7 as the model strain, it was observed that three cinnamic acid derivatives (ferulic acid, coumaric acid, and caffeic acid) and one benzoic acid derivative (2,5-dihydroxybenzoic acid) presented strong synergistic antibacterial activity with UV-A light radiation, where 1 mM levels of these compounds plus with 15 min of UV-A light (total light dose of 6.1 cm-2) led to more than 7-log CFU mL-1 of bacterial inactivation. In contrast, synergistic antibacterial activity between UV-A light and most benzoic acid derivatives (benzoic acid, gallic acid, vanillic acid, and 2,5-dimethoxybenzoic acid) were only observed after higher concentrations of these compounds were applied (10 mM). Lastly, from the three gallates tested (methyl gallate, ethyl gallate, and propyl gallate), only propyl gallate showed strong antibacterial synergism with UV-A light, where 10 mM of propyl gallate plus 15 min of UV-A light led to approximately 6.5-log of bacterial reduction. Presence of antioxidant compounds mitigated the light-mediated antibacterial activity of gallic acid, 2,5-dihydroxybenzoic acid, and propyl gallate. Similarly, the light-mediated antibacterial activity of these compounds was significantly (P < 0.05) reduced against metabolic-inhibited bacterial cells (sodium azide pretreatment). On the other hand, the antibacterial synergism between ferulic acid and UV-A light was not affected by the presence of antioxidants or the metabolic state of the bacterial cells. Due to the increasing concerns of antimicrobial resistant (AMR) pathogens, the study also investigated the proposed synergistic treatment on AMR Salmonella. Combinations of 1 mM of ferulic acid or 1 mM of 2,5-dihydroxybenzoic acid with UV-A light radiation was able to inactivate more than 6-log of a multi-drug resistant Salmonella Typhimurium strain.


Health systems analysis and evaluation of the barriers to availability, utilisation and readiness of sexual and reproductive health services in COVID-19-affected areas: a WHO mixed-methods study protocol.
COVID-19 has led to an unprecedented increase in demand on health systems to care for people infected, necessitating the allocation of significant resources, especially medical resources, towards the response. This, compounded by the restrictions on movement instituted may have led to disruptions in the provision of essential services, including sexual and reproductive health (SRH) services. This study aims to assess the availability of contraception, comprehensive abortion care, sexually transmitted infection prevention and treatment and sexual and gender-based violence care and support services in local health facilities during COVID-19 pandemic. This is a standardised generic protocol designed for use across different global settings. This study adopts both quantitative and qualitative methods to assess health facilities' SRH service availability and readiness, and clients' and providers' perceptions of the availability and readiness of these services in COVID-19-affected areas. The study has two levels: (1) perceptions of clients (and the partners) and healthcare providers, using qualitative methods, and (2) assessment of infrastructure availability and readiness to provide SRH services through reviews, facility service statistics for clients and a qualitative survey for healthcare provider perspectives. The health system assessment will use a cross-sectional panel survey design with two data collection points to capture changes in SRH services availability as a result of the COVID-19 epidemic. Data will be collected using focus group discussions, in-depth interviews and a health facility assessment survey. Ethical approval for this study was obtained from the WHO Scientific and Ethics Review Committee (protocol ID CERC.0103). Each study site is required to obtain the necessary ethical and regulatory approvals that are required in each specific country.


Phylogeographic Analysis of Soft-Rot-Causing Pectobacterium spp. Strains Obtained from Cabbage in Serbia.
The aim of this study was to establish a link between genetic diversity and the geographic origin of Pectobacterium strains belonging to three species-P. carotovorum, P. versatile, and P. odoriferum-isolated from cabbage in Serbia by comparing their sequences with those of strains sourced from different hosts and countries in Europe, Asia, and North America. Phylogeographic relatedness was reconstructed using the Templeton, Crandall, and Sing's (TCS) haplotype network based on concatenated sequences of the housekeeping genes dnaX, icdA, mdh, and proA, while pairwise genetic distances were computed by applying the p-distance model. The obtained TCS haplotype networks indicated the existence of high intra-species genetic diversity among strains of all three species, as reflected in the 0.2-2.3%, 0.2-2.5%, and 0.1-1.7% genetic distance ranges obtained for P. carotovorum, P. versatile, and P. odoriferum, respectively. Five new haplotypes (denoted as HPc1-HPc5) were detected among cabbage strains of P. carotovorum, while one new haplotype was identified for both P. versatile (HPv1) and P. odoriferum (HPo1). None of the TCS haplotype networks provided evidence of significant correlation between geographic origin and the determined haplotypes, i.e., the infection origin. However, as haplotype network results are affected by the availability of sequencing data in public databases for the used genes and the number of analyzed strains, these findings may also be influenced by small sample size.


Different expression of calpains in the anterior vaginal wall of women with and without uterovaginal prolapse.
Tissue ischemia-hypoxia can activate the calpain proteolytic system. Mechanical trauma to the upper vaginal wall and pelvic floor could compromise vascular perfusion and could also result in calpain expression. The aims of this investigation were to assess the expression messenger RNA and proteins for m-calpain and micro-calpain in the vaginal walls of women with and without uterovaginal prolapse. The anterior vaginal walls of 22 women with and without uterovaginal prolpase were evaluated using a reverse transcription polymerase chain reaction and western blotting for detecting calpain expression. The number of messenger RNA transcripts of m- and micro-calpain was significantly less in women with uterovaginal prolapse than in women without uterovaginal prolapse (two of 11 and zero of 11 versus eight of 11 and five of 11, P < .05). All women had m-calpain protein expression in the anterior vaginal wall. However, the concentration of m-calpain protein was less, but not significantly different, in women with uterovaginal prolapse than in the women without uterovaginal prolapse (0.386 +/- 0.018 versus 0.439 +/- 0.011 optical density/mm2, P > .05). None of the women with uterovaginal prolapse had expression of micro-calpain mRNA or protein (zero of 11). Expression of protein of calpains in the anterior vaginal wall is not consistent with mRNA transcripts. Calpain expression may be compromised in the anterior vaginal wall of women with uterovaginal prolapse who have abnormal histologic changes in the vaginal connective tissues or have anterior vaginal laxity.


Wasting syndrome in neonatal mice after administration of salivary gland homogenate.
A wasting syndrome, similar to that occurring after cortisol treatment, was induced in neonatal mice by means of the daily i.p. administration of salivary gland homogenate: 24 h after a single injection of the homogenate, profuse cell necrosis was observed in the thymic cortex, 48 h later the cortex was devoid by lymphocytes. It is hypothesized that the submandibular glands of mice contain substances which are capable of inducing a cortisol-like effect.


Mood disorders and the outcome of suicidal thoughts and attempts.
Suicidal ideation and attempts are common reasons for visits to the emergency department and critical care hospitalizations and a common public health problem. Most patients who make a suicide attempt have a psychiatric disorder, most frequently a mood, psychotic, substance use, or personality disorder. Patients who are at high risk of another attempt and cannot be transferred promptly to a psychiatric service should be managed jointly by the psychiatric and critical care teams with an emphasis on protection of the patient, identification of substance intoxication and withdrawal, making the environment safe, and instituting treatment of the psychiatric disorder. Antidepressants reduce suicide risk but their slow onset of action may make electroconvulsive therapy a desirable alternative for severely depressed patients. Parenteral treatment is possible with benzodiazepines and antipsychotic drugs but not antidepressants.


Incidence of second metachronous head and neck cancers: population-based outcomes over 25 years.
The primary objective was to determine the incidence of second metachronous head and neck cancers (HNC) following an index HNC and estimate their overall survival. Retrospective cohort study. A total of 1,658 consecutive primary HNC patients diagnosed in 1986 to 1990 were identified through the prospectively maintained provincial BC Cancer Registry database. They were followed up for a period of 25 years. Survival analysis and second cancer estimates were performed with standard Kaplan-Meier & Cox regression analysis. Out of a total of 443 (27%) second cancers, 89 (5%) second HNC occurred in 1,658 HNC patients, with an actuarial metachronous HNC incidence rate at 5, 10, 15, 20, and 25 years that was 3.9%, 8.1%, 10.4%, 13.2%, and 14.5%, respectively. Second primary cancer (SPC) in lung and esophagus occurred in 155 (9%) and 32 (2%) patients, respectively. The median follow-up time for all patients and alive patients was 4.05 years (range, 0.2-25.0 years) and 23.2 years (range, 20.76-25.0 years), respectively. Of second HNC, 83 (93%) were metachronous. Oral cavity (P < 0.001) and oropharyngeal (P < 0.002) index cancers were more likely to develop a metachronous HNC. The overall survival rate for the metachronous HNC patients at 5 years is 15%. SPCs in esophagus and lung had lower overall survival compared to second HNC (P < 0.001). Oral cavity and oropharyngeal cancers carry the highest risk of a subsequent metachronous HNC. Given the incidence and prognosis of second HNC, future research should address the frequency and duration of screening the head and neck region for a second cancer.


Amino acid residues of both the extracellular and transmembrane domains influence binding of the antiparasitic agent milbemycin to Haemonchus contortus AVR-14B glutamate-gated chloride channels.
Glutamate-gated chloride (GluCl) channels are pentameric receptors for the inhibitory neurotransmitter glutamate in invertebrates and are a major target for macrolide anthelmintics. Three amino acids in GluCl channels are reported to render macrolide resistance in nematodes and insects. To examine whether these three amino acids are involved in binding of the antiparasitic agent milbemycin (MLM) to the GluCl channels of the nematode parasite Haemonchus contortus, the equivalent amino acids (L256, P316, and G329) of the Hco-AVR-14B subunit were substituted with various amino acids. cDNAs encoding the wild type and mutants of this subunit were transfected into COS-1 cells for transient expression and analysis of GluCl channels. The abilities of these mutant channels to bind [(3)H]MLM A(4) were remarkably decreased when compared with the wild-type channel. In patch clamp analysis, L256F and P316S mutant channels were 37- and 100-fold less sensitive to MLM A(4) when compared with the wild-type channel, respectively. These findings indicate that amino acid changes in the β10 strand, the M2-M3 linker, and the M3 region influence MLM A(4) binding to the channel. Homology modeling and ligand docking studies suggest the presence of two potential binding sites for MLM A(4).


Evaluation of risk scoring in a preterm birth prevention study of indigent patients.
A total of 4591 indigent patients were scored for risk of preterm labor and birth by the Creasy et al. scoring system and delivered at greater than or equal to 20 weeks' gestation. Of 462 preterm deliveries (less than 37 weeks), only 39.6% were contributed by the 18.1% of patients who scored at high risk (score greater than or equal to 10). Of the 44 risk factors in the scoring system, 25 were not statistically significant by univariate chi 2 analysis. The spontaneous preterm birth rate was 8.0%. The positive predictive value of the Creasy et al. system was 18.3%. With multiple logistic analyses we excluded infrequent risk factors and identified five factors that remained significant (prepregnancy weight less than 45.5 kg, black race, single marital status, one preterm labor and delivery, preterm labor, and delivery greater than or equal to 2). With these five risk factors we created an equation that allowed identification of 12% of patients at high risk of preterm delivery with a positive predictive value of 21.9%. Because of the importance of previous preterm delivery, risk scoring of primigravid patients is of limited value.


Cardiothoracic injuries after CardioPump CPR: a report of two cases and review of the literature.
Although many clinical trials have demonstrated its efficacy during active compression-decompression cardiopulmonary resuscitation (ACD-CPR), the Ambu® CardioPump seems likely to cause severe and sometimes lethal injuries. In this paper, we report two cases observed at the Institute of Legal Medicine of Nancy, France. A 67-year-old man collapsed in the street, in the presence of witnesses, and without any sign of trauma. The autopsy revealed a flail chest, a wound of the left ventricle, a rupture of the right ventricle, and a wrenching of the inferior vena cava. A 71-year-old woman was found in her apartment during an accidental fire. The autopsy revealed a sternal fracture, many rib fractures, and a perforation of the superior vena cava, the pericardium, and the heart. Despite articles focusing on complications of the use of the CardioPump in the late 1990s, this technique is still used in practice. These two cases emphasize that iatrogenic injuries must be taken into account in the CardioPump benefit/risk balance and the relevance of its daily use.


Evaluation of the accuracy of a 3D surface imaging system for patient setup in head and neck cancer radiotherapy.
To evaluate the accuracy of three-dimensional (3D) surface imaging system (AlignRT) registration algorithms for head-and-neck cancer patient setup during radiotherapy. Eleven patients, each undergoing six repeated weekly helical computed tomography (CT) scans during treatment course (total 77 CTs including planning CT), were included in the study. Patient surface images used in AlignRT registration were not captured by the 3D cameras; instead, they were derived from skin contours from these CTs, thereby eliminating issues with immobilization masks. The results from surface registrations in AlignRT based on CT skin contours were compared to those based on bony anatomy registrations in Pinnacle(3), which was considered the gold standard. Both rigid and nonrigid types of setup errors were analyzed, and the effect of tumor shrinkage was investigated. The maximum registration errors in AlignRT were 0.2° for rotations and 0.7 mm for translations in all directions. The rigid alignment accuracy in the head region when applied to actual patient data was 1.1°, 0.8°, and 2.2° in rotation and 4.5, 2.7, and 2.4 mm in translation along the vertical, longitudinal, and lateral axes at 90% confidence level. The accuracy was affected by the patient's weight loss during treatment course, which was patient specific. Selectively choosing surface regions improved registration accuracy. The discrepancy for nonrigid registration was much larger at 1.9°, 2.4°, and 4.5° and 10.1, 11.9, and 6.9 mm at 90% confidence level. The 3D surface imaging system is capable of detecting rigid setup errors with good accuracy for head-and-neck cancer. Further investigations are needed to improve the accuracy in detecting nonrigid setup errors.


Brain penetration of ketamine: Intranasal delivery VS parenteral routes of administraion.
Ketamine is approved by the FDA to be used as an anesthetic however, recent reports have exhibited its success in the treatment of major depressive disorder (MDD). Studies have suggested that a sub-anesthetic dose produces rapid antidepressant activity providing significant symptomatic relief particularly in patients with a history of treatment resistant depression (TRD). Many reports have been published on the intranasal (IN) efficacy of ketamine in the treatment of depression, however studies that have investigated the effects of the route of administration on drug delivery to the brain appear to be absent in literature. Therefore, in this study, a single dose (15 mg/kg body weight) was administered via different routes of administration [oral (PO), intranasal (IN) and intraperitoneal (IP)] to healthy male Sprague-Dawley rats in order to determine the brain tissue pharmacokinetics of ketamine. A novel validated liquid chromatography-mass spectrometry (LC-MS) method was developed using a fused core column for the determination of ketamine in plasma and brain homogenates. While IP administration resulted in favorable concentrations in the brain and plasma; IN administration, which is supposed to favour drug delivery to the brain, exhibited moderately low drug levels post administration. PO administration produced significantly lower levels due to extensive first-pass metabolism in the liver and intestines. These results have implications for future studies exploring the use of ketamine for the treatment of MDD in order to optimize treatment regimens and suggest that parenteral administration of ketamine should be used in the treatment of depression.


Recurrent fever of unknown origin, coma, and meningismus due to a leaking craniopharyngioma.
A cyclic leaking craniopharyngioma was found to be the source of recurrent fevers, meningismus, and coma. A sterile persistent neutrophilic pleocytosis with normal glucose and protein was the only clue in an extensive workup. Three head computed tomographic scans, including double contrast with 5-mm cuts, failed to locate the large suprasellar cyst outlined finally by head computed tomographic scan with metrizamide. A handful of case reports exist about leaking central nervous system cysts, but their presentation tended to be different: increased protein, lymphocytosis, and positive cranial imaging. It is believed this is a unique case that adds to the spectrum of chronic neutrophilic meningitis.


Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin.
AIFM1 encodes a mitochondrial flavoprotein with a dual role (NADH oxidoreductase and regulator of apoptosis), which uses riboflavin as a cofactor. Mutations in the X-linked AIFM1 were reported in relation to two main phenotypes: a severe infantile mitochondrial encephalomyopathy and an early-onset axonal sensorimotor neuropathy with hearing loss. In this paper we report two unrelated males harboring AIFM1 mutations (one of which is novel) who display distinct phenotypes including progressive ataxia which partially improved with riboflavin treatment. For both patients trio whole exome sequencing was performed. Validation and segregation were performed with Sanger sequencing. Following the diagnosis, patients were treated with up to 200 mg riboflavin/day for 12 months. Ataxia was assessed by the ICARS scale at baseline, and 6 and 12 months following treatment. Patient 1 presented at the age of 5 years with auditory neuropathy, followed by progressive ataxia, vermian atrophy and axonal neuropathy. Patient 2 presented at the age of 4.5 years with severe limb and palatal myoclonus, followed by ataxia, cerebellar atrophy, ophthalmoplegia, sensorineural hearing loss, hyporeflexia and cardiomyopathy. Two deleterious missense mutations were found in the AIFM1 gene: p. Met340Thr mutation located in the FAD dependent oxidoreductase domain and the novel p. Thr141Ile mutation located in a highly conserved DNA binding motif. Ataxia score, decreased by 39% in patient 1 and 20% in patient 2 following 12 months of treatment. AIFM1 mutations cause childhood cerebellar ataxia, which may be partially treatable in some patients with high dose riboflavin.


Overall and patient-specific comparative effectiveness of dimethyl fumarate versus teriflunomide: A novel approach to precision medicine applied to the German NeuroTrans Data Multiple Sclerosis Registry.
Multiple sclerosis (MS) comparative effectiveness research needs to go beyond average treatment effects (ATEs) and post-host subgroup analyses. This retrospective study assessed overall and patient-specific effects of dimethyl fumarate (DMF) versus teriflunomide (TERI) in patients with relapsing-remitting MS. A novel precision medicine (PM) scoring approach leverages advanced machine learning methods and adjusts for imbalances in baseline characteristics between patients receiving different treatments. Using the German NeuroTransData registry, we implemented and internally validated different scoring systems to distinguish patient-specific effects of DMF relative to TERI based on annualized relapse rates, time to first relapse, and time to confirmed disease progression. Among 2791 patients, there was superior ATE of DMF versus TERI for the two relapse-related endpoints (p = 0.037 and 0.018). Low to moderate signals of treatment effect heterogeneity were detected according to individualized scores. A MS patient subgroup was identified for whom DMF was more effective than TERI (p = 0.013): older (45 versus 38 years), longer MS duration (110 versus 50 months), not newly diagnosed (74% versus 40%), and no prior glatiramer acetate usage (35% versus 5%). The implemented approach can disentangle prognostic differences from treatment effect heterogeneity and provide unbiased patient-specific profiling of comparative effectiveness based on real-world data.


Hibernoma: distinctive light and electron microscopic features and relationship to brown adipose tissue.
Four hibernomas and samples of developing human brown and white adipose tissue were observed. Distinctive features of hibernomas were 1) lobules of closely apposed large polygonal cells and capillaries; 2) three principal cell types (granular eosinophilic, multivacuolated, and univacuolated) varying in prominence from case to case; 3) investment of each tumor cell by basal lamina; 4) an inverse relationship between lipid droplet size and the number of mitochondria per unit of cytoplasm; 5) pleomorphic mitochondria with dense matrixes or large, round mitochondria with transverse lamellar cristae; 6) undulating plasmalemmal invaginations; 7) micropinocytotic vesicles; 8) periodic short plasmalemmal densities; and 9) a conspicuous lack of cytoplasmic membrane systems. The frequent association of micropinocytotic vesicles and undulating plasmalemmal invaginations in proximity to capillaries strongly suggests that the invaginations represent a localized cell membrane adaptation for efficient endocytosis. In human fetal brown adipose tissue, which is first recognizable in fetuses of 21 weeks' gestational age, the most characteristic cell was the polygonal multivacuolated cell. Univacuolated cells were present in brown adipose tissue of older fetuses, and in infants and adults entire lobules containing univacuolated cells coexisted with lobules of multivacuolated cells and granular eosinophilic cells. The ultrastructure of human brown adipose tissue resembled that of hibernomas and was similar to previously described features of this tissue in animals. Developing white adipose tissue differed from brown adipose tissue by its loose plexiform arrangement of capillaries and spindle-shaped cells in less circumscribed lobules and by the absence of polygonal multivacuolated cells. The authors did not identify centripetal lobular maturation in white adipose tissue, but peripheral growth "caps" were a common finding in maturing brown adipose tissue. They consider brown adipose tissue to be a special form of adipose tissue, the variable cytologic composition of which is reflected in the histologic spectrum of hibernomas.


Impact of pharmacist intervention in antibiotic stewardship programmes for critically ill neonates: A systematic review and meta-analysis.
Antibiotic stewardship programmes (ASPs) are introduced to ensure effective antibiotic use. Pharmacists can be involved in ASPs to facilitate the appropriate antibiotic use. Prolonged use of antibiotics causes adverse events in critically ill neonates. Hence, this systematic review and meta-analysis was aimed at investigating pharmacists' functions in ASPs in critically ill neonates and the effect of ASP implementation on antibiotic use. A comprehensive search of PubMed/Medline, Embase, and Cochrane Library databases until January 2021 was conducted and studies that reported the functions of pharmacists in ASPs for critically ill neonates and the results of ASP implementation were included in this review. All processes were performed by two reviewers independently, and any discordance between the two was resolved by discussion. In all, 19 studies were included in this review. Pharmacists were found to have various functions in ASPs, such as participating in the development of antibiotic use guidelines, auditing antibiotic prescriptions, participating in multidisciplinary ward rounds, educating other ASP team members, checking blood culture or laboratory data, and monitoring antibiotic use. A meta-analysis revealed that ASP implementation in critically ill neonates was significantly associated with a 23% reduction in the overall antibiotic use rate (ratio of means: 0.77, 95% confidence interval: 0.69-0.87, p < 0.001). Moreover, the overall duration of antibiotic therapy significantly reduced by 15% with ASP implementation (ratio of means: 0.85, 95% confidence interval: 0.78-0.91, p < 0.001). The implementation of ASPs involving pharmacists, especially in critically ill neonates, was associated with the reduced use and duration of antibiotic treatment. Thus, pharmacists played a key role in ASPs in critically ill neonates.


Endogenous Rab38 regulates LRRK2's membrane recruitment and substrate Rab phosphorylation in melanocytes.
Point mutations in leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's disease and augment LRRK2's kinase activity. However, cellular pathways that endogenously enhance LRRK2 kinase function have not been identified. While overexpressed Rab29 draws LRRK2 to Golgi membranes to increase LRRK2 kinase activity, there is little evidence that endogenous Rab29 performs this function under physiological conditions. Here, we identify Rab38 as a novel physiologic regulator of LRRK2 in melanocytes. In mouse melanocytes, which express high levels of Rab38, Rab32, and Rab29, knockdown (or CRISPR knockout) of Rab38, but not Rab32 or Rab29, decreases phosphorylation of multiple LRRK2 substrates, including Rab10 and Rab12, by both endogenous LRRK2 and exogenous Parkinson's disease-mutant LRRK2. In B16-F10 mouse melanoma cells, Rab38 drives LRRK2 membrane association and overexpressed kinase-active LRRK2 shows striking pericentriolar recruitment, which is dependent on the presence of endogenous Rab38 but not Rab32 or Rab29. Consistently, knockdown or mutation of BLOC-3, the guanine nucleotide exchange factor for Rab38 and Rab32, inhibits Rab38's regulation of LRRK2. Deletion or mutation of LRRK2's Rab38-binding site in the N-terminal armadillo domain decreases LRRK2 membrane association, pericentriolar recruitment, and ability to phosphorylate Rab10. In sum, our data identify Rab38 as a physiologic regulator of LRRK2 function and lend support to a model in which LRRK2 plays a central role in Rab GTPase coordination of vesicular trafficking.


Severe vitreous hemorrhage associated with closed-globe injury.
The presence of marked vitreous hemorrhage is associated with poor visual prognosis in ocular trauma involving the posterior segment. The purpose of this study was to investigate the clinical features, prognostic factors, and visual outcomes in such eyes after closed-globe injury. Retrospective chart review of patients with severe vitreous hemorrhage after closed-globe injury between January 2000 and December 2002. The study included 33 eyes in 32 patients with a mean age of 41.5 (range, 3-78 years) and a median follow-up period of 12 (range, 3-50 months). Presenting visual acuity was between 4/200, and there was light perception in 32 eyes (97%) and no light perception in one eye (3%). Fifteen eyes (45%) had one or more posterior segment pathologies beneath the vitreous hemorrhage. There were retinal tears in six eyes (18%), retinal detachment in six (18%), submacular hemorrhage in six (15%), choroidal rupture in three (9%), macular pucker in three (9%), retinal dialysis in one (3%), macular hole in one (3%), and retinal vessels occlusion in one (3%). Seven eyes (21%) had final visual acuity 20/40 or better, and 18 eyes (54%) had less than 20/200. Poor prognostic factors included presenting visual acuity of light perception or lower (p=0.032), hyphema (p=0.007), traumatic cataract (p=0.027), and age 55 years or younger (p=0.039). The most common cause of poor visual outcome was macular scar. The visual prognosis of severe vitreous hemorrhage after closed-globe injury was guarded. This was frequently associated with various anterior and posterior segment pathologies. In order to provide early visual rehabilitation and management of any potentially treatable posterior pathology, early vitrectomy may be considered.


[Protein crystals and tubuli bundles in yeast cells. VI. Light-and electron microscopy studies as well as biochemical studies on alcohol dehydrogenase activity of isolated crystals].
Isolated crystals from Saccharomyces carlsbergensis, stabilized by Cd2+ or Zn2+, retain their enzymatic activity as shown by topochemical reactions. During these reactions the crystals disintegrate characteristically. Stages of this disintegration and deposition of reaction products have been demonstrated by light and electron microscopy. Ground plasmatic and mitochondrial alcoholdhydrogenase has been solubilized by means of 0.01 M EDTA from Zn2+ stabilized crystals separated by gel electrophoresis and proved to be active.


If we offer, will they come: Perceptions of yoga among Hispanics.
Yoga is underutilized by the Hispanics. This study examined perceptions of benefits and barriers to yoga among Hispanic adults, to provide information that may increase their participation in this practice. Participants were recruited from a Community Center serving low-income Hispanics. Self-administered cross-sectional questionnaires assessing benefits and barriers to yoga were conducted in Spanish and English. Fisher's exact test was used to examine perceptions of yoga by gender, age, and prior experience. Participants (ages 18-85, 65 % women, n = 121) reported several benefits to yoga. Hispanic women, individuals 65 y or older, and those with prior experience, perceived more benefits. Barriers to yoga also differed by demographics. Men reported that time and the perception that they would have to do unrealistic pretzel-like poses as deterrents to yoga practice; younger individuals perceived yoga to be boring, and those with no experience perceived lack of flexibility and feeling like an outsider in class, as barriers to yoga. The most common barrier, across subgroups, was the cost associated with yoga practice. The majority of participants reported being willing to attend yoga classes if offered at a low cost. Perceived barriers related to yoga reflect a lack of knowledge about yoga and what it entails and the cost of classes. Despite these barriers, Hispanic adults from a low-income population said they would be willing to attend yoga classes if offered at a low cost. Understanding and addressing these barriers can help researchers and health practitioners improve diversity in yoga classes and research.


Speech characteristics after articulation therapy in children with cleft palate and velopharyngeal dysfunction - A single case experimental design.
The aim of this study was to investigate the impact of an intensive 10-week course of articulation therapy on articulation errors in cleft lip and palate patients who have Velopharyngeal Insufficiency (VPI), non-oral and passive cleft speech characteristics. Five children with cleft palate (+/-cleft lip) with VPI and non-oral and passive cleft speech characteristics underwent 40 intensive articulation therapies over 10 weeks in a single case experimental design. The percentage of non-oral CSCs (NCSCs), passive CSCs (PCSCs), stimulable consonants (SC), correct consonants in word imitation (CCI), and correct consonants in picture naming (CCN) were captured at baseline, during intervention and in follow up phases. Visual analysis and two effect size indexes of Percentage of Nonoverlapping Data and Percentage of Improvement Rate Difference were analyzed. Articulation therapy resulted in visible decrease in NCSCs for all 5 participants across the intervention phases. Intervention was effective in changing percentage of passive CSCs in two different ways; it reduced the PCSCs in three cases and resulted in an increase in PCSCs in the other two cases. This was interpreted as intervention having changed the non-oral CSCs to consonants produced within the oral cavity but with passive characteristics affecting manner of production including weakness, nasalized plosives and nasal realizations of plosives and fricatives. Percent SC increased throughout the intervention period in all five patients. All participants demonstrated an increase in percentage of CCI and CCN suggesting an increase in the consonant inventory. Follow-up data showed that all the subjects were able to maintain their ability to articulate learned phonemes correctly even after a 4-week break from intervention. This single case experimental study supports the hypothesis that speech intervention in patients with VPI can result in an improvement in oral placements and passive CSCs.


DIA-MS proteome analysis of formalin-fixed paraffin-embedded glioblastoma tissues.
Developments in quantitative proteomics and data-independent acquisition (DIA) methodology is enabling quantification of proteins in biological samples. Currently, there are a few reports on DIA mass spectrometry (MS) approaches for proteome analysis of formalin-fixed paraffin-embedded (FFPE) tissues. Therefore, to facilitate detection and quantification of immune- and glioblastoma (GBM)-relevant proteins from FFPE patient materials, we established a simple and precise DIA-MS workflow. We first evaluated different lysis buffers for their efficiency in protein extractions from FFPE GBM tissues. Our results showed that more than 1700 proteins were detected and over 1400 proteins were quantified from GBM FFPE tissue microdissections. GBM-relevant proteins (e.g., GFAP, FN1, VIM, and MBP) were quantified with high precision (median coefficient of variation <12%). In addition, immune-related proteins (e.g., ILF2, MIF, and CD38) were consistently detected and quantified. The strategy holds great potential for routinizing protein quantification in FFPE tissue samples.