Right ventricle myocardial perfusion scintigraphy: feasibility and expected values in children.
Stress myocardial perfusion scintigraphy imaging (SMPSI) has important applications for evaluating coronary disease and ventricular function. Studies consistently focus on the left ventricle (LV), with no normal right ventricle (RV) data available. This study sought to evaluate the feasibility of RV perfusion with technetium (Tc-99m) sestamibi using a low radiotracer dose for children free of coronary artery (CA) anomalies and to determine its normal pattern. Patients with a history of Kawasaki disease who showed no coronary complications on selective angiography or no LV perfusion defects on SMPSI were studied at rest and during an exercise challenge. The RV uptake counts were compared with those for different segments of the LV, and multiple ratios of the uptakes between RV and LV segments were calculated. The study subjects were 23 children (age, 11.1 ± 3.3 years) imaged with 0.12 ± 0.03 mCi/kg at rest and 0.31 ± 0.06 mCi/kg during stress. The RV to LV uptake proportion was approximately 6%. Exercise-related uptake increased threefold in both the RV and the LV. The findings showed RV myocardial scintigraphy to be feasible with reproducible ratios. Potential clinical applications include acquired and congenital CA anomalies such as Kawasaki disease, right CA ostium stenosis after a switch operation, and anomalous origin of the right CA.


Network pharmacology: the next paradigm in drug discovery.
The dominant paradigm in drug discovery is the concept of designing maximally selective ligands to act on individual drug targets. However, many effective drugs act via modulation of multiple proteins rather than single targets. Advances in systems biology are revealing a phenotypic robustness and a network structure that strongly suggests that exquisitely selective compounds, compared with multitarget drugs, may exhibit lower than desired clinical efficacy. This new appreciation of the role of polypharmacology has significant implications for tackling the two major sources of attrition in drug development--efficacy and toxicity. Integrating network biology and polypharmacology holds the promise of expanding the current opportunity space for druggable targets. However, the rational design of polypharmacology faces considerable challenges in the need for new methods to validate target combinations and optimize multiple structure-activity relationships while maintaining drug-like properties. Advances in these areas are creating the foundation of the next paradigm in drug discovery: network pharmacology.


Choline levels are increased in cerebrospinal fluid of Alzheimer patients.
We measured choline (Ch), acetylcholinesterase activity (AChE) and total protein in the cerebrospinal fluid (CSF) of 66 Alzheimer patients (ages 54-89 years) and 22 age-matched controls (ages 52-80 years), looking for markers of the well-established cholinergic deficit and neuronal degeneration in Alzheimer disease (AD). Three or more lumbar punctures were performed in 21 patients over a span of 24 months in order to study the changes in these CSF components with disease progression. We found a statistically significant reduction in AChE and an increase in Ch with advancing dementia. These changes were not related to patient age. We suggest that the rise in CSF choline is related to neuronal membrane breakdown and reduced Ch uptake by cholinergic neurons. The reduction in CSF AChE is consistent with the depletion of cholinergic neurons in AD.


Application of biochar to soil reduces cancer risk via rice consumption: a case study in Miaoqian village, Longyan, China.
Consumption of rice contaminated with potentially toxic elements (PTEs) is a major pathway for human exposure to PTEs. This is particularly true in China's so called "Cancer Villages". In this study, sewage sludge biochar (SSBC) was applied to soil (at 5% and 10%) to suppress PTE phytoavailability and as a consequence to reduce PTE levels in rice grown in mining impacted paddy soils. Risk assessment indicated that SSBC addition (10%) markedly (P≤0.05) decreased the daily intake, associated with the consumption of rice, of PTEs (As, Cd, Co, Cu, Mn, Pb and Zn by: 68, 42, 55, 29, 43, 38 and 22%, respectively). In treatments containing SSBC (10%) the health quotient (HQ) indices for PTEs (except for As, Cu and Mn) were <1, indicating that SSBC suppressed the health risk associated with PTEs in rice. The addition of SSBC (10%) markedly (P≤0.01) reduced AsIII (72%), dimethylarsinic acid (DMA) (74%) and AsV (62%) concentrations in rice. Consequentially, following SSBC application (10%), the incremental lifetime cancer (ILTR) value for iAs (AsIII+AsV) associated with the consumption of rice was significantly (P≤0.01) reduced by 66%. These findings suggest that SSBC could be a useful soil amendment to mitigating PTE exposure, through rice consumption, in China's "Cancer Villages".


Managing Migraine: Medication Overuse Headache and Treatment with Eptinezumab.
Medication overuse headache (MOH) places both a physical and emotional burden on patients. MOH may occur as a consequence of a negative spiral of events comprising an increasing number of headache days while taking frequent or excessive amounts of medications for acute treatment of headaches or migraine. Despite acute and prophylactic treatment options, there remains a complex subset of patients who fail first-line oral prophylactic therapies due to insufficient response or failure to tolerate, and require access to new prophylactic treatment options, including calcitonin gene-related peptide (CGRP) inhibitors such as eptinezumab. In this article I present a series of clinical scenarios in which the use of eptinezumab may be beneficial, based on the extensive experience I have gained using the treatment, in more than 25 patients, (and over 40 infusions), over a 2-year period. Eptinezumab provides an additional therapeutic modality for patients who are refractory to other migraine medications, including other CGRP pathway monoclonal antibody (mAb) therapies. I discuss within this article the potential role for eptinezumab in various clinical scenarios such as refractory migraine, including MOH, in which the rapid bioavailability of the preparation may be of particular utility. It is important to tailor treatment plans to the individual patient needs and provide other lifestyle and non-drug-based recommendations when treating patients with MOH, who may be appropriate for treatment with eptinezumab.


The effect of PDGF on the healing of full thickness wounds in hairless guinea pigs.
1. Platelet-derived growth factor (PDGF), administered daily for 5 days and every other day for 9 additional days or the day of wounding and the following day, caused dose dependent (0.2, 1.0 or 5.0 micrograms PDGF/wound) increased granulation tissue. 2. The two day 5.0 micrograms treatment resulted in a 73% increase and the multi-day treatment resulted in a 52% increase of alkaline phosphatase activity three days after wounding. 3. Multi-day treatment resulted in significant increases in protein synthesis (132%), vimentin content (160%) and excised wound weight (76%) three days after wounding. 4. These results indicate that limited administration of PDGF alters wound healing although multiple applications provoke a more dramatic response.


Bone substitutes: an update.
Autograft is considered ideal for grafting procedures, providing osteoinductive growth factors, osteogenic cells, and an osteoconductive scaffold. Limitations, however, exist regarding donor site morbidity and graft availability. Allograft on the other hand, posses the risk of disease transmission. Synthetic graft substitutes lack osteoinductive or osteogenic properties. Composite grafts combine scaffolding properties with biological elements to stimulate cell proliferation and differentiation and eventually osteogenesis. We present here an overview of bone grafts and graft substitutes available for clinical applications.


Alpha2B-adrenoceptors couple to Ca2+ increase in both endogenous and recombinant expression systems.
The ability of cloned human alpha2B-adrenoceptors heterologously expressed in Sf9 cells and endogenous alpha2B-adrenoceptors in NG 108-15 neuroblastoma x glioma cells to couple to increase of intracellular Ca2+ was studied. Ca2+ increases in NG 108-15 cells were detectable but slight, whereas those in alpha2B-adrenoceptor-expressing Sf9 cells were greater. In the latter, the maximum Ca2+ increase correlated positively, and the EC50-value of noradrenaline negatively, with the receptor expression density. The order of potency of the agonists was D-medetomidine ([D]-4-[5]-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole) > noradrenaline approximately = clonidine > oxymetazoline, with clonidine and UK14,304 (5-bromo-N-[4,5-dihydro-1H-imidazole-2-yl]-6-quinoxalinamine) being weak partial agonists. In Sf9 cells Ca2+ increases consisted of concomitant mobilization from an intracellular store and influx of extracellular Ca2+. In these cells alpha2B-adrenoceptor stimulation also increased the inositol 1,4,5-trisphosphate mass. We conclude that alpha2B-adrenoceptors can couple to intracellular Ca2+ increases which may involve prior activation of phospholipase C.


Laterality defect of the heart in non-teleost fish.
Dextrocardia is a rare congenital malformation in humans in which most of the heart mass is positioned in the right hemithorax rather than on the left. The heart itself may be normal and dextrocardia is sometimes diagnosed during non-related explorations. A few reports have documented atypical positions of the cardiac chambers in farmed teleost fish. Here, we report the casual finding of a left-right mirrored heart in an 85 cm long wild-caught spiny dogfish (Squalus acanthias) with several organ malformations. Macroscopic observations showed an outflow tract originating from the left side of the ventricular mass, rather than from the right. Internal inspection revealed the expected structures and a looped cavity. The inner curvature of the loop comprised a large trabeculation, the bulboventricular fold, as expected. The junction between the sinus venosus and the atrium appeared normal, only mirrored. MRI data acquired at 0.7 mm isotropic resolution and subsequent 3D-modeling revealed the atrioventricular canal was to the right of the bulboventricular fold, rather than on the left. Spurred by the finding of dextrocardia in the shark, we revisit our previously published material on farmed Adriatic sturgeon (Acipenser naccarii), a non-teleost bony fish. We found several alevins with inverted (left-loop) hearts, amounting to an approximate incidence of 1%-2%. Additionally, an adult sturgeon measuring 90 cm in length showed abnormal topology of the cardiac chambers, but normal position of the abdominal organs. In conclusion, left-right mirrored hearts, a setting that resembles human dextrocardia, can occur in both farmed and wild non-teleost fish.


Life history data from the gateway to global ageing data platform: resources for studying life courses across Europe.
Research from a range of disciplines highlights the need to adopt a life course perspective that considers earlier life courses to explain outcomes in later life (e.g. later life health, cognitive ageing or retirement behaviour). This includes a more comprehensive assessment of earlier life courses over time and of how they are shaped by societal and political contexts. But quantitative data with detailed information on life courses that allow to address these questions are rare. Or, in case the data are available, the data are rather difficult to handle and appears to be underused. This contribution introduces the harmonized life history data from the gateway to global ageing data platform from two European Surveys, SHARE and ELSA, with data from 30 European countries. Besides providing some details on the collection of life history data in the two surveys, we also describe the way how raw data were rearranged in a user-friendly state sequence format and additionally give some examples based on the resulting data. This illustrates the potential of collected life history data from SHARE and ELSA, clearly going beyond the description of single aspects of the life course. By providing harmonized data of two prominent studies on ageing in Europe in a user-friendly format, the gateway to global ageing data platform provides a unique data source that is easily accessible for research, and permits to study life course and their links to later life in a cross-national perspective.


An enzyme-assisted nanoparticle crosslinking approach to enhance the mechanical strength of peptide-based supramolecular hydrogels.
In this work we reported an enzyme-assisted nanoparticle crosslinking (EANC) strategy to enhance the mechanical stability of peptide-based supramolecular hydrogels by more than 3000 times.


The role of social constraints and catastrophizing in pelvic and urogenital pain.
Pelvic and urogenital pain is complex and highly prevalent in women, and increased attention to psychosocial influences can guide more effective treatments. This study tested the hypothesis that social constraints (the perception that close others inhibit, discourage, or dissuade a person from disclosing one's feelings or talking about one's problems) would be associated with distress, pain, and problems with functioning, beyond the influence of the widely recognized risk factor of pain catastrophizing. A total of 122 women completed psychosocial and pain questionnaires during an initial evaluation at a multidisciplinary urology center. Correlational and multiple regression analyses examined pain catastrophizing and social constraints in association with general distress, general pain severity, urogenital pain, and pain interference with functioning. In zero-order correlations, pain catastrophizing and social constraints were significantly associated with all pain measures (p < 0.05) and distress. In regressions, both pain catastrophizing and social constraints were simultaneously independent predictors of general distress (β = 0.48 and 0.33, p < 0.001 respectively), general pain severity (β = 0.55 and 0.21, p < 0.001 and 0.01 respectively), and pain interference with functioning (β = 0.65, p < 0.001, and β = 0.16, p < 0.05 respectively), and together explained a moderate portion of the variance in outcome variables. Pain catastrophizing (but not social constraints) also significantly predicted urogenital pain (β = 0.43, p < 0.001). Both pain catastrophizing and social constraints are important to the experience of pelvic and urogenital pain, and effective pain treatment should include attention to these psychological and social factors.


FAS deficiency reduces apoptosis, spares axons and improves function after spinal cord injury.
After spinal cord injury (SCI), apoptosis of neurons and oligodendrocytes is associated with axonal degeneration and loss of neurological function. Recent data have suggested a potential role for FAS death receptor-mediated apoptosis in the pathophysiology of SCI. In this study, we examined the effect of FAS deficiency on SCI in vitro and in vivo. FAS(Lpr/lpr) mutant mice and wildtype background-matched mice were subjected to a T5-6 clip compression SCI, and complementary studies were done in an organotypic slice culture model of SCI. Post-traumatic apoptosis in the spinal cord, which was seen in neurons and oligodendrocytes, was decreased in the FAS-deficient mice both in vivo and in vitro particularly in oligodendrocytes. FAS deficiency was also associated with improved locomotor recovery, axonal sparing and preservation of oligodendrocytes and myelin. However, FAS deficiency did not result in a significant increase in surviving neurons in the spinal cord at 6 weeks after injury, likely reflecting the importance of other cell death mechanisms for neurons. We conclude that inhibition of the FAS pathway may be a clinically attractive neuroprotective strategy directed towards oligodendroglial and axonal preservation in the treatment of SCI and neurotrauma.


Adaptive immune regulation in autoimmune diabetes.
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the loss of insulin-producing pancreatic β-cells. The pathogenesis of T1D is complex and multifactorial and involves a genetic susceptibility that predisposes to abnormal immune responses in the presence of ill-defined environmental insults to the pancreatic islets. This review discusses how adaptive immunoregulatory T cells contribute to the modulation of the development and evolution of T1D, together with potential approaches that target these cells for new therapies in the disease.


Development of a deep learning model to identify hyperdense MCA sign in patients with acute ischemic stroke.
The aim of this study was to develop an interactive deep learning-assisted identification of the hyperdense middle cerebral artery (MCA) sign (HMCAS) on non-contrast computed tomography (CT) among patients with acute ischemic stroke. 35 HMCAS-positive and 39 HMCAS-negative samples extracted by 50-pixel-diameter circular regions of interest were obtained as training and validation datasets according to the consensus decisions of two experienced neuroradiologists. Data augmentation was performed to increase the number of training samples. A deep convolutional neural network (DCNN) (Xception) was used to classify input images as HMCAS-positive or -negative. Leave-one-case-out cross-validation was achieved to estimate sensitivity, specificity, and accuracy of the deep learning-based training model for identifying HMCAS. In terms of diagnostic performance, DCNN for HMCAS offered 82.9% sensitivity, 89.7% specificity, and 86.5% accuracy in leave-one-case-out cross-validation. Area under the receiver operating characteristic curve for HMCAS was 0.947 (95% confidence interval 0.895-0.998; P < 0.05). The deep learning method appears potentially beneficial for identifying HMCAS on non-contrast CT in patients with acute ischemic stroke.


Agomelatine pretreatment prevents development of hyperglycemia and hypoinsulinemia in streptozotocin-induced diabetes in mice.
The main objective of this study was to investigate potential effectiveness of agomelatine pretreatment in the prevention of diabetes itself and encephalopathy, with a focus on brain tissue oxidative stress and inflammatory processes in streptozotocin (STZ)-induced diabetic mice. Interleukine-1β (IL-1β) and TACR1 (NK1), which is a tachykinine receptor, were used for the investigation of inflammation in the brain regions including raphe nucleus, periaqueductal gyrus (PAG), amygdala, and nucleus accumbens. The effects of agomelatine on total antioxidant capacity were also evaluated. In the in vitro part of the study, the effects of agomelatine on cell viability were investigated in dorsal root ganglion (DRG) neurons. Fasting blood glucose levels were measured 72 h after STZ injection to determine the diabetic condition. Agomelatine pretreatment prevented both hyperglycemia and hypoinsulinemia in STZ-treated mice. When STZ was injected to induce diabetes in mice, neither hyperglycemia nor hypoinsulinemia was developed in agomelatine pretreated mice and 6 weeks after development of diabetes, agomelatine treatment significantly decreased levels of IL-1β mRNA in raphe nucleus and nucleus accumbens. TACR1 mRNA levels were lower in raphe nucleus, PAG, and amygdala of agomelatine-treated diabetic mice. The increase in total antioxidant capacity after agomelatine administration may responsible for its beneficial effect in the prevention of diabetes. We showed that agomelatine reversed high glucose-induced cell viability decreases in DRG neurons. Both the antihyperglycemic and antioxidant effects of agomelatine might have contributed to the DRG neuron viability improvement. In conclusion, agomelatine seems to both prevent development of diabetes and reverse the encephalopathic changes caused by diabetes.


The role of p23, Hop, immunophilins, and other co-chaperones in regulating Hsp90 function.
Molecular chaperones are a diverse group of highly conserved proteins that transiently interact with partially folded polypeptide chains during normal cellular processes, such as protein translation, translocation, and disassembly of protein complexes (1). Prior to folding or after denaturation, hydrophobic residues that are normally sequestered within a folded protein are exposed to the aqueous environment and are prone to aggregation or misfolding. Multiple classes of molecular chaperones, such as Hsp70s and Hsp40s, recognize and transiently bind polypeptides with exposed hydrophobic stretches in order to prevent misfolding. Other types of chaperones, such as Hsp90, have more specialized functions in that they appear to interact with only a subset of cellular proteins. This chapter focuses on the role of Hsp90 and partner co-chaperones in promoting the folding and activation of a diverse group of proteins with critical roles in cellular signaling and function.


A bacterial protease inhibitor protects antigens delivered in oral vaccines from digestion while triggering specific mucosal immune responses.
We report here that a bacterial protease inhibitor from Brucella spp. called U-Omp19 behaves as an ideal constituent for a vaccine formulation against infectious diseases. When co-administered orally with an antigen (Ag), U-Omp19: i) can bypass the harsh environment of the gastrointestinal tract by inhibiting stomach and intestine proteases and consequently increases the half-life of the co-administered Ag at immune inductive sites: Peyer's patches and mesenteric lymph nodes while ii) it induces the recruitment and activation of antigen presenting cells (APCs) and increases the amount of intracellular Ag inside APCs. Therefore, mucosal as well as systemic Ag-specific immune responses, antibodies, Th1, Th17 and CD8(+) T cells are enhanced when U-Omp19 is co-administered with the Ag orally. Finally, this bacterial protease inhibitor in an oral vaccine formulation confers mucosal protection and reduces parasite loads after oral challenge with virulent Toxoplasma gondii.


Perioperative Risk Factors for Post-operative Pneumonia after Type A Acute Aortic Dissection Surgery.
Type A acute aortic dissection (TAAAD) is a dangerous and complicated condition with a high death rate before hospital treatment. Patients who are fortunate to receive prompt surgical treatment still face high in-hospital mortality. A series of post-operative complications further affects the prognosis. Post-operative pneumonia (POP) also leads to great morbidity and mortality. This study aimed to identify the prevalence as well as the risk factors for POP in TAAAD patients and offer references for clinical decisions to further improve the prognosis of patients who survived the surgical procedure. The study enrolled 89 TAAAD patients who underwent surgical treatment in Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei province, China from December 2020 to July 2021 and analyzed the perioperative data and outcomes of these patients. Logistic regression analyses were used to identify the risk factors for POP. In the study, 31.5% of patients developed POP. Patients with POP had higher proportions of severe oxygenation damage, pneumothorax, reintubation, tracheotomy, renal replacement therapy, arrhythmia, gastrointestinal bleeding, and longer duration of mechanical ventilation, fever, ICU stay, and length of stay (all with P<0.05). The in-hospital mortality was 2.3%. Smoking, preoperative white blood cells, and intraoperative transfusion were the independent risk factors for POP in TAAAD. Patients who underwent TAAAD surgery suffered poorer outcomes when they developed POP. Furthermore, patients with risk factors should be treated with caution.


Extracellular dopamine in rat striatum following uptake inhibition by cocaine, nomifensine and benztropine.
A microdialysis/smallbore chromatographic system was used to monitor changes in extracellular dopamine concentration in the striatum of the rat following administration of drugs that block catecholamine uptake. Analysis of 0.5 microliter of dialysate every 5 min showed dose-dependent elevations in extracellular dopamine following systemic administration of nomifensine (1 and 10 mg/kg), benztropine (5 and 25 mg/kg) and cocaine (3, 10 and 30 mg/kg). The order of potency in vivo was nomifensine greater than cocaine greater than benztropine. The short sampling interval allows accurate temporal profiles following pharmacological manipulations to be acquired.


Diagnostic screening of NEUROD1 (MODY6) in subjects with MODY or gestational diabetes mellitus.
Diagnostic screening of NEUROD1 in patients with maturity-onset diabetes of the young (MODY) without mutations in the known MODY-genes (MODYX) and in subjects diagnosed with gestational diabetes mellitus. Direct sequencing of NEUROD1 was performed in (i) 73 probands with clinical MODY without mutations in hepatocyte nuclear factor (HNF)-4alpha (MODY1), glucokinase (MODY2) and hepatocyte nuclear factor (HNF)-1alpha (MODY3), and (ii) 51 subjects diagnosed with gestational diabetes. Control material consisted of 105 anonymous blood donors. Mean age at diagnosis of diabetes was 22 and 30 years in the MODYX patients and gestational diabetes mellitus subjects, respectively. Mean fasting blood glucose (9.6 +/- 4.3 vs. 5.7 +/- 1.0 mml/l) as well as glycosylated haemoglobin (8.2 +/- 2.4 vs. 6.0 +/- 0.6%) were higher in the MODYX patients than subjects with gestational diabetes. NEUROD1 mutations were not detected in our two study groups. Three previously reported polymorphisms were found: Ala45Thr, Pro197His and IVS1 -32 nt C>T. The amino acid substitution serine to cysteine in codon 29 (designated Ser29Cys) was detected in one out of 105 control subjects. As the control material consisted of anonymous blood donors, we were prevented from investigation of possible co-segregation between the sequence variant Ser29Cys and diabetes mellitus. As we found no NEUROD1 mutations, diagnostic screening for this gene is not warranted in Norwegian MODYX patients. Our study also suggests that NEUROD1 is not a candidate gene in gestational diabetes mellitus (GDM). The sequence variant Ser29Cys was identified in one anonymous DNA sample, but we were prevented from studying possible co-segregation with diabetes mellitus.


Management of the brown recluse spider bite.
The objectives in the treatment of the brown recluse spider bite are to prevent skin necrosis and the need for reconstructive surgery. A simple technique that consists of curetting the subcutaneous tissue in the necrotic area of the lesion, to prevent the local destructive actions of the toxin, is described. From 1981 to 1987, 18 patients were treated with this technique. The wounds were generally curetted under local anesthesia in an outpatient setting. In all but one case, the erythema, edema, and pain resolved significantly in 24 to 48 hours, and the wounds healed primarily with minimal scarring. We consider curettage the treatment of choice for brown recluse spider bites when the lesions are noted in relatively early stages. It can be performed as an outpatient procedure; it controls the symptoms and prevents further necrosis, with excellent cosmetic results.


Mn doping improves in-situ H2O2 generation and activation in electro-Fenton process by Fe/Mn@CC cathode using high-temperature shock technique.
Fe/Mn@carbon cloth (CC) was successfully fabricated through high-temperature shock (HTS) technique and used as cathode modification in heterogeneous electro-Fenton (hetero-EF) process for methylisothiazolinone (MIT) degradation. The nanocrystalline on Fe/Mn@CC electrode is doped with Fe and Mn oxides and coated with carbon layer, which could markedly enhance the electrocatalysis with high electro-chemical active area and low resistance. Fe/Mn@CC modified cathode can efficiently in-situ produce and activate H2O2, showing high electrocatalytic activity to MIT degradation. The 95.2% MIT degradation with in 100 min were achieved under the condition of 30 mA current, 0.75 L min-1 aeration intensity and initial pH = 3. Based on the CV curves and stability test, the high degradation activity revealed the kinetically beneficial regeneration of FeII/MnII in Fe/Mn@CC and activation of H2O2. The electron transfer between FeII/III and MnII/III, together with the direct FeII/MnII regeneration on the cathode, could markedly promote the H2O2 utilization, and eventually lead to MIT degradation.


Combining a Customized Immobilization System with an Innovative Use of the ExacTrac System for Precise Volumetric Modulated Arc Therapy of Challenging Forearm Sarcomas.
High-precision image-guided radiation therapy (RT) for tumors abutting the appendicular skeleton may mean technical difficulties and concerns among practitioners. This technical note addresses the specific challenge for normofractionated image-guided RT of a tumor target in a forearm through an unconventional use of a treatment verification system usually devoted to stereotactic RT.


Intraamniotic ethacridine lactate instillation versus vaginal PGE1 in second trimester termination of pregnancy.
To report on our experience with intraamniotic injection of ethacridine lactate (EL) for second trimester termination of pregnancy (TOP) and to compare its effectiveness with vaginal PGE1 in this setting. (a) Retrospective analysis of 54 intraamniotic EL-induced TOP. (b) Matched pair analysis of 50 second trimester TOP, using intraamniotic EL in group A (n=25) and vaginal PGE1 suppositories in group B (n=25). success rate, induction-delivery interval, analgesic use, drop in maternal hemoglobin, complications. (a) TOP with EL alone was successful in 50 cases (93%). Mean duration from instillation to delivery was 40.5 h (range 14-58, S.D.: +/-9.0). Mean analgesic need was low. Mean drop in hemoglobin was low (1.0 g/dl, S.D.: +/-1.1). (b) The matched pair analysis revealed a significantly shorter induction-delivery interval in the vaginal PGE1 group (mean 26.9 h, range 8-80, S.D.: +/-16.8 versus 41.0 h, range 24-55, S.D.: +/-7.3, p<.05). There were no significant differences in analgesic use or drop in hemoglobin. In both groups one case of post partum hemorrhage occurred. Intraamniotic instillation of ethacridine lactate in second trimester TOP is safe, cheap and successful in the vast majority of cases. Disadvantages are the longer induction-delivery interval compared to modern prostaglandins and the invasive mode of application. However, by the use of EL the side effects of repeated prostaglandin application can be avoided as well as multiple vaginal examinations. Furthermore, the time of delivery can be predicted in a narrower interval.


Maternal autonomy but not social support is a predictor of child feeding indicators in the Northern Region, Ghana.
Child malnutrition may be mediated by poor infant and young child feeding (IYCF) practices. This study sought to explore if maternal social support or autonomy was related to IYCF indicators in Northern Region, Ghana. An analytical cross-sectional study was conducted with 395 randomly sampled mother-child pairs from 8 health facilities. Data were collected on socio-demographic characteristics, social support and autonomy statuses of mothers, and dietary intake and anthropometry of children. Maternal social support and autonomy statuses were derived and classified into tertiles and IYCF and child growth indicators were derived based on WHO protocol. Logistic regression analysis was used to explore the association of maternal social support and autonomy statuses to IYCF indicators and child nutritional status. The mean age of the women was 27 (± 5.10) years and most belonged to the lowest tertile of social support (52.4%), and autonomy (44.1%). About half of the children, 53.2% and 44.6%, received Minimum Dietary Diversity (MDD) and Minimum Acceptable Diet (MAD) respectively but the majority (72.9%) received Minimum Meal Frequency (MMF). About a fifth of the children, 21.0%, 24.1%, and 20.5%, were wasted, stunted, and underweight respectively. Maternal autonomy was associated with IYCF but not growth indicators of young children. Compared to children of mothers of richest autonomy tertile, children of women of middle autonomy tertile were 67% less likely to receive MDD [Adjusted Odds Ratio (AOR): 0.33; 95% Confidence Interval (CI): 0.18-0.59], and 56% less likely to receive MAD (AOR: 0.44; 95% CI: 0.24-0.77). Also, children belonging to mothers of poorest autonomy tertile were 56% less likely to receive MMF compared to children of richest maternal autonomy tertile (AOR: 0.44; 95% CI: 0.23-0.84). Maternal autonomy and not social support is associated with IYCF indicators of children in Northern Ghana; child survival programmes should incorporate or strengthen women empowerment interventions to improve child nutrition.


Control of active B and L cathepsins in tissues of colorectal cancer using cystatins isolated from chicken egg proteins: in vitro studies.
The activity of cysteine peptidases (cathepsins B and L) was estimated in homogenates of tissues sampled during surgery from 60 patients operated due to colorectal tumors. The results were compared to those obtained using tissues in which histopathology disclosed no tumorous cells, obtained from 20 patients of the same group, treated as a control. Activity of the enzymes was inhibited using cysteine peptidase inhibitors isolated from chicken egg proteins. Application of the inhibitors was found to inhibit activity of the enzymes which play a key role in tumor development. It is suggested that in future the inhibitors may provide a component of new generation drugs in the so-called inhibitor therapy.


Thunberg's Barospirator, a Fully Encasing Predecessor of the Iron Lung.
Used as a ventilator for assisting victims of polio, the barospirator was described by Swedish physician-scientist Torsten Thunberg in 1924. An immediate predecessor of the iron lung of Philip Drinker, the barospirator fully encased the entire body. Cyclic air-pressure changes within the chamber achieved ventilation during equilibrations of intrapulmonary and ambient pressures. Pulmonary medicine innovator Alvan Leroy Barach used a modified barospirator for lung rest as a treatment of tuberculosis in the 1940s. Adverse effects included damage to patients' tympanic membranes. Despite its limited clinical success, the barospirator was successfully used by one of Drinker's competitors, John H. Emerson, to invalidate Drinker's US patent filings.


Efficacy in anterior uveitis of two known steroids and topical tolmetin.
We have compared the anti-inflammatory efficacy of 5% tolmetin sodium dihydrate, 0.5% prednisolone disodium phosphate, and 0.1% betamethasone disodium phosphate in 71 consecutive patients presenting with acute endogenous non-granulomatous uveitis randomly assigned to one of these treatment groups. Inflammatory symptoms and signs were scored during the course of the 21-day trial period. There was no statistically significant difference in the effect on the signs or symptoms of the three drugs tested. 90% of the Betnesol (betamethasone sodium phosphate, benzalkonium chloride) treated group were clinically judged cured compared with 68% of the Predsol (prednisolone sodium phosphate, benzalkonium chloride) treated group, and 57% of the tolmetin treated group.


Malignant minor pleural effusion detected on thoracotomy for patients with non-small cell lung cancer: is tumor resection beneficial for prognosis?
This study attempts to clarify the benefit of surgery for non-small cell lung cancer (NSCLC) with malignant minor pleural effusion that is detected at thoracotomy. Records of surgical patients with NSCLC were reviewed, with a definition of minor pleural effusion as less than 300 mL. The patients were divided into three groups as follows: (1) group C consisted of patients who underwent grossly complete resection; group I, patients with incomplete tumor resection; and group E, patients who underwent exploratory thoracotomy only. There were 196 patients who had minor pleural effusion; of these, 96 (46%) underwent an examination to define the malignancy status of pleural effusion after surgery. In 43 patients (45%), the effusion was found to be malignant. The median survival time and 5-year survival rate, respectively, were 13 months and 9% for group C (n = 11); 34 months and 10% for group I (n = 14; p = 0.3); and 17 months and 0% for group E (n = 18; p = 0.8). Tumor resection is not beneficial for the survival of patients with NSCLC who have a minor malignant pleural effusion.


Neurokinin 3 receptor antagonism for menopausal hot flashes.
Menopausal hot flashes are common and debilitating. Menopausal Hormone Therapy (MHT) is effective for hot flashes but has risks and side effects that limit its use. NK3 receptor antagonism has emerged as a novel therapeutic strategy, leading to the recent FDA approval of fezolinetant, a first-in-class nonhormonal treatment for menopausal hot flashes. To view this Bench to Bedside, open or download the PDF.


The development of an instrument for evaluating clinical teachers: involving stakeholders to determine content validity.
Research indicates that the quality of supervision strongly influences the learning of medical students in clinical practice. Clinical teachers need feedback to improve their supervisory skills. The available instruments either lack a clear theoretical framework or are not suitable for providing feedback to individual teachers. We developed an evaluation instrument based on the 'cognitive apprenticeship model'. The aim was to estimate the content validity of the developed instrument. Item relevance was rated on a five-point scale (1 = highly irrelevant, 5 = highly relevant) by three groups of stakeholders in undergraduate clinical teaching: educationalists (N = 12), doctors (N = 16) and students (N = 12). Additionally, stakeholders commented on content, wording and omission of items. The items were generally rated as very relevant (Mean = 4.3, SD = 0.38, response = 95%) and any differences between the stakeholder groups were small. The results led to elimination of 4 items, rewording of 13 items and addition of 1 item. The cognitive apprenticeship model appears to offer a useful framework for the development of an evaluation instrument aimed at providing feedback to individual clinical teachers on the quality of student supervision. Further studies in larger populations will have to establish the instrument's statistical validity and generalizability.


An Exploratory Study of Units of Reporting Opium Usein Iran: Implications for Epidemiologic Studies.
Measuring the amount of opium use is a challenge in epidemiologic studies. Self-report of amount of opium use at each consumption, widely used in the literature, usually fails to provide a good estimate. The purpose of this study is to systematically study the perceived weight units of reported opium use in Iran, and compare them to the standardized units of weight measurement. An exploratory descriptive study was conducted in six major cities of Iran. Study participants were interviewed and asked to use a Play-Doh-like material to demonstrate the amount of opium they use. To obtain an estimate of the weight of the material used, we multiplied the volume by the density of the opium product. We experimentally determined the density of the commonly used opium products. We used medians and inter-quartile ranges (IQRs) to report the typical amount of each unit. A total of 108 individuals participated in this study. The most frequently reported unit was "gram"; the median perceived weight for one gram (g) of opium was 0.24 (IQR: 0.16) g. The second most commonly used unit was nokhod with a median of 0.16 (IQR: 0.16) g, followed by mesghaal and hab/habeh, which were 1.28 (IQR: 0.81) and 0.16 (IQR: 0.16) g, respectively. The median perceived weight of mesghaal and gram in the studied cities was less than the expected standardized values. In conclusion, the reported amount of opium use is highly inaccurate and unreliable, and is mainly subject to underestimation.


Muscarinic receptor stimulation induces TASK1 channel endocytosis through a PKC-Pyk2-Src pathway in PC12 cells.
Muscarinic receptor stimulation or protein kinase C (PKC) activation in rat adrenal medullary and PC12 cells rapidly induces tyrosine phosphorylation of TWIK-related-acid-sensitive K+ 1 (TASK1) channels with the subsequent clathrin-dependent endocytosis. Our previous study suggested that the muscarinic signal is transmitted to the non-receptor tyrosine kinase Src through PKC and Pyk2. Although PKC activation is known to stimulate Pyk2 in certain types of cells, its molecular mechanism remains unclear. In this study, proximity ligation assay (PLA) and other molecular biological approaches were used to elucidate the details of this muscarinic signaling in PC12 cells. When green fluorescent protein (GFP)-TASK1 was expressed, the majority of GFP-TASK1 was located at the cell periphery. However, the simultaneous expression of GFP-TASK1 and PKCα, but not PKCδ, led to GFP-TASK1 internalization. Muscarinic receptor stimulation resulted in transient co-localization of Pyk2 and Src at the cell periphery, and expression of kinase dead (KD) Pyk2 and Src, but not Pyk2 and KD Src, resulted in GFP-TASK1 internalization. PLA analysis revealed that in response to muscarine, PKCαactivates Pyk2 through phosphorylating its serine residues. These results indicate that muscarinic receptor stimulation induces TASK1 channel endocytosis sequentially through PKCα, Pyk2, and Src, and PKCα activates Pyk2 through phosphorylation.


Skin testing.
To provide the reader with a relevant review of the literature regarding skin testing in the allergist's office. A PubMed search for the years 1970 through 2005 was performed using the following keywords: allergy skin testing, skin prick testing, and intradermal skin testing. Articles that highlighted aspects of sentinel to clinical allergists' use of skin testing in the office, such as methods of skin testing, intradermal vs skin prick testing, skin test devices, and methods of expressing skin test results, were selected for further review. Skin testing remains the central test to confirm an allergic response. It is minimally invasive and when performed correctly has good reproducibility. Results are easily quantifiable and correlate well with end organ challenge. It is imperative however that technicians who perform the skin tests and the clinicians who order or interpret these tests understand the characteristics of the specific tests they are administering. It is also important that the clinician express skin test results in a manner that allows easy interpretation by another physician. Allergists must consider controllable variables that affect skin test results and their interpretation. When not considered, they may be responsible for some of the inaccuracies associated with allergy skin testing.


Radiological Evaluation Criteria for Chronic Subdural Hematomas : Review of the Literature.
The methodology of measuring chronic subdural hematoma (cSDH) extent and its effect on intracranial structures is relevant for patient classification and outcome measurements and affects the external validity of cSDH studies. With embolization of the middle meningeal artery (MMA) as a possible treatment of cSDHs, the topic has gained substantial interest. We sought to summarize the heterogeneity of radiologic measurements, specifically in the evaluation of cSDHs based on literature review. In this review, we identified and described the most common radiological methodologies for measurements of cSDH thickness, cSDH volume and of midline shift. There are numerous published methods on how to evaluate cSDH thickness, cSDH volume and midline shift but no common standard. The definition of measurement methods and reporting standards for MMA embolization in cSDH patients and their validation needs to be addressed.


Treatment of peritoneal carcinomatosis with intraperitoneal administration of Ad-hARF.
Peritoneal dissemination of cancer is a terminal condition with limited therapeutic options. Because the peritoneal cavity is a single enclosed space, regional treatment approaches for isolated peritoneal cancrinomatosis are appealing. There is a potential role for gene therapy in the management of peritoneal cancrinomatosis. An adenoviral construct of the human p14ARF gene (a tumor suppressor) and a 22 amino acid sequence of the ARF gene product, which has cell membrane penetrating properties, were assayed for proapoptotic properties in a human colorectal cancer cell line (Clone A) cells in vitro. Peritoneal carcinomatosis derived from Clone A cells was also established in nude mice and then treated with intraperitoneal administration of an adenoviral construct of the human p14ARF gene. Treatment of ARF-negative Clone A cells with Ad-hARF in vitro reestablished ARF function. However, the cell penetrating ARF-related peptide did not restore ARF function in Clone A cells. Treatment of Clone A peritoneal xenografts with a single intraperitoneal dose of Ad-hARF (9 × 10(6) viral particles) suppressed the progression of peritoneal disease. Weekly (six times) administration of the Ad-hARF at a lower dose (3 × 10(6) viral particles) also suppressed tumor progression. Treatment of peritoneal carcinomatosis by intraperitoneal administration of adenoviral constructs of inactivated tumor suppressor genes may be a feasible clinical approach, and ARF may represent a suitable molecular target for tumors where the ARF gene is inactivated.


EEG effects of microinjection of naloxone in the region of the nucleus tractus solitarius of the rat.
In recent years, we have carried out several studies on brainstem mechanisms associated with pain modulation. Of particular interest has been the region of the nucleus tractus solitarius (NTS) at the level of the area postrema (AP) in the dorsomedial medulla. This region has been found to be rich in opiate receptors and to be involved in pain modulation. Having previously demonstrated the EEG and behavioral effects of systemic administration of morphine, we initiated the present study to determine whether microinjection of naloxone directly into the region of the NTS will modify any or all of the EEG effects induced by subsequent systemic administration of morphine. Our results have shown that microinjections of naloxone into the region of the NTS block the cortical EEG synchronizing effects of systemically administered morphine. These results indicate that morphine-induced cortical EEG synchronization is mediated through the region of the NTS. This region may, therefore, comprise part of an opiate sensitive system which can influence cortical EEG activity.


Parapharyngeal neurilemmomas.
Parapharyngeal neurilemmomas are uncommon benign tumours. Two patients are reported with one tumour arising from the vagus and the other from the hypoglossal nerve. Access to the vagal tumour was accomplished with the aid of an osteotomy at the angle of the mandible. Theoretically these lesions can be enucleated with preservation of the nerve or resected and repaired with a nerve graft. However, these alternative procedures were impractical in both these patients and the explanations for this are discussed.


Enhancing the cavitation erosion resistance of D8m-Ta5Si3 nanocrystalline coatings through Al alloying.
To investigate the effects of Al alloying on the erosion-corrosion resistance of β-Ta5Si3, both a β-Ta5Si3 coating and an Al-alloyed β-Ta5(Si0.83Al0.17)3 coating were synthesized on a 316 substrate by the double cathode glow discharge technique. The phase constitution, composition and microstructure of the two coatings were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The two coatings were composed of nearly rounded D8m-β-Ta5Si3 grains with an average size of ∼4 nm, and after the addition of Al, the preferred growth orientation for the β-Ta5Si3 coating changed from (4 0 0) to (0 0 2). The hardness, elastic modulus and contact damage resistance of the coatings were measured using a nanoindentation tester. The results showed that Al alloying improved the contact damage resistance of β-Ta5Si3 with only a slight decrease in hardness. The erosion-corrosion behavior of the two coatings was performed in a 3.5 wt% NaCl solution containing a 12 wt% concentration of silica sand under two phase slurry flow condition and in a 3.5 wt% NaCl solution under ultrasonic cavitation erosion conditions. This revealed that the Al alloyed β-Ta5Si3 has a higher resistance to both erosion-corrosion and ultrasonic cavitation erosion as compared to the binary β-Ta5Si3 coating.


Low-Dose Topical 5-Aminolevulinic Acid Photodynamic Therapy in the Treatment of Different Severity of Acne Vulgaris.
The objective of this article is to investigate the effectiveness and safety of photodynamic therapy (PDT) with 3.6 % topical aminolevulinic acid (ALA) and a short incubation time with red light in moderate to severe acne. One hundred and thirty-six patients with moderate to severe acne were treated with 3.6 % topical ALA-PDT for three sessions with an interval of 2 weeks. Patients were evaluated for efficacy and safety on week 2, 4, 6, 8, and 12 after the initial treatment. Most patients showed apparent clearance of acne lesions at the treated site after three sessions. The effective treatment rates were increased after the multiple therapies. The clinical outcomes are the best at 4 weeks after the final treatment. The total effectiveness rate and cure rate of the low-dose ALA-PDT procedure is 92.65 and 47.06 %, respectively. Thirty-one patients and nineteen patients showed apparent exacerbation of acne lesions before the 2nd and 3rd treatment, respectively, but all of them showed good or excellent improvement after a three-course treatment. A few patients showed mild relapse including papules and comedos at 8 weeks after the final treatment. No significant differences are found in the effects of different acne severity and different genders. Adverse reactions are mild and transient. A 3.6 % topical ALA-PDT with a short time incubation with red light is a simple and an effective treatment option for moderate to severe acne with mild side effects in Chinese people.


75,77Br- and 123I-analogues of D-glucose as potential tracers for glucose utilisation in heart and brain.
A number of D-glucose analogues labelled with either the positron emitter 75Br (T 1/2 = 1.6 h) or the single photon emitter 123I (T 1/2 = 13.3 h) were studied as potential tracers for glucose utilisation in heart and brain. Of these, 3-deoxy-3-bromo-D-glucose, 3-deoxy-3-iodo-D-glucose, methyl 2-deoxy-2-bromo-beta-D-glucoside and methyl 2-deoxy-2-iodo-beta-D-glucoside showed little uptake of radioactivity into brain and an unfavourable ratio of heart-to-blood and heart-to-lung concentrations. In contrast, methyl 3,4,6-tri-O-acetyl-2-deoxy-2-iodo-beta-D-glucoside (MTIG) and methyl 3,4,6-tri-O-acetyl-2-deoxy-2-bromo-beta-D-glucoside (MTBG) showed promising brain uptake (160% MBC for MTBG) with a good brain-to-blood concentration ratio of 0.8. MTBG is not metabolically altered in the brain. Thus, this compound may be a promising tracer for measuring glucose transport if it proves to be a substrate for the hexose carrier at the blood-brain-barrier.


RapidPlan development of VMAT plans for cervical cancer patients in low- and middle-income countries.
Cervical cancer has a high incidence and mortality rate in low- and middle-income countries (LMICs) largely due to limited resources and insufficient staffing. Knowledge-based planning (KBP) could alleviate understaffing issues by streamlining the radiotherapy treatment planning process. Varian's KBP system (RapidPlan) was used to develop a model capable of producing volumetric modulated arc therapy (VMAT) plans for cervical cancer patients. Plan data from 46 patients previously treated at MD Anderson Cancer Center (MDACC) were used to create and train the model which was then applied to 32 patients excluded from the training process. Dose volume histogram (DVH) values for the planning target volume (PTV_High), bladder, rectum, and bowel were evaluated for the validation plans and found to have satisfied the required PTV coverage and organ-at-risk (OAR) dose constraints. The average value for PTV_High D95.0% was 48.0 Gy (sd = 3.0 Gy) for existing clinical plans and 48.4 Gy (sd = 2.6 Gy) for the validation plans. The mean dose for the bladder, rectum, and bowel was 39.8 Gy (sd = 3.9 Gy), 41.6 Gy (sd = 5.2 Gy), and 21.6 Gy (sd = 5.0 Gy) for existing clinical plans and 38.9 Gy (sd = 4.0 Gy), 40.3 Gy (sd = 4.8 Gy), and 21.5 Gy (sd = 4.6 Gy) for validation plans, respectively. A TOST test showed that the p values for the PTV_High D95.0% (p < 0.001), rectum V30Gy (p = 0.039), and mean dose to the bladder (p = 0.0014), rectum (p = 0.025), and bowel (p = 0.006) were statistically significant within a 5% equivalence margin of the clinical value thereby providing strong evidence of equivalence. Based on this statistical analysis, it was determined that the model was capable of generating treatable VMAT plans for cervical cancer patients.


The isolation, characterization and partial sequence of a peptide rich in glutamic acid and aspartic acid (HGA-2 peptide) from calf thymus non-histone chromosomal protein HMG 2. Comparison with a similar peptide (HGA-1 peptide) from calf thymus non-histone chromosomal protein HMG 1.
A 41-residue peptide (HGA-2) containing a continuous sequence of 35 glutamic and aspartic residues was isolated from non-histone chromosomal protein HMG 2. This highly acidic peptide is compared with a similar peptide (HGA-1) isolated from non-histone chromosomal protein HMG 1.


Psychological profile of Taiwanese interstitial cystitis patients.
The correlation between anxiety and interstitial cystitis has, as best we know, not yet been reported on. The present study investigated the psychological profile, including anxiety and depression, of patients suffering from interstitial cystitis (IC). A total of 47 IC patients, all of whom met National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases (NIDDK) criteria, plus a group of 31 age-matched, asymptomatic women received a structured interview on depression (Hamilton Rating Scale for Depression) and also on anxiety symptoms (Hamilton Rating Scale for Anxiety). IC patients also completed questionnaires relating to IC symptom severity, including urgency and frequency (visual analog scale) and O'Leary Sant index. A total of 85% of our IC patients featured significant affective symptoms. The average depression scores were 16.6. Fifteen patients (31.9%) featured mild depressive symptoms, five (10.6%) had mild to moderate and 20 (42.6%) had moderate to severe depression symptoms. The mean anxiety score was 21.0, with 21 (44.7%), nine (19.1%) and 17 (36.2%) patients revealing mild, mild to moderate, and moderate to severe anxiety symptoms, respectively. Further, IC patients reported a significantly greater extent of depression and anxiety than was the case for controls. Pain scale and O'Leary Sant index were significantly correlated to anxiety and depression score. Most of our IC patients feature significant depression and anxiety. The extent of affective symptoms would appear to correlate well with IC symptom severity.


The nature of qualitative comments in evaluating professionalism.
We analysed written comments on clerkship evaluation forms to determine if they furthered our understanding of students' professional behaviour. We transcribed all written comments related to professional behaviour for 1 medical school class in 4 major clerkships, then categorised the comments. Comments were coded into categories by two raters. They were also coded as positive, negative or equivocal. The 3 types of comments were each correlated with a Likert-type score for professionalism for each student in these same clerkships. Most comments covered initiative, working well with others, patient skills and working hard. Of the 1845 comments, 1721 were positive, 106 were negative and 18 were equivocal, neither wholly positive nor wholly negative. The total number of positive comments correlated with the students' numerical professionalism score (r = 0.29, P < 0.001); negative comments correlated negatively with the numerical professionalism score (r = -0.44, P < 0.001). Equivocal comments were significantly negative (r = -0.25, P = 0.002). Qualitative analysis revealed that equivocal comments were focused on maturity, initiative and teamwork. Written comments contain unique indicators of students' professional behaviour and are largely positive in nature; negative comments stand out by their rarity and intensity. There is a set of negative comments masked by evaluators in language that appears neutral or even partly positive that statistically resemble negative comments and should be regarded as such by students who receive this type of comments. Evaluators should be encouraged and trained to express their qualitative views of students.


Optimal design of batch and simulated moving bed chromatographic separation processes.
Preparative chromatography, especially simulated moving bed (SMB) chromatography, is a key technology for the separation of fine chemicals on a production scale. Most of the design methods for batch and SMB processes proposed in the open literature deal with the optimisation of the operating conditions for a given chromatographic unit only. Therefore, a comparison of the process economy may lead to incorrect results. In this contribution, an effective strategy for the optimal choice of all process parameters (operation and design parameters) is proposed. The main idea of this strategy is to apply a detailed and experimentally validated process model and to reduce the number of influencing parameters by introducing and optimising dimensionless process parameters. It is shown that there is an infinite choice of design and operating parameters to achieve maximum productivity or minimum separation costs and not at the maximum pressure drop only. The detailed design of the chromatographic unit and the selection of the operating conditions can be adjusted by considering the availability of columns and packing materials. As the model system, the separation of a racemic mixture (EMD53986) on Chiralpak AD was investigated. After complete optimisation of a batch and a SMB unit, a real comparison of the process economy can be achieved. Finally, the influences of two different objective functions, productivity and specific separation cost, are analysed.


Assessment of an intervention to train teaching hospital care providers in quality management.
Successful implementation of continuous quality improvement (CQI) programs in hospitals remains rare in all countries, making it necessary to experiment with implementation methods while considering the cultural factors of resistance to change. To assess the impact of an educational intervention on involvement of clinical department staff in the quality process. Twelve voluntary clinical departments (six experimental and six controls) in a French 2000-bed university hospital comprising 40 clinical departments. Three day training seminar to a group of 12-20 staff members from each department. Quasi-experimental post-test only design study with control group conducted 12 months after the intervention with a questionnaire completed in a face-to-face interview. 98 trained staff and 100 untrained staff from the six experimental departments and 100 staff from the six control departments. Declared knowledge of the CQI methods and participation in quality management activities. 286 people (96%) were involved in the study. More of the trained staff knew the CQI methods (62.4%) than staff in the control departments (16.5%) (adjusted odds ratio (ORa) = 10.6 (95% CI 4.97 to 22.62)). More trained staff also participated in quality improvement work groups than control department staff (76.3% v 14.0%; ORa = 27.4 (95% CI 11.6 to 64.4)). In the experimental departments the untrained staff's knowledge of CQI methods and their participation in work groups did not differ from that of control department staff. A continuing education intervention can involve care providers in CQI. Dissemination of knowledge from trained personnel to other staff members remains limited.


Temperature-dependent kinetic pathways featuring distinctive thermal-activation mechanisms in structural evolution of ice VII.
Ice amorphization, low- to high-density amorphous (LDA-HDA) transition, as well as (re)crystallization in ice, under compression have been studied extensively due to their fundamental importance in materials science and polyamorphism. However, the nature of the multiple-step "reverse" transformation from metastable high-pressure ice to the stable crystalline form under reduced pressure is not well understood. Here, we characterize the rate and temperature dependence of the structural evolution from ice VII to ice I recovered at low pressure (∼5 mTorr) using in situ time-resolved X-ray diffraction. Unlike previously reported ice VII (or ice VIII)→LDA→ice I transitions, we reveal three temperature-dependent successive transformations: conversion of ice VII into HDA, followed by HDA-to-LDA transition, and then crystallization of LDA into ice I. Significantly, the temperature-dependent characteristic times indicate distinctive thermal activation mechanisms above and below 110-115 K for both ice VIII-to-HDA and HDA-to-LDA transitions. Large-scale molecular-dynamics calculations show that the structural evolution from HDA to LDA is continuous and involves substantial movements of the water molecules at the nanoscale. The results provide a perspective on the interrelationship of polyamorphism and unravel its underpinning complexities in shaping ice-transition kinetic pathways.


Modeling the Arden Syntax for medical decisions in XML.
A new model expressing Arden Syntax with the eXtensible Markup Language (XML) was developed to increase its portability. Every example was manually parsed and reviewed until the schema and the style sheet were considered to be optimized. When the first schema was finished, several MLMs in Arden Syntax Markup Language (ArdenML) were validated against the schema. They were then transformed to HTML formats with the style sheet, during which they were compared to the original text version of their own MLM. When faults were found in the transformed MLM, the schema and/or style sheet was fixed. This cycle continued until all the examples were encoded into XML documents. The original MLMs were encoded in XML according to the proposed XML schema and reverse-parsed MLMs in ArdenML were checked using a public domain Arden Syntax checker. Two hundred seventy seven examples of MLMs were successfully transformed into XML documents using the model, and the reverse-parse yielded the original text version of MLMs. Two hundred sixty five of the 277 MLMs showed the same error patterns before and after transformation, and all 11 errors related to statement structure were resolved in XML version. The model uses two syntax checking mechanisms, first an XML validation process, and second, a syntax check using an XSL style sheet. Now that we have a schema for ArdenML, we can also begin the development of style sheets for transformation ArdenML into other languages.


Allelic loss in clinically and screening-detected primary hyperparathyroidism.
Parathyroid adenomas frequently harbour deletions of genomic DNA at chromosome regions 1p, 6q and 11q. In this study we related clinical characteristics in 56 patients with primary hyperparathyroidism (pHPT) to loss of heterozygosity (LOH) in these chromosome regions. LOH analysis was performed on 56 sporadic parathyroid tumours using a total of 18 microsatellite markers for chromosome regions 1p, 6q and 11q. LOH was identified, for either radioactive or fluorescent labelled markers, as total absence or reduction of > or = 50% of the signal intensity of an allele in the tumour DNA vs. constitutional DNA. Twenty-one of the patients were recruited by a population-based screening for pHPT and the remaining pHPT patients were gathered from routine clinical practice. In total, 27%, 23% and 23% of the tumours showed LOH at 1p, 6q and 11q, respectively. LOH at both 1p and 11q was more common in the screening-detected pHPT patients compared to those recruited from clinical practice (38% vs. 20%; P = 0.02 and 43% vs. 11%; P = 0.001, respectively), while allelic loss at 6q was more prevalent in the latter group (11% vs. 31%; P = 0.001). No apparent relationships between LOH at 1p, 6q, and 11q and clinical characteristics, such as glandular weight, serum levels of PTH or calcium, were demonstrated. Moreover, additional LOH analysis of chromosome 1p suggested a putative parathyroid tumour suppressor gene(s) in the region between markers DS214 and D1S503, spanning approximately 6 cM. A high frequency of LOH at 1p and 11q in tumours of screening-detected pHPT patients is intriguing, and may suggest that inactivation of known (the MEN1 gene) and putative tumour suppressor genes at these chromosomal regions is associated with a more benign disease.


Prostatic cancer with metastasis to the testis.
Metastasis to the testis is rare. The site of primary tumor may be the lungs, the prostate or the large bowel. The clinical parameter is illustrated by a case history. The immunohistochemical method is taken into account.


Glial and neuronal damage markers in patients with anorexia nervosa.
Anorexia nervosa (AN) commonly arises during adolescence leading to interruptions of somatic and psychological development as well as to atrophic brain changes. It remains unclear whether these brain changes are related to the loss of neurons, glia, neuropil or merely due to fluid shifts. We determined leptin levels and two brain-derived damage markers: glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE) of 43 acute AN patients and 50 healthy control woman (HCW). Peripheral GFAP and NSE concentrations of AN patients were not elevated and not different from HCW. Subjects with particularly low leptin concentration, indicating severe malnutrition, did not show abnormal values either. During weight recovery the marker proteins remained unchanged. Our preliminary results are in line with neuroimaging studies supporting the reversibility of brain changes in AN and do not substantiate hypotheses relying on the extensive damage of brain cells as an explanation for cerebral atrophy in AN.


Characterization of Enterovirus Associated m6A RNA Methylation in Children With Neurological Symptoms: A Prospective Cohort Study.
Little is known about the particular changes of N6-methyladenosine (m6A) RNA methylation in enterovirus (EV) infection among children with neurologic symptoms. Here, we determined the characterization of EV associated m6A RNA methylation in this population. A prospective cohort study was conducted from 2018/2 to 2019/12 at the Guangzhou Women and Children's Medical Center. We included EV infected children with and without neurological symptoms. High-throughput m(6)A-RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq analysis were used to evaluate the m6A RNA methylation and transcript expression of cerebrospinal fluid samples. The functional annotation and pathways of differentially methylated m6A genes with synchronously differential expression were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Seven patients were enrolled in the control group, and 13 cases were in the neurological symptoms (NS) group. A total of 3472 differentially expressed genes and 957 m6A modified genes were identified. A conjoint analysis of MeRIP-seq and RNA-seq data found 1064 genes with significant changes in both the m6A modifications and mRNA levels. The different m6A RNA methylation was increased in the transcriptome's CDS regions but decreased in both the 3'UTRs and stop codon among the NS group. Functional annotation like the "oxidative phosphorylation" gene pathway, "Parkinson's disease" and GO terms like "respiratory electron transport chain," "cellular metabolic process," and "oxidation-reduction process" was enriched in symptomatic patients. Our study elucidated the changes of RNA m6A methylation patterns and related cellular functions and signaling pathways in EV patients with neurologic symptoms.


Sheep red blood cells enhance T-lymphocyte proliferation.
Small numbers of sheep red blood cells (SRBC) markedly augmented the proliferation of T lymphocytes activated by antigens or mitogens. This effect occurred with as few as one SRBC per T lymphocyte and with intact or osmotically lysed red cells. When increasing numbers of SRBC was added to T lymphocyte cultures stimulated with PHA or autologous cells, T lymphocyte proliferation peaked sharply at 10 to 50 SRBC per T cell. The SRBC did not influence resting T-lymphocytes. Rather, the effect occurred after T lymphocyte activation during cell division. There was a detectable increase in interleukin 2 (IL-2) receptor generation but not in IL-2 production by activated T lymphocytes cultured with SRBC versus medium alone. Finally, anti-T11 antibody could inhibit the SRBC enhancing effect on T-lymphocyte function, suggesting that an empty erythrocyte (E) receptor on the T lymphocyte was necessary for the SRBC action.


Comparison of Near-Infrared Spectroscopy-Based Cerebral Autoregulatory Indices in Extremely Low Birth Weight Infants.
Premature infants are born with immature cerebral autoregulation function and are vulnerable to pressure passive cerebral circulation and subsequent brain injury. Measurements derived from near-infrared spectroscopy (NIRS) have enabled continuous assessment of cerebral vasoreactivity. Although NIRS has enabled a growing field of research, the lack of clear standardization in the field remains problematic. A major limitation of current literature is the absence of a comparative analysis of the different methodologies. To determine the relationship between NIRS-derived continuous indices of cerebral autoregulation in a cohort of extremely low birth weight (ELBW) infants. Premature infants of birth weight 401-1000 g were studied during the first 72 h of life. The cerebral oximetry index (COx), hemoglobin volume index (HVx), and tissue oxygenation heart rate reactivity index (TOHRx) were simultaneously calculated. The relationship between each of the indices was assessed with Pearson correlation. Fifty-eight infants with a median gestational age of 25.8 weeks and a median birth weight of 738 g were included. Intraventricular hemorrhage (IVH) was detected in 33% of individuals. COx and HVx demonstrated the highest degree of correlation, although the relationship was moderate at best (r = 0.543, p < 0.001). No correlation was found either between COx and TOHRx (r = 0.318, p < 0.015) or between HVx and TOHRx (r = 0.287, p < 0.029). No significant differences in these relationships were found with respect to IVH and no IVH in subgroup analysis. COx, HVx, and TOHRx are not numerically equivalent. Caution must be applied when interpreting or comparing results based on different methodologies for measuring cerebral autoregulation. Uniformity regarding data acquisition and analytical methodology are needed to firmly establish a gold standard for neonatal cerebral autoregulation monitoring.


Impact of the Momentum pilot project on male involvement in maternal health and newborn care in Kinshasa, Democratic Republic of the Congo: a quasi-experimental study.
The World Health Organization recommends that programs that seek to improve maternal and newborn health outcomes actively involve men during pregnancy, childbirth, and postpartum. However, there is little evidence on what strategies work to increase male knowledge of and involvement in antenatal and postnatal care. This study assessed the impact of the Momentum project on male involvement in maternal health and newborn care. The project involved monthly home visits to a cohort of first-time mothers aged 15-24 recruited at six-months gestation and group education sessions for their male partners using the Program P toolkit. Participants were followed-up for 16 months. The study used a quasi-experimental design with three intervention and three comparison health zones. Baseline data were collected in 2018 and endline data in 2020. Exploratory factor analysis was used to develop scales of male involvement. We measured the causal influence of Momentum using an intent-to-treat analysis at the health-zone level and a dose-response analysis at the individual level. We used random-effects probit and linear models for outcomes measured at baseline and endline, and treatment effects models with inverse-probability weighting for outcomes measured only at endline. The impact analysis involved 1,204 male partners of first-time mothers with live births. Intervention health zones were associated with an 18.1 percentage point (95% CI [(10.6, 25.6]) increase in knowledge of three or more obstetric danger signs and a 13.9 percentage point (95% CI [6.3, 21.6]) increase in knowledge of newborn danger signs. Significant increases in male involvement in antenatal care (average treatment effect (ATE) = 0.728, 95% CI [0.445, 1.010]), birth planning (ATE = 0.407, 95% CI [0.157, 0.657]), and newborn care (ATE = 0.690, 95% CI [0.359, 1.021]) were found. The magnitude of Momentum's impact increased steadily with the number of prenatal home visits and was statistically significant for all behavioral outcomes except shared decision making. Exposure to both home visits and group education sessions during the prenatal period had a significant impact on all outcomes relative to no exposure. The study demonstrated the effectiveness of Momentum on male involvement in maternal health and newborn care.


Inhibitory effect of hesperetin on α-glucosidase: Molecular dynamics simulation integrating inhibition kinetics.
The α-glucosidase inhibitor is of interest to researchers due to its association with type-2 diabetes treatment. Hesperetin is a flavonoid with natural antioxidant properties. This paper presents an evaluation on the effects of hesperetin on α-glucosidase via inhibitory kinetics using a Molecular Dynamics (MD) simulation integration method. Due to the antioxidant properties of hesperetin, it reversibly inhibits α-glucosidase in a slope-parabolic mixed-type manner (IC50=0.38±0.05mM; Kslope=0.23±0.01mM), accompanied by tertiary structural changes. Based on computational MD and docking simulations, two hesperetin rings interact with several residues near the active site on the α-glucosidase, such as Lys155, Asn241, Glu304, Pro309, Phe311 and Arg312. This study provides insight into the inhibition of α-glucosidase by binding hesperetin onto active site residues and accompanying structural changes. Hesperetin presents as a potential agent for treating α-glucosidase-associated type-2 diabetes based on its α-glucosidase-inhibiting effect and its potential as a natural antioxidant.


High-plex immunofluorescence imaging and traditional histology of the same tissue section for discovering image-based biomarkers.
Precision medicine is critically dependent on better methods for diagnosing and staging disease and predicting drug response. Histopathology using hematoxylin and eosin (H&E)-stained tissue (not genomics) remains the primary diagnostic method in cancer. Recently developed highly multiplexed tissue imaging methods promise to enhance research studies and clinical practice with precise, spatially resolved single-cell data. Here, we describe the 'Orion' platform for collecting H&E and high-plex immunofluorescence images from the same cells in a whole-slide format suitable for diagnosis. Using a retrospective cohort of 74 colorectal cancer resections, we show that immunofluorescence and H&E images provide human experts and machine learning algorithms with complementary information that can be used to generate interpretable, multiplexed image-based models predictive of progression-free survival. Combining models of immune infiltration and tumor-intrinsic features achieves a 10- to 20-fold discrimination between rapid and slow (or no) progression, demonstrating the ability of multimodal tissue imaging to generate high-performance biomarkers.


Problems with enuresis management-A personal view.
Much has happened since the end of the era when enuresis was blamed on the parents or the children themselves. Still, there are large gaps in our knowledge and large parts of modern enuresis management guidelines are (still) not based on firm evidence. In this review I will question the following commonly made assumptions regarding enuresis evaluation and treatment: •It is important to subdivide enuresis according to the presence of daytime symptoms•Voiding charts are crucial in the primary evaluation of the enuretic child•All children with enuresis need to be screened for behavioral or psychiatric issues•Concomittant daytime incontinence needs to be successfully treated before addressing the enuresis•Concomittant constipation needs to be successfully treated before addressing the enuresis•Urotherapy is a first-line treatment against enuresis In this review I will argue that much of what we do with these children is based more on experience and well-meant but poorly supported assumptions than on evidence. Some advice and therapies are probably ineffective whereas for other treatments we lack reliable predictors of treatment response. More research is obviously needed, but awaiting new results enuresis management could be substantially simplified.


Xylooligosaccharides production from wheat middlings bioprocessed with Bacillus subtilis.
Prebiotic compounds are substrates selectively metabolized by beneficial gut microbiota causing a health-promoting effect. Despite some prebiotic carbohydrates have been largely studied, xylooligosaccharides (XOS) are important prebiotics derived from arabinoxylans, which are polysaccharides found in cereals. This study aimed to investigate the production of xylanolytic enzymes and XOS during bioprocessing of wheat middlings, a product derived from wheat flour production, using a probiotic Bacillus subtilis. The composition of XOS and the enzymatic and prebiotic activities of resulting B. subtilis cultures were evaluated. The activity of xylanolytic enzymes continuously enhanced during the 72 h bacterial growth, where β-xylosidase presented the highest value (70.31 U/mL). XOS profile and concentration varied considerably between control and bioprocessed samples and among these at different times. Maximum prebiotic activity score was found for the 24 h and 72 h bioprocessed samples (1.73 and 1.61, respectively) using the commercial probiotic Lactobacillus acidophilus LA-5. Wheat middlings showed to be a promising substrate for production of prebiotics like XOS and B. subtilis FTC01 appears to be a good source of xylanolytic enzymes.


Highly stereoselective synthesis, structure, and application of (E)-9-[2-(silyl)ethenyl]-9H-carbazoles.
(E)-N-(Silyl)vinylcarbazole has been easily prepared via a new catalytic route, silylative coupling (SC) of vinylcarbazole with vinyltrisubstituted silanes catalyzed by [RuH(Cl)(CO)(PCy3)2]. X-ray structures of two silylvinylcarbazoles as first N-vinylcarbazole derivatives have been resolved. The Pd-catalyzed Hiyama coupling reaction (also as the tandem reaction with SC) of synthesized (E)-N-(triethoxysilyl)vinylcarbazole with iodobenzene has been performed to afford (E)-N-(phenylvinyl)carbazole with high yield and stereoselectivity.


Anatomical characteristics of the cerebral surface in bulimia nervosa.
The aim of this study was to examine morphometric features of the cerebral surface in adolescent and adult female subjects with bulimia nervosa (BN). Anatomical magnetic resonance images were acquired from 34 adolescent and adult female subjects with BN and 34 healthy age-matched control subjects. We compared the groups in the morphological characteristics of their cerebral surfaces while controlling for age and illness duration. Significant reductions of local volumes on the brain surface were detected in frontal and temporoparietal areas in the BN compared with control participants. Reductions in inferior frontal regions correlated inversely with symptom severity, age, and Stroop interference scores in the BN group. These findings suggest that local volumes of inferior frontal regions are smaller in individuals with BN compared with healthy individuals. These reductions along the cerebral surface might contribute to functional deficits in self-regulation and to the persistence of these deficits over development in BN.


Surgical treatment of renovascular hypertension in the pediatric patient.
Of 27 children who underwent surgical treatment for renovascular hypertension 16 (59 per cent) were cured, 5 (19 per cent) were improved and 6 (22 per cent) were failures. Improved results were obtained in patients with unilateral renal artery stenosis. Several reconstructive vascular procedures were used, and their relative efficacy and indications are discussed. Renovascular hypertension in children is a curable disease and revascularization with preservation of renal parenchyma should be the aim of surgical therapy in most cases.


[Changes in intracellular regeneration and the indices of endocrine function and cardiac microcirculation in exposure to decimeter waves].
An electron-microscopic study of rabbit heart with experimental myocardial infarction revealed that extracardiac exposure to decimetric waves (DW) activated intracellular regeneration in the myocardium. This was associated with enhanced circulation and endocrine activity in the heart. Most pronounced regeneration was registered in adrenal exposure, the effect of the parietal exposure being somewhat less.


Wastage of gonadotropins during IVF cycles: Real life data from two Italian infertility centers.
Gonadotropins represent an important component of IVF costs. In order to reduce costs, much attention was given to the type of gonadotropins (recombinant versus urinary) and the daily dose. In this study, we decided to focus on gonadotropin wastage, a neglected aspect that may harbor a relevant source of useless economic expenditure. Women who performed oocytes collection following ovarian hyperstimulation with gonadotropins in two Italian IVF Centers were prospectively recruited. They were interviewed using a standardized questionnaire aimed at capturing drug wastage. Physicians of the participating units were blinded to the study. Recruited women were requested to hide their participation to their physicians. Three-hundred nine women were recruited. Two hundred eighty-eight (93 %; 95 %CI: 90-96 %) reported to have wasted some drug. For the whole cohort, the median [Interquartile range] IUs of drug used and drug wasted was 2,100 [1,575 - 2,850] and 825 [400 - 1,200], respectively. This corresponds to a median increase in the costs of ovarian hyperstimulation of 39 %. When data on wastage was analyzed separately for the different available drugs, a statistically significant difference emerged (p = 0.026). Reasons behind this difference could not be clearly disentangled. IVF is associated with a considerable wastage of gonadotropins. Improving this aspect can allow to reduce the costs of the procedure.


[The use of pesticides in disinfecting soil from ascaris eggs].
Low-toxicity pesticides--polycarbazin and prometrin--are suggested for use in decontamination of helminths' invaded soils. Soils in the invasion foci and microfoci should be treated with pesticides dosed at 50 g/5 l of water per 1 m2, in autumn, after the crop, and in early spring after the snow melt, with respect to the periods of maximal accumulation of helminths' ova in soil and preparations' degradation period (about 6 months).


Unanticipated coordination of tris buffer to the Radical SAM cluster of the RimO methylthiotransferase.
Radical SAM enzymes generally contain a [4Fe-4S](2+/1+) (RS cluster) cluster bound to the protein via the three cysteines of a canonical motif CxxxCxxC. The non-cysteinyl iron is used to coordinate SAM via its amino-carboxylate moiety. The coordination-induced proximity between the cluster acting as an electron donor and the adenosyl-sulfonium bond of SAM allows for the homolytic cleavage of the latter leading to the formation of the reactive 5'-deoxyadenosyl radical used for substrate activation. Most of the structures of Radical SAM enzymes have been obtained in the presence of SAM, and therefore, little is known about the situation when SAM is not present. In this report, we show that RimO, a methylthiotransferase belonging to the radical SAM superfamily, binds a Tris molecule in the absence of SAM leading to specific spectroscopic signatures both in Mössbauer and pulsed EPR spectroscopies. These data provide a cautionary note for researchers who work with coordinative unsaturated iron sulfur clusters.


Developing content for American Board of Pediatric Dentistry certification examinations using practice analysis.
The American Board of Pediatric Dentistry (ABPD) conducted a practice analysis to guide the development of its certification examination outlines for assessing the knowledge, skills, and abilities of pediatric dentists. This article describes the systematic approach used by the ABPD. The ABPD conducted its practice analysis in 4 phases: (1) preparation, (2) focus group meetings, (3) survey, and (4) examination blueprint development. Phase 2 resulted in 150 job tasks relevant to entry-level pediatric dental practice, organized into 10 domains. In Phase 3, 8,730 pediatric dentists received an electronic survey, with 10% returning a completed survey. Respondents rated tasks in terms of frequency and risk, which were analyzed to determine the combined relevance of each task. Phase 4 organized a final list of tasks within each domain and the recommended weighting of domains by certifying examination. The ABPD practice analysis created a comprehensive outline of the job tasks an entry-level pediatric dentist is expected to perform. The ABPD plans to use the results to help develop the examination content for continuing certification and will use a similar process every 5 through 7 years to update the examination content blueprints to ensure their continued relevance to the practice of pediatric dentistry. The ABPD used a process known as practice analysis to ensure that its examinations and continued competency assessments measure the knowledge, skills, and abilities required for safe and effective clinical practice.


Methylcobalamin.
Methylcobalamin is one of the two coenzyme forms of vitamin B12. Evidence indicates this form of vitamin B12, in addition to having a theoretical advantage over cyanocobalamin, actually has some metabolic and therapeutic applications not shared by the other forms of vitamin B12. This monograph provides an overview of the pharmacokinetics of methylcobalamin, and will highlight the potential therapeutic relevance for Bell's palsy, cancer, diabetic neuropathy, eye function, heart rate variability, HIV, homocysteinemia, male impotence, and sleep disorders.


Increased desmin expression in hindlimb muscles of aging rats.
BACKGROUND: Aging skeletal muscle frequently exhibits a reduction in force produced per unit muscle tissue, variously termed muscle quality, specific tension or dynapenia. Muscles from animals in which desmin expression is reduced exhibit similar properties, raising the possibility that reduced desmin expression contributes to impaired force production in aging muscles. METHODS: We examined expression of desmin and synemin, both intermediate filament proteins, in the plantarflexor muscles of adult (6-8 months) and older (24 months) rats. We have previously reported age-related reductions in muscle quality and sarcoplasmic reticulum function in these animals. RESULTS: Significant effects of age and muscle were found for the expression of desmin (P = 0.040 and <0.001 respectively), but not synemin. Desmin expression was increased in the aging muscles, with the greatest changes observed in the gastrocnemius muscles. Muscle quality, but not muscle mass, was reduced in the aging plantarflexor muscles. CONCLUSIONS: Loss of desmin does not account for reduced force production in aging muscles. The potential effects of the age-related increase in desmin on muscle function remain unclear, but may include dissipation of contractile force.


Increased sLRP1 and decreased atrial natriuretic peptide plasma levels in newly diagnosed T2DM patients are normalized after optimization of glycemic control.
Low-density lipoprotein receptor-related protein 1 (LRP1) negatively modulates circulating atrial natriuretic peptide (ANP) levels. Both molecules are involved in the regulation of cardiometabolism. To evaluate soluble LRP1 (sLRP1) and ANP levels in people with newly diagnosed type 2 diabetes mellitus (T2DM) and determine the effects of metabolic optimization. This single-center longitudinal observational study recruited patients with newly diagnosed T2DM (n = 29, HbA1c > 8.5%), and 12 healthy control, age- and sex-matched volunteers. sLRP1 and ANP levels were measured by immunoassays at T2DM onset and at one year after optimization of glycemic control (HbA1c ≤ 6.5%). T2DM had higher sLRP1 levels than the control group (p = 0.014) and lower ANP levels (p =0.002). At 12 months, 23 T2DM patients reached the target of HbA1c ≤ 6.5%. These patients significantly reduced sLRP1 and increased ANP levels. Patients who did not achieve HbA1c < 6.5% failed to normalize sLRP1 and ANP levels. There was an inverse correlation in the changes in sLRP1 and ANP (p = 0.031). The extent of sLRP1 changes over 12 months of metabolic control positively correlated with those of total cholesterol, LDL cholesterol, TG, TG/HDLc, and apolipoprotein B. Newly diagnosed T2DM patients have an increased sLRP1/ANP ratio, and increased sLRP1 and decreased ANP levels are normalized in the T2DM patients that reached an strict glycemic and metabolic control. sLRP1/ANP ratio could be a reliable marker of cardiometabolic function.


Endometriosis Patients Show an Increased M2 Response in the Peritoneal CD14+low/CD68+low Macrophage Subpopulation Coupled with an Increase in the T-helper 2 and T-regulatory Cells.
Endometriosis is a chronic inflammatory disease associated with an impaired immune response at the site of lesion implantation. The ability of macrophages to respond to changes in their environment is critical for an effective immune response. However, the existing knowledge of the peritoneal immune cell populations, their activation state and contribution to the immunological changes that occur in endometriosis are still controversial and inconclusive. In this study, we have examined the relative abundance of peritoneal macrophage subtypes, in women with (n = 21) versus without (n = 18) endometriosis and disease-associated changes in the adaptive T cell response. Using flow cytometry, we showed that peritoneal fluid monocyte/macrophages are composed of two populations of cells that exhibit major differences in the levels of the CD14 and CD68 markers, which we classified as the CD14+low/CD68+low and CD14+high/CD68+high subpopulations. Moreover, endometriosis-associated changes in the macrophage subtypes occurred only in the CD14+low/CD68+low subpopulation. In this subpopulation, we found an increased macrophage type 2 response that was coupled with an increase in peritoneal T-helper 2 and T-regulatory cell populations in women with endometriosis, compared with controls. In summary, this study resolves conflicting data in the literature regarding changes in the peritoneal immune cell population in endometriosis and identifies CD14+low/CD68+low macrophages as the subpopulation that changes in response to the disease.


Tumor suppressor ZHX2 inhibits NAFLD-HCC progression via blocking LPL-mediated lipid uptake.
Non-alcoholic fatty liver disease (NAFLD) leads to hepatocellular carcinoma (HCC). However, the underlying mechanism remains largely unclear. Here, we investigated the role of the tumor suppressor Zinc fingers and homeoboxes 2 (ZHX2) in the progression of NAFLD to HCC. ZHX2 expression was significantly decreased in fatty liver tissues, especially in the liver with NAFLD-HCC. ZHX2 overexpression disturbed lipid homeostasis of cultured HCC cells, and inhibited lipid deposition in hepatocytes both in vitro and in vivo. Moreover, ZHX2 inhibited uptake of exogenous lipids through transcriptional suppression of lipid lipase (LPL), leading to retarded proliferation of HCC cells. Importantly, LPL overexpression significantly reversed ZHX2-mediated inhibition of HCC cell proliferation, xenograft tumor growth, lipid deposition, and spontaneous liver tumor formation. Consistently, IHC staining demonstrated a negative correlation of ZHX2 with LPL in an HCC cohort. Collectively, ZHX2 protects hepatocytes from abnormal lipid deposition in NAFLD through transcriptional repression of LPL, which subsequently retards cell growth and NAFLD-HCC progression. These findings illustrate a novel mechanism of NAFLD progression into HCC.


Response rates of standard interferon therapy in chronic HCV patients of Khyber Pakhtunkhwa (KPK).
Interferon based therapy is used to eradicate the Hepatitis C Virus from the bodies of the infected individuals. HCV is highly prevalent in Khyber Pakhtunkhwa (KPK) that is why it is important to determine the response of standard interferon based therapy in Chronic HCV patients of the region. A total of 174 patients were selected for interferon based therapy. The patients were selected from four different regions of KPK. After confirmation of active HCV infection by Real Time PCR, standard interferon with ribavirn was given to patients for 6 months. After completion of therapy, end of treatment virologic response (ETR) was calculated. Out of total 174 patients, 130 (74.71%) showed ETR and 44 (25.28%) did not show ETR. In district Bunir, out of 52 patients, 36 (69.23%) showed ETR and 16 (30.79%) did not show ETR. In district Mardan, out of the total 74 patients, 66 (89.18%) were negative for HCV RNA and 8 (10.81%) were resistant to therapy. In Peshawar, out of 22, 16 (60%) were negative and 6 (40%) were positive for HCV RNA at the end of 6 months therapy. In the Federally Administered Tribal Area (FATA), out of 18 only 10 (55.5%) were negative and 8 (44.45%) were positive for active HCV infection. It is concluded that the response of antiviral therapy against HCV infection in chronic HCV patients of KPK province is 74.71%. The high response rate may be due to the prevalence of IFN-responsive HCV genotypes (2 and 3) in KPK.


Assessing the Fidelity of Evidence-Based Practices: History and Current Status of a Standardized Measurement Methodology.
Evidence-based practices are effective only when implemented faithfully. This paper explicates the history, standardization, and methods for developing and validating measures of fidelity. We overviewed the past 20 years of developing fidelity measures, summarized standardization of the development procedures, and described needed psychometric assessments. Fidelity assessment has become the sine qua non of implementation, technical assistance, and research on evidence-based practices. Researchers have established standardized procedures for scale development and psychometric testing. Widescale use of fidelity measurement remains challenging. The implementation of evidence-based practice and the development and validation of fidelity measures are interdependent. International improvements of mental health care will require attention to both.


Efficacy and safety of rivaroxaban in cerebral venous thrombosis: insights from a prospective cohort study.
Rivaroxaban, as a novel oral anticoagulant agent, emerged in thrombosis management. This study aimed to compare the efficacy and safety of once-daily rivaroxaban versus dose-adjusted warfarin for cerebral venous thrombosis treatment in a real-world clinical setting. This is a prospective cohort study based on the real-world clinical data analysis of the patients with imaging-confirmed CVT enrolled from August 2016 through January 2020 and their outcomes were followed up. Patients were grouped according to their treatment strategies: rivaroxaban (15-20 mg daily) or warfarin (dosage-adjusted according to international normalized ratio), which were matched 1:2 on the propensity score. The primary efficacy outcome was recanalization assessed by magnetic resonance venography. Thrombus burden, CVT recurrence and modified Rankin Scale (mRS) were also compared. The safety outcome was major bleeding. Baseline characteristics were well balanced between the 33 patients in rivaroxaban group and 49 in warfarin group after propensity score matching. During 6-month (median) follow-up, 29 patients (87.9%) in rivaroxaban group and 38 patients (77.6%) in warfarin group obtained recanalization (OR, 1.44; 95% CI 0.63-3.30). The thrombus reduction at the 6-month follow-up did not reach statistical difference (p = 0.118). No CVT recurrence was observed in both groups. All patients in rivaroxaban group obtained favorable functional outcomes (mRS = 0-2), whereas in warfarin group, 1 patient remained physically disable (mRS = 3) at the follow-up. No major bleeding events occurred in two groups. Rivaroxaban might have the same or stronger efficacy in facilitating CVT recanalization and preventing CVT recurrence with a lower incidence of bleeding than that of warfarin in Chinese population.


Enantiomorphic Single Crystals of Linear Lead(II) Bromide Perovskitoids with White Circularly Polarized Emission.
Chiroptical hybrid organic-inorganic perovskites are emerging as a new class of promising materials with mirror optical signal responses for optoelectronic applications. However, chiroptical white-emission materials have been scarcely unearthed. Herein, four pairs of hybrid lead(II) bromide perovskitoids were obtained, namely, (R)- and (S)-(H2 MPz)PbBr4 (R/S-MPz=(R)-(-)/(S)-(+)-2-methylpiperazine) (1 and 2), (R)- and (S)-(H2 MPz)3 Pb2 Br10 ⋅2 DMAc (3 and 4), (R)- and (S)-(H2 MPz)PbBr4 ⋅0.5 MeCN (5 and 6) and (R)- and (S)-(H2 MPz)2 Pb2 Br8 ⋅DCM (7 and 8). Notably, they all exhibit ultrabroadband emission and chiroptical signals. Perovskitoids 3-6 even achieve white circularly polarized emission with a high dissymmetric factor (glum ) (±3×10-3 for 3 and 4; ±8×10-3 for 5 and 6). This new type of hybrid perovskitoids will attract attention and find applications in chiroptical fields because of the extensively and easily tunable photophysical properties.