High-frequency ultrasound features in vulvar lichen sclerosus and correlation with histopathology.
Vulvar lichen sclerosus (VLS) is a chronic inflammatory disease initially involving anogenital areas. Noninvasive assessment is essential for precise management in VLS. We aim to analyze high-frequency ultrasound (HFUS) features and correlate HFUS with histopathological changes. Forty patients with histopathologically confirmed VLS lesions were retrospectively identified from August 2020 to September 2021. The clinical manifestations, dermoscopic images as well as both 20 and 50 MHz HFUS images were assessed. HFUS assessment included epidermal morphology, hypoechoic dermal band thickness, and hypoechoic dermal band internal echo. We compared HFUS images with histopathology, and Pearson's correlation coefficient was used to assess the relationship between hypoechoic dermal band thickness and histopathological depth. Hypoechoic dermal band was present in 100% (40/40) VLS lesions. There was a significant linear positive correlation between the histopathological depth and corresponding hypoechoic dermal band thickness, with a Pearson correlation coefficient of 0.685 (p < 0.001). Besides, 95% (38/40) lesions revealed smooth epidermis, and the internal echo of hypoechoic dermal band was assessed as homogeneous in 60% (24/40) and inhomogeneous in 40% (16/40) lesions. HFUS characteristics, as well as measurable hypoechoic dermal band thickness, may provide valuable information in the precise diagnosis and the treatment monitoring of VLS.


Desensitization of 5-HT1A autoreceptors by chronic administration of 8-OH-DPAT.
The function of 5-HT1A autoreceptors was examined by measuring the ability of the 5-HT1A receptor agonist 8-OH-DPAT to reduce 5-HT release in the striatum using in vivo microdialysis. 8-OH-DPAT reduced the release of 5-HT in the striatum. Chronic treatment with 8-OH-DPAT (1.0 mg/kg s.c.) for 7 days, but not 1 day, attenuated the effect of an acute challenge dose of 8-OH-DPAT. The results of the present study indicate that in vivo microdialysis can be used to study the effects of activation of 5-HT1A autoreceptors on 5-HT release and the regulation of 5-HT release by chronic administration of psychoactive drugs.


Selective inhibitors of terminal deoxyribonucleotidyltransferase (TdT): baicalin and genistin.
Studies of mammalian terminal deoxyribonucleotidyltransferase (TdT) are facilitated by use of inhibitors that selectively knock down the activity of the enzyme. We have screened for selective inhibitors of TdT and identified a natural compound with this property in the Japanese vegetable, Arctium lappa. The compound has little effect on the activities of mammalian DNA polymerases, such as alpha, beta, delta or lambda polymerase, and prokaryotic DNA polymerases, such as Taq DNA polymerase, T4 DNA polymerase and Klenow fragment. H1- and C13-NMR spectroscopic analyses showed the compound to be baicalin, a compound previously reported as an anti-inflammatory or antipyretic agent. The IC50 value of baicalin to TdT was 18.6 microM. We also found that genistin, a baicalin derivative known to be antimutagenic, more selectively inhibited TdT activity than baicalin, although its IC50 value was weaker (28.7 microM). Genistin and baicalin also inhibited the activity of truncated TdT (the so-called pol beta core domain) in which the BRCT motif was deleted in its N-terminal region. In kinetic analyses, inhibition by either genistin or baicalin was competitive with the primer and non-competitive with the dNTP substrate. The compounds may, therefore, bind directly to the primer-binding site of TdT and simultaneously disturb dNTP substrate incorporation into the primer. Genistin and baicalin should prove to be useful agents for studying TdT.


Differential effects of olfactory toxicants on olfactory regeneration.
The aim was to study the long-term response in the olfactory mucosa of NMRI mice after exposure to the olfactory toxicants dichlobenil (a herbicide) or methimazole (an antithyroid drug). Three and six months after exposure to dichlobenil (2x or 1 x 25 mg/kg i.p.), the dorsomedial part of the olfactory region showed a respiratory metaplasia with abundant invaginations and a fibrotic lamina propria. In contrast, 3 months after exposure to a toxic dose of methimazole (2 x 50 mg/kg i.p.), the olfactory neuroepithelium and lamina propria had been restored. To study the regenerative events, we used an antibody derived against growth-associated protein 43 (GAP-43), which stains immature neurons. To study epithelial differentiation and horizontal basal cells (HBCs) we used an antibody derived against some cytokeratins. Two weeks after methimazole treatment, there was a marked increase of GAP-43-stained cells in the whole olfactory region, which correlated with the observed regeneration at that time. Two weeks after dichlobenil treatment, the damaged atypical epithelium in the olfactory region showed a distinct keratin staining of basal and columnar cells whereas GAP-43-stained cells were not found. Despite a transient increase of GAP-43-stained cells in the border zone between damaged and undamaged olfactory mucosa, an expansion of a normal neuroepithelium into the damaged olfactory region was not detected in the dichlobenil-treated mice. An intact lamina propria is suggested as a prerequisite for repopulation of the neuroepithelium after toxicant-induced injury.


Enzymatic degradation of the hydrogels based on synthetic poly(α-amino acid)s.
Biodegradable hydrogels are studied as potential scaffolds for soft tissue regeneration. In this work biodegradable hydrogels were prepared from synthetic poly(α-amino acid)s, poly(AA)s. The covalently crosslinked gels were formed by radical copolymerization of methacryloylated poly(AA)s, e.g. poly[N (5)-(2-hydroxy-ethyl)-L-glutamine-ran-L-alanine-ran-N (6)-methacryloyl-L-lysine], as a multifunctional macro-monomer with a low-molecular-weight methacrylic monofunctional monomer, e.g. 2-hydroxyethyl methacrylate (HEMA). Methacryloylated copolypeptides were synthesized by polymerization of N-carboxyanhydrides of respective amino acids and subsequent side-chain modification. Due to their polypeptide backbone, synthetic poly(AA)s are cleavable in biological environment by enzyme-catalyzed hydrolysis. The feasibility of enzymatic degradation of poly(AA)s alone and the hydrogels made from them was studied using elastase, a matrix proteinase involved in tissue healing processes, as a model enzyme. Specificity of elastase for cleavage of polypeptide chains behind the L-alanine residues was reflected in faster degradation of L-alanine-containing copolymers as well as of hydrogels composed of them.


Perfusion-Based Fluorescent Dye Labeling to Sort Cancer Cells Based on Their Distance from Blood Vessels.
Tumor vasculature is the major extrinsic factor that shapes Intra-tumoral heterogeneity (ITH). Non-uniform exposure of microenvironmental cues greatly impacts cancer cell phenotypes leading to ITH, which exacerbates therapy resistance. This raises a need to study the influence of non-uniform perfusion patterns and the resulting heterogeneity that persists within the tumor microenvironment (TME). A method was developed to identify cancer cells based on their proximity to functional blood vessels (BVs) called perfusion-based fluorescent dye labeling of cells (PFDLC). PFDLC works on the principle of perfusion, where a freely diffusible nuclear binding fluorescent dye (Hoechst 33342) is injected intravenously (i.v.) through a tail vein into atumor-bearing mice. The tumors are retrieved post dye perfusion, dissociated into single cells, and sorted based on their dye uptake proportional to their distance from the nearest blood capillary. This method is amenable to multi-omics as well as functional assays.


The feasibility of using Hcy, CRP, and Cys-C to analyze AMI patients' disease conditions and prognoses.
This study was conducted to investigate the feasibility of using the serum homocysteine (Hcy), C-reactive protein (CRP), and cystatin C (Cys-C) levels to evaluate the conditions and prognoses of acute myocardial infarction (AMI) patients. One hundred and twenty patients with AMI were enrolled as an observation group (the AMI group). Eighty patients with stable angina pectoris were included in a control group (the SA group). Eighty healthy volunteers were enrolled as a healthy control group (the NCHD group). The AMI patients were divided into groups of >20 (n = 32), 10-20 (n = 45) and <10 (n = 43) according to their APACHE-II scores. The groups were divided into a death group (n = 23) and a survival group (n = 97) according to the patients' 1-year follow-up outcomes. The differences in the serum Hcy, CRP, and Cys-C levels among the different groups, and the correlations between the serum levels were calculated. The serum Hcy, CRP, and Cys-C levels in the AMI group were significantly higher than they were in the SA and NCHD groups (P<0.05), and the serum levels in the APACHE-II score >20 group were significantly higher than the serum levels in the 10-20 group. The dead group exhibited higher serum Hcy, CRP, and Cys-C levels than the survival group (P<0.05), and our Spearman's correlation analysis showed that the serum Hcy, CRP and Cys-C levels were positively correlated with the APACHE II scores (r = 0.9157, r = 0.8519, r = 0.8598, P<0.001). The area under curve of Hcy, CRP, and Cys-C for the AMI diagnoses were 0.9638 (95% CI: 0.9183-1.000), 0.8125 (95% CI: 0.6652-0.9598), and 0.7515 (95% CI: 0.5847-0.9184), respectively. Serum Hcy, CRP, and Cys-C levels can reflect the severity of the patients' conditions.


VHUT-cryo-FIB, a method to fabricate frozen hydrated lamellae from tissue specimens for in situ cryo-electron tomography.
Cryo-electron tomography (cryo-ET) provides a promising approach to study intact structures of macromolecules in situ, but the efficient preparation of high-quality cryosections represents a bottleneck. Although cryo-focused ion beam (cryo-FIB) milling has emerged for large and flat cryo-lamella preparation, its application to tissue specimens remains challenging. Here, we report an integrated workflow, VHUT-cryo-FIB, for efficiently preparing frozen hydrated tissue lamella that can be readily used in subsequent cryo-ET studies. The workflow includes vibratome slicing, high-pressure freezing, ultramicrotome cryo-trimming and cryo-FIB milling. Two strategies were developed for loading cryo-lamella via a side-entry cryo-holder or an FEI AutoGrid. The workflow was validated by using various tissue specimens, including rat skeletal muscle, rat liver and spinach leaf specimens, and in situ structures of ribosomes were obtained at nanometer resolution from the spinach and liver samples.


Fat embolism: physiopathology, diagnosis with management.
This paper describes the components of the post-traumatic syndrome. The pathological state of fat macroglobulinemia by occlusion of arteriolar terminal branches of vital organs causes the fat embolic syndrome. The main physiopathological problem is pulmonary insufficiency in an acute or subacute form. The cerebral embolus is second. The symptomatology varies and is not characteristic. According to their importance they were described as minor or major in the diagnosis of fat emboli. Only recently, treatment for the fat emboli syndrome has been initiated, consisting mainly in supportive measures, respiratory care and anti-inflammatory drugs, mainly cortisone.


The dilemma of localizing language: John Abercrombie's unexploited evidence.
John Abercrombie (1780-1844) was considered the most eminent Scottish physician of his time. In his Pathological and Practical Researches on the Diseases of the Brain and Spinal Cord (1836, Edinburgh: John Carfrae and Son, 3rd ed.) he described the cases of 140 patients with cerebral disorders, 48 of whom suffered from language disturbances. Despite the overwhelming clinical and neuropathological evidence of a close association between language disorder and right-sided hemiparesis or diseases of the left hemisphere, and in spite of his great interest in language disorders, he made no attempt to localize the aphasic syndrome to a specific brain area.


Causal discovery for the microbiome.
Measurement and manipulation of the microbiome is generally considered to have great potential for understanding the causes of complex diseases in humans, developing new therapies, and finding preventive measures. Many studies have found significant associations between the microbiome and various diseases; however, Koch's classical postulates remind us about the importance of causative reasoning when considering the relationship between microbes and a disease manifestation. Although causal discovery in observational microbiome data faces many challenges, methodological advances in causal structure learning have improved the potential of data-driven prediction of causal effects in large-scale biological systems. In this Personal View, we show the capability of existing methods for inferring causal effects from metagenomic data, and we highlight ways in which the introduction of causal structures that are more flexible than existing structures offers new opportunities for causal reasoning. Our observations suggest that microbiome research can further benefit from tools developed in the past 5 years in causal discovery and learn from their applications elsewhere.


Use of Patterned Collagen Coated Slides to Study Normal and Scleroderma Lung Fibroblast Migration.
Systemic sclerosis (SSc) is a spreading fibrotic disease affecting the skin and internal organs. We aimed to model pathogenic fibroblast migration in SSc in order to identify enhancing factors, measure the effect of migrating cells on underlying extracellular matrix (ECM) and test possible therapeutic inhibitors. Novel patterned collagen substrates were used to investigate alignment and migration of skin and lung fibroblasts from SSc patients and healthy controls. Normal lung but not skin fibroblasts consistently elongated and aligned with underlying collagen and migrated dependent on PDGF or serum. SSc lung fibroblasts remained growth factor dependent, did not migrate more rapidly and were less restricted to alignment of the collagen. Multiple collagen proline and lysine-modifying enzymes were identified in SSc but not control fibroblast extracellular matrix preparations, indicating differential levels of ECM modification by the diseased cells. Profiling of migrating cells revealed a possible SCF/c-Kit paracrine mechanism contributing to migration via a subpopulation of cells. Heparin, which binds ligands including PDGF and SCF, and imatininib which blocks downstream tyrosine kinase receptors, both inhibited lung fibroblast migration individually but showed synergy in SSc cells. Pathologic lung fibroblasts from SSc patients modify ECM during migration but remain growth factor dependent and sensitive to inhibitors.


Gap junctions are non-randomly distributed inDrosophila wing discs.
The distribution of gap junctions in mature larvalDrosophila melanogaster wing discs was analyzed by means of quantitative electron microscopy. Gap junctions are non-randomly distributed in the proximal-distal disc axis and in the apical-basal cell axis of the epithelium. In the epithelial cells, the surface density, number and length of gap junctions are greatest in the apical cell region and distal disc region. The average gap junction surface density is 0.0572 μm-1 and 2.77% of the lateral cell surface is composed of gap junctions. In the adepithelial cells, the gap junction surface density is 0.0005 μm-1 and 0.06% of the cell surface is composed of gap junctions. No gap junctions were observed between epithelial cells and adepithelial cells. The absolute area of gap junctions was estimated in a proximal-distal strip of cells in the disc and is considerably less in the folded regions of the epithelium compared to the flat notum and wing pouch regions. The results are discussed with respect to pattern formation and growth control in imaginal discs.


Effects of top-down and bottom-up attention on post-selection posterior contralateral negativity.
We examined the effect of combined top-down and bottom-up attentional control sources in easy and difficult visual search tasks. Applying a new analysis on previously acquired data, we focused on the sustained posterior contralateral negativity (SPCN) and the response-locked posterior contralateral negativity (RLpcN), to better understand processes following target selection. We used the signed-area approach to measure the negative area, where the signal was either locked to the target or the response onsets. We further split the RLpcN into an early and a late segment to capture the dynamics of selection and post-selection processes. In Experiment 1, participants reported the orientation of a uniquely tilted target. In Experiment 2, participants reported the position of a small gap within the uniquely tilted target. In both experiments, endogenous cues manipulated top-down attention (valid vs. neutral), and salient color singletons (either the target or a distractor) manipulated bottom-up attention. We hypothesized that the SPCN and the later segment of the RLpcN would be modulated by task difficulty and target salience, as they are associated with post-selection processes, such as response selection and working memory. The early segment of the RLpcN was hypothesized to be modulated by the cueing manipulation and presence of a salient distractor, as they affect target selection. An effect of distractor presence was observed on the early segment of the RLpcN, and our results further supported the hypotheses regarding the SPCN and the later segment of the RLpcN, providing novel insights into post-selection processes in visual search.


Effect of orotic acid on the mitosis of phytohaemagglutinin stimulated human lymphocytes in culture.
The addition of excess orotic acid to cultures of normal human lymphocytes stimulated with phytohaemagglutinin causes a reduction in the mitotic rate. It is suggested that this is caused by competition for the available 5-phosphoribosyl-1-pyrophosphate in the cell leading to a reduced purine synthesis. The significance of these results with regard to orotic aciduria is discussed.


Efficacy of aqua-based plyometric exercises in the rehabilitation of patients with juvenile dermatomyositis: A randomized crossover pilot study.
Patients with juvenile dermatomyositis (JDM) experience muscle weakness, tiredness, and loss of energy, which restrict their abilities in performance of their daily living activities. To explore the effect of aquatic-based plyometric (Aqua-PLYO) exercises on muscle strength, fatigue, and functional ability in patients with JDM. This was a randomized, single-blind, crossover pilot study that included 16 patients with JDM (age 13.44 ± 2.85 years). They were assigned randomly to receive either the Aqua-PLYO exercises (n = 8) or the standard outpatient care (SoC ; n = 8) first. After a 1-month washout, the treatment was reversed. Lower limb muscle strength, fatigue perception, functional ability, and disease activity were evaluated before and after each treatment period. Irrespective of the treatment order, the Aqua-PLYO treatment yielded greater improvement in muscle strength (hip flexors and abductors [P < 0.001] or knee flexors [P < 0.001] and extensors [P = 0.0008]), fatigue perception (P < 0.001), functional ability (P = 0.009), and disease activity (P = 0.0001) than the SoC treatment. By using the shortest confidence intervals (100[1-2α]%) of the difference, the average bioequivalence of the Aqua-PLYO and SoC has not been established at P = 0.05, because the upper and lower confidence bounds of all outcomes were not between the acceptance limits. No period or carryover effects were detected in all outcomes. The Aqua-PLYO exercise protocol as implemented in this study is safe, feasible, and well-tolerated in patients with JDM and seemingly useful to help increase muscle strength, reduce fatigue, and enhance functional ability in such a patient population.


[Body mass index and quantitative osseous ultrasonography of the phalanges in Lebanese post-menarcheal adolescent girls].
To explore the relation between body mass index and phalanx ultrasound measurements in a group of Lebanese post-menarchal girls. Amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT) were measured in 168 post-menarchal girls aged 12-17 years using a DBM sonic bone profiler device. Anthropometrical characteristics (weight and height) were measured. Age and maturation index (years since menarche) were positively related to AD-SoS and BTT (p < 0.01). AD-SoS values were negatively related to BMI and body weight (r = -0,27; p < 0.001 and r = - 0,25; p < 0.001 respectively). There was no relation between BTT values and neither BMI nor body weight. Overweight girls (n = 36) had lower AD-SoS values than normal-weight girls (n = 122) (1994 +/- 87 m x sec(-1) vs 2041 +/- 82 m x sec(-1) respectively; p < 0.01). Obese girls (n = 10) had lower AD-SoS values than normal-weight girls (n = 122) (1976 +/- 96 m x sec(-1) vs 2041 +/- 82 m x sec(-1) respectively; p < 0.05). In this group of Lebanese post-menarchal girls, AD-SoS values are inversely correlated to BMI while BTT values were not related to BMI.


Family nursing with the assistance of network improves clinical outcome and life quality in patients underwent coronary artery bypass grafting: A consolidated standards of reporting trials-compliant randomized controlled trial.
Family nursing with the assistance of network (FNAN) improves nurses' practice and provides family/community-oriented nursing care. This study aimed to explore the effects of FNAN on the clinical outcome and life quality of coronary atherosclerotic heart disease (CHD) patients underwent coronary artery bypass grafting (CABG). This study is a randomized, placebo-controlled and double-blind trial. One-hundred and twelve patients underwent CABG were randomly divided into control group (CG, routine family nursing care) and experimental group (EG, FNAN) and the allocation ratio was 1:1. The situation of anxiety and depression were analyzed using the Hamilton Anxiety Scale (HAMA) scale and Hamilton Depression Scale (HAMD). Sleep quality was measured by using Pittsburgh Sleep Quality Index (PSQI). Lung function parameters were measured, including minute ventilation (MVV), partial pressure of oxygen (PaO2), partial pressure of arterial carbon dioxide (PaCO2), oxygen saturation measurement by pulse oximetry (SpO2), forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). Life quality was measured by using Chronic Obstructive Pulmonary Disease Assessment Test (CAT). After a 3-month intervention, 10 and 6 patients were lost in the CG and EG groups, respectively. The scores of HAMA, HAMD, PSQI and CAT were reduced in the EG group when compared with the CG group (P < .05). The values of MVV, PaO2, SpO2, FEV1 and FVC in the EG group was higher than those in the CG group whereas the levels of PaCO2 in the EG group was lower than those in the CG group (P < .05). PSQI score had a strong relationship with the values of MVV, PaO2, PaCO2, SpO2, FEV1, and FVC. FNAN improves the clinical outcome and life quality in the patients underwent CABG.


Impact of body mass index in patients receiving atezolizumab plus bevacizumab for hepatocellular carcinoma.
Atezolizumab plus bevacizumab (Atezo/Bev) is first line-treatment for unresectable hepatocellular carcinoma (HCC). Body mass index (BMI) has demonstrated predictive value for response to immunotherapy in non-HCC cancer types. Our study investigated the effect of BMI on safety and efficacy of real-life use of Atezo/Bev for unresectable HCC. 191 consecutive patients from seven centres receiving Atezo/Bev were included in the retrospective study. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in overweight (BMI ≥ 25) and non-overweight (BMI < 25) patients. Treatment-related adverse events (trAEs) were evaluated. Patients in the overweight cohort (n = 94) had higher rates of non-alcoholic fatty liver disease (NAFLD) and lower rates of Hepatitis B compared to non-overweight cohort (n = 97). Baseline Child-Pugh class and Barcelona Clinic Liver Cancer stage were similar between cohorts, with lower rates of extrahepatic spread in the overweight group. Overweight patients had similar OS compared to non-overweight (median OS 15.1 vs. 14.9 months; p = 0.99). BMI did not influence median PFS (7.1 vs. 6.1 months; p = 0.42), ORR (27.2% vs. 22.0%; p = 0.44) and DCR (74.1% vs. 71.9%; p = 0.46). There were higher rates of atezolizumab-related fatigue (22.3% vs. 10.3%; p = 0.02) and bevacizumab-related thrombosis (8.5% vs. 2.1%; p = 0.045) in the overweight patients, but overall trAEs and treatment discontinuation were comparable between cohorts. Atezo/Bev has comparable efficacy in overweight HCC patients, with an increase in treatment-related fatigue and thrombosis. Combination therapy is safe and efficacious to use in overweight patients, including those with underlying NAFLD.


E.L., a modern-day Phineas Gage: Revisiting frontal lobe injury.
How the prefrontal cortex (PFC) recovers its functionality following lesions remains a conundrum. Recent work has uncovered the importance of transient low-frequency oscillatory activity (LFO; < 4 Hz) for the recovery of an injured brain. We aimed to determine whether persistent cortical oscillatory dynamics contribute to brain capability to support 'normal life' following injury. In this 9-year prospective longitudinal study (08/2012-2021), we collected data from the patient E.L., a modern-day Phineas Gage, who suffered from lesions, impacting 11% of his total brain mass, to his right PFC and supplementary motor area after his skull was transfixed by an iron rod. A systematic evaluation of clinical, electrophysiologic, brain imaging, neuropsychological and behavioural testing were used to clarify the clinical significance of relationship between LFO discharge and executive dysfunctions and compare E.L.´s disorders to that attributed to Gage (1848), a landmark in the history of neurology and neuroscience. Selective recruitment of the non-injured left hemisphere during execution of unimanual right-hand movements resulted in the emergence of robust LFO, an EEG-detected marker for disconnection of brain areas, in the damaged right hemisphere. In contrast, recruitment of the damaged right hemisphere during contralateral hand movement, resulted in the co-activation of the left hemisphere and decreased right hemisphere LFO to levels of controls enabling performance, suggesting a target for neuromodulation. Similarly, transcranial magnetic stimulation (TMS), used to create a temporary virtual-lesion over E.L.'s healthy hemisphere, disrupted the modulation of contralateral LFO, disturbing behaviour and impairing executive function tasks. In contrast to Gage, reasoning, planning, working memory, social, sexual and family behaviours eluded clinical inspection by decreasing LFO in the delta frequency range during motor and executive functioning. Our study suggests that modulation of LFO dynamics is an important mechanism by which PFC accommodates neurological injuries, supporting the reports of Gage´s recovery, and represents an attractive target for therapeutic interventions. Fundação de Amparo Pesquisa Rio de Janeiro (FAPERJ), Universidade Federal do Rio de Janeiro (intramural), and Fiocruz/Ministery of Health (INOVA Fiocruz).


Does surgical approach affect early outcomes following primary total hip replacement in obese patients?
The aim of this study was to assess whether obese patients undergoing primary total hip replacement (THR) via a posterior approach had superior revision rates and Oxford Hip Scores (OHS) compared to those via a lateral approach. This is a retrospective cohort study using prospective data from the New Zealand Joint Registry applying STROBE and RECORD guidelines. Patients undergoing THR since 2010 were stratified by body mass index (BMI) into obese (BMI 30-39 kg/m2), and morbidly obese (BMI ⩾40 kg/m2) groups. All-cause revision rates, and 6-month OHS post-surgery were compared between groups. Multivariate analysis was performed. 12,109 unilateral THRs in obese patients were identified. The mean follow-up was 2.8 years (range 0.01-6.95 years). Univariate analysis in the BMI ⩾ 40 group showed the posterior approach had a significantly lower all-cause revision rate (0.99/100 observed component years (ocys); 95% CI, 0.65-1.44/100 ocys) than the lateral approach (1.71/100 ocys (95% CI, 0.98-2.77/100 ocys), p < 0.05). There was no significant difference in dislocation rates between the surgical approaches. OHS was statistically higher in the posterior approach group in BMI 30-39 patients (p < 0.001) but not clinically significant. Multivariate analysis showed femoral head size significantly influenced all-cause revision rates and mitigated against the increased risk associated with the surgical approach. The choice of surgical approach in obese patients conveys no advantage in overall revision rates in the short-term. Choosing an appropriate size of femoral head may be of greater importance than choice of surgical approach for obese patients in primary THR.


Mitochondrial targeted hierarchical drug delivery system based on HA-modified liposomes for cancer therapy.
Chemotherapy targeting mitochondrial is a faster and more sensitive anti-tumor therapy strategy. In this study, a hierarchical drug delivery system HA-GDT-Lip was constructed by coupling glycyrrhetinic acid (GA), triphenylphosphine (TPP), and doxorubicin (DOX), encapsulating them in cationic liposomes (CLs), then coating the surface of CLs with HA. HA-GDT-Lip nanoparticles can be accumulated in tumor tissue through the EPR effect, then achieve tumor cell-specific endocytosis mediated by the CD44 receptor, DOX can be successfully delivered into mitochondria through the combined action of GA and TPP. Physicochemical properties analysis showed that HA-GDT-Lip nanoparticles were uniform in size and spherical in shape. In vitro cell experiments showed that HA-GDT-Lip had high cell uptake efficiency and mitochondrial targeting ability. In addition, HA-GDT-Lip could induce MPTP opening and accelerate cell apoptosis. Meanwhile, HA-GDT-Lip showed excellent antitumor activity and in vivo safety in tumor-bearing nude mice. In conclusion, HA-GDT-Lip may serve as a promising mitochondrial delivery system to reduce the side effects of anticancer drugs and improve their antitumor efficacy.


The Combined Analysis of Pleiotropy and Epistasis (CAPE).
Epistasis, or gene-gene interaction, contributes substantially to trait variation in organisms ranging from yeast to humans, and modeling epistasis directly is critical to understanding the genotype-phenotype map. However, inference of genetic interactions is challenging compared to inference of individual allele effects due to low statistical power. Furthermore, genetic interactions can appear inconsistent across different quantitative traits, presenting a challenge for the interpretation of detected interactions. Here we present a method called the Combined Analysis of Pleiotropy and Epistasis (CAPE) that combines information across multiple quantitative traits to infer directed epistatic interactions. By combining information across multiple traits, CAPE not only increases power to detect genetic interactions but also interprets these interactions across traits to identify a single interaction that is consistent across all observed data. This method generates informative, interpretable interaction networks that explain how variants interact with each other to influence groups of related traits. This method could potentially be used to link genetic variants to gene expression, physiological endophenotypes, and higher-level disease traits.


Protein condensation diseases: therapeutic opportunities.
Condensed states of proteins, including liquid-like membraneless organelles and solid-like aggregates, contribute in fundamental ways to the organisation and function of the cell. Perturbations of these states can lead to a variety of diseases through mechanisms that we are now beginning to understand. We define protein condensation diseases as conditions caused by the disruption of the normal behaviour of the condensed states of proteins. We analyze the problem of the identification of targets for pharmacological interventions for these diseases and explore opportunities for the regulation of the formation and organisation of aberrant condensed states of proteins.


Treatment of amiodarone associated thyrotoxicosis by simultaneous administration of potassium perchlorate and methimazole.
Amiodarone iodine induced thyrotoxicosis occurs frequently in patients residing in areas of mild iodine deficiency and in patients with preexisting goiter. Drug therapy of the hyperthyroidism is often unsuccessful. Twenty-three patients with amiodarone induced thyrotoxicosis were either not treated, treated with 40 mg methimazole daily or with methimazole and 1 gm potassium perchlorate daily for up to 40 days and then with methimazole alone. Thyrotoxicosis was more likely to spontaneously remit in patients without goiter. Therapy with methimazole alone was unsuccessful in inducing euthyroidism in 5 patients with goiter. However, combined therapy with methimazole and potassium perchlorate rapidly alleviated hyperthyroidism in almost all patients with goiter. This drug combination is successful because perchlorate inhibits the active transport of iodine into the thyroid and methimazole blocks the intrathyroidal synthesis of thyroid hormones.


Low-hazard metallography of moisture-sensitive electrochemical cells.
A low-hazard approach is presented to prepare metallographic cross-sections of moisture-sensitive battery components. The approach is tailored for evaluation of thermal (molten salt) batteries composed of thin pressed-powder pellets, but has general applicability to other battery electrochemistries. Solution-cast polystyrene is used to encapsulate cells before embedding in epoxy. Nonaqueous grinding and polishing are performed in an industrial dry room to increase throughput. Lapping oil is used as a lubricant throughout grinding. Hexane is used as the solvent throughout processing; occupational exposure levels are well below the limits. Light optical and scanning electron microscopy on cross-sections are used to analyse a thermal battery cell. Spatially resolved X-ray diffraction on oblique angle cut cells complement the metallographic analysis.


An integrated metabolism in vivo analysis and network pharmacology in UC rats reveal anti-ulcerative colitis effects from Sophora flavescens EtOAc extract.
Ulcerative colitis (UC), an immune system disease, is characterized by long duration and easy relapse. Sophora flavescens (S. flavescens), also named "Kushen", is a traditional Chinese medicine, widely used to treat UC in clinics. Alkaloids and flavonoids are the main constituents of S. flavescens. Previous studies indicated that the effects of S. flavescens against UC mainly attribute to its alkaloids. In view of the clinical applications of its flavonoids and our preliminary experiments on the effects of S. flavescens treatment, we speculated that flavonoids also could exert an anti-UC effect, but its efficacy and mechanism are still not yet to be revealed. Herein, we examined the pharmacodynamic effects of the ethyl acetate (EtOAc) extract of S. flavescens EtOAc (SFE) against dextran sodium sulfate-induced UC rats for the first time. Pharmacodynamic effects indicated that SFE could significantly alleviate the loss in the body weight and shortening of the colon length, reduce colon bleeding and improve colon tissue damage of UC rats. A total of 28 prototypes and 41 metabolites were unambiguously or tentatively detected in rat's plasma and urine. Among them, 28 prototypes and 3 phase I metabolites shared 40 UC targets, the targets contributed to 51 metabolic pathways in 5 modules. Additionally, genistein, formononetin, isokurarinone, kurarinone, maackiain, kushenol N, trifolirnizin, kuraridin and norkurarinone were suggested to be potential active compounds in SFE for treating UC by comprehensively investigating the results of network pharmacology analysis, metabolic analysis in vivo, and previous researches. Finally, a combination of metabolic analysis in vivo with network pharmacology can elucidate the material basis and pharmacodynamic effect of traditional Chinese medicines, and lay the foundation for further clarify the anti-UC mechanism of SFE.


Decision-making competence and adherence to treatment in adolescents with diabetes.
To examine decision-making competence (the ability to form effective plans for managing different situations) in a sample of adolescents with type I diabetes and their parents. We hypothesized that adolescent decision-making competence would mediate the relationship between parent-adolescent communication and adherence to treatment. The sample consisted of 63 adolescents and their parents. Parent-adolescent communication during a problem-solving task was assessed, as well as adolescent maladaptive decision-making (adolescent report), adherence to treatment (parent and provider report; number of glucose tests), and metabolic control (HbA1C). Parent-adolescent communication was associated with adherence to treatment but not with adolescent decision-making. Poorer decision-making was associated with lower adherence per parent report but not provider report or the number of glucose tests. Decision-making competence did not mediate the relationships between parent-adolescent communication and adherence. These results are consistent with prior research demonstrating associations between parent-adolescent communication and adherence and identify adolescent decision-making competence as another potentially important correlate of adherence. These findings highlight several areas for future research.


Atypical and rare variants of central neurocytomas.
This article reviews the variation in imaging, histopathology, clinical course, and management seen with central neurocytomas (CNs). CNs have often been misdiagnosed as oligodendrogliomas and ependymomas; however, synaptophysin positivity can correctly diagnose these neurocytic neoplasms. Atypical CNs, an important variant first described in 1997, are marked by increased proliferative potential and associated with worse clinical outcomes in terms of long-term survival and local tumor control. Complete surgical resection is the cornerstone of therapy, and postoperative radiation is recommended in the setting of residual disease. Other less aggressive variants of central neurocytomas, including liponeurocytomas, ganglioneurocytomas, and pigmented neurocytomas, are also discussed.


Quantitative analysis of the ultrastructural distribution of GABA-like immunoreactivity in the intermediate and medial part of hyperstriatum ventrale of chick.
The intermediate and medial part of the hyperstriatum ventrale of the chick telencephalon plays a crucial role in the learning processes of imprinting. The distribution within the intermediate and medial part of the hyperstriatum ventrale of the neurotransmitter gamma-amino butyric acid was studied with light and electron microscopy using an antibody against this amino acid. The antibody labelled 18.4% of neuronal somata. GABA-labelled terminals made symmetrical synapses onto somata and dendrites of labelled and unlabelled neurons. Labelled somata received about three times as many synaptic boutons as unlabelled somata. Approximately 21% of synaptic terminals on labelled somata were themselves labelled; unlabelled somata received a higher proportion (37.6%) of such terminals. Most labelled terminals synapsing with dendrites were confined to the shafts; very few labelled terminals contributed to axospinous synapses. Synaptic contacts made on dendritic shafts by labelled boutons were intermingled with symmetrical and asymmetrical contacts from non-immunoreactive terminals. The proportion of labelled terminals received by labelled dendrites (33.1%) was approximately twice that received by unlabelled dendrites (15.9%). Labelled neurons therefore received a higher proportion of labelled terminals on their dendrites and a lower proportion on their somata compared with unlabelled neurons. No immunoreactivity was seen in glial cells or ependyma.


[The reasons for refusal and abandonment of treatment in the emergency surgery at the University Hospital Center of Bouake, Ivory Coast].
The refusal and abandonment of treatment is a behavior frequently observed in our daily practice. The purpose of this study was to describe the epidemiology and to identify the reasons for refusals and abandonment of treatment. We conducted a prospective study in the emergency surgery at the University Hospital Center of Bouake from 1st January 2018 to 31st December 2018. It involved all patients admitted with traumatic lesions who had refused or abandoned treatment. Data from 106 cases (16%) of refusal and abandonment of treatment out of 662 cases admitted with limb traumas were examined over this period. The average age of patients was 37 years. The study enrolled 77 men (72.6%). Tertiary sector workers accounted for 56.6% (n= 60) of cases. Lesions were dominated by closed fractures (82.1%; n= 87) and pelvic limbs were the most achieved (78.3%; n=83). Treatment was based on surgery (n=85; 80.2% ) and orthopaedic treatment (n=21; 19.8%). The cost of orthopedic treatment was estimated at 26 500 CFA francs (40 euros) while at 250 000 FCFA (380 euros) for surgical treatment. These costs varied as a function of implant prescribed and its location. Refusal of tratment was expressed by patients (n=30; 28.3%) and by parents (n=76; 71.7%). Reported reasons were dominated by financial problems (n=62; 58.5%), trust in traditional medicine (n=42; 39.6%), religious belief (n=2; 1.9%). The average time of refusal was 22 hours. Eighty eight point seven percent (n=94) of patients signed discharge while 11.3% (n=12) escaped. Refusal of care is a recurrent theme in our context and is due to inadequate health care management of people with limited financial resources.


Pyroptosis as a double-edged sword: The pathogenic and therapeutic roles in inflammatory diseases and cancers.
Pyroptosis is a programmed cell death mode discovered in recent years. It is caused by inflammasomes and the perforation of Gasdermin family proteins, and results in the release of inflammatory factors and triggering of an inflammatory cascade response. The pathways of pyroptosis include the caspase-1-dependent canonical pathway, the caspase-4/5/11-dependent non-canonical pathway, other caspase-dependent pathways and caspase-independent pathways. Its morphological features are different from other programmed cell death modes (apoptosis, autophagy, etc.). Pyroptosis can be observed microscopically that abundant pores are formed in the cell membrane, resulting in cell swelling and rupture, and eventually leading to the outflow of cellular contents. In addition to causing tissue damage and dysfunction through inflammation, pyroptosis can also become a potential cancer treatment strategy by reducing drug resistance in cancer cells. However, many details are still unclear on the molecular mechanisms of its role in pathogenicity and therapeutics, and therefore lots of work needs to be done. This article reviews the morphological characteristics, pathogenic and therapeutic mechanisms of pyroptosis and its related research progress in inflammatory diseases and cancers. It helps to further understand the mechanism of pyroptosis and provide new ideas for the research and prevention of inflammatory diseases and cancers.


A single point mutation (Y89F) within the non-structural protein 1 of influenza A viruses limits epithelial cell tropism and virulence in mice.
The nonstructural protein 1 (A/NS1) of influenza A viruses (IAV) harbors several src homology (SH)-binding motifs (bm) that mediate interactions with cellular proteins. In contrast to the sequence variability of the second SH3bm, tyrosine 89, within the SH2bm is a highly conserved residue among IAV strains. This prompted us to evaluate the necessity of this SH2bm for IAV virulence. In an in vivo mouse model, we observed drastic reductions in weight loss, mortality, and virus titers in lung and bronchoalveolar lavage fluid after infection with the mutant virus PR8 A/NS1-Y89F (PR8 Y89F) when compared with wild-type virus (PR8 wt). Concomitantly, we observed decreased inflammation and less severe pathologic changes, reflecting reduced levels of virus titers. At histologic analysis, lungs infected with PR8 wt virus showed widespread destruction of the bronchiolar epithelium, with extensive distribution of virus antigen within tracheal, bronchial, bronchiolar, and alveolar epithelium. In marked contrast, the bronchiolar epithelium after infection with the mutant PR8 Y89F virus was entirely intact, and the severity and extent of viral infection was reduced and strongly restricted to alveoli. These findings demonstrate that change of a single residue of the highly conserved SH2bm within the A/NS1 results in restricted virus spread in mouse lung and strongly reduced virulence, which illustrates the necessity of the SH2bm for IAV-induced pathogenicity.


Local feedback loop of ghrelin-GH in the pig ovary: action on estradiol secretion, aromatase activity and cell apoptosis.
Ghrelin is recognized as an important regulator of growth hormone (GH) secretion, food intake and a factor which controls reproduction. In the present studies, the effect of GH and insulin-like growth factor (IGF-I) on ghrelin synthesis and secretion and the effects of ghrelin on GH synthesis and secretion in cultured whole porcine follicles were studied. Ghrelin and GH levels were measured in the follicular wall and in the culture medium. Moreover, the action of combined treatment with ghrelin and GH on estradiol secretion, aromatase activity and cell apoptosis were examined. We demonstrated that ghrelin increased GH secretion but not GH synthesis by ovarian follicles. GH stimulated both ghrelin synthesis and secretion in the ovarian follicles. The increase in estradiol secretion, aromatase activity and the decrease in caspase-3 activity were noted in ghrelin alone- and ghrelin in combination with GH-treated cells. In culture treated with combination of both these hormones, all investigated parameters were similar to those noted in ghrelin alone-treated cells. In conclusion, our study provides novel evidence for the gonadal feedback loop between GH and ghrelin secretion in the ovary. However, results of the presented research suggest independent action of GH and ghrelin in the ovary.


Assignment of 6-phosphogluconate dehydrogenase and malate dehydrogenase to chromosome 3 of Anopheles stephensi.
Genetics and linkage analysis of 6-phosphogluconate dehydrogenase (6-PGD) and malate dehydrogenase (MDH) have been investigated in Anopheles stephensi. Both these markers were found to be autosomal and linked and have been assigned to linkage group III. Two mutant markers, Black larva (Bl) and golden-yellow larva (gy), were used to establish the map distances, and the current sequence of loci on chromosome 3 is as follows: Bl (3.75)-gy (14.53)-Mdh-2 (49.83)-6-pgd.


Retrieval of a retained guide wire from the deltoid muscle-A rare and delayed presentation post cardiac resynchronization therapy lead replacement.
Fracture and retention of a guidewire after cardiac resynchronization therapy device implantation has not been reported in the literature so far, although it is an uncommon but known complication during cardiac interventions like percutaneous coronary interventions and other cardiac catheterization procedures. A 53 years old female patient presented with severe pain over the left arm and shoulder for a period of 1 to 2 days. The patient had a history of dilated cardiomyopathy with severe left ventricular dysfunction and underwent cardiac resynchronization therapy device implant 3 years back with subsequent lead replacement 6 months back due to lead dysfunction. On evaluation, a coronary guidewire which might have fractured and been retained inadvertently during previous surgical procedure, was discovered in her deltoid muscle. Her symptoms were attributed to the guide wire which may have been aggravated by the movements of her arm. Emergency surgical exploration was done and the guidewire was removed. We are reporting a case of unlikely and unusual delayed presentation of retained intervention guide-wire post cardiac resynchronization therapy, which was retrieved from the left deltoid muscle.


Effect of zinc and iron fortification of the feed on liver and thyroid function in rats.
Changes in plasma glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), triiodothyronine (T3), and thyroxin (T4) of male rats, following 8 weeks of administration of different concentrations of elemental iron (EI), sodium iron ethylenediaminetetraacetate (NaFeEDTA), zinc sulfate (ZnSO(4)), and zinc oxide (ZnO) in whole wheat flour were investigated. Liver enzymes and thyroid hormones were determined using colorimetric methods and enzyme immune assay, respectively. Ingestion of fortified diets by the male rats did not show a marked effect on GOT and GPT, the exception being NaFeEDTA fed alone and EI with ZnO-fortified diets indicating a significant (p < 0.05) decrease in GOT levels in rats. Similarly, only NaFeEDTA significantly (p < 0.05) increased thyroxin, while EI, ZnSO(4), and ZnO either alone or in any combination did not alter thyroid secretions. Changes in GOT, GPT, T3, and T4 levels, as a result of ingesting iron and zinc-fortified diets by rats, ranged in the safe limits.


KLF5-induced lncRNA IGFL2-AS1 promotes basal-like breast cancer cell growth and survival by upregulating the expression of IGFL1.
Basal-like breast cancer (BLBC) is the most malignant subtype of breast cancer and has a poor prognosis. Kruppel-like factor 5 (KLF5) is an oncogenic transcription factor in BLBCs. The mechanism by which KLF5 promotes BLBC by regulating the transcription of lncRNAs has not been fully elucidated. In this study, we discovered that lncRNA IGFL2-AS1 is a downstream target gene of KLF5 and that IGFL2-AS1 mediates the pro-proliferation and pro-survival functions of KLF5. Additionally, we demonstrated that IGFL2-AS1 functions by upregulating the transcription of its neighboring gene IGFL1 via two independent mechanisms. On the one hand, nuclear IGFL2-AS1 promotes the formation of a KLF5/TEAD4 transcriptional complex at the IGFL1 gene enhancer. On the other hand, cytoplasmic IGFL2-AS1 inhibits the expression of miR4795-3p, which targets the IGFL1 gene. TNFα induces the expression of IGFL2-AS1 and IGFL1 through KLF5. Taken together, the results of this study indicate that IGFL2-AS1 and IGFL1 may serve as new therapeutic targets for BLBCs.


Electropherotyping of human rotaviruses: an epidemiological survey of rotavirus infections in Sicily.
An electrophoretic analysis of rotavirus RNA segments was carried out on 522 faecal specimens, obtained from children hospitalized in Sicily in the period 1981/85. One hundred and one viral isolates could be characterized with respect to the electrophoretic pattern of their genomic RNAs. This analysis revealed that in 1981/82 different electropherotypes cocirculated in the infant population. In 1983 one of the patterns became prevalent; in 1984/85 only one electropherotype was detected, both in Palermo and Catania specimens. The serotyping showed that all viral strains with the prevalent electropherotype were subgroup II and serotype 1. These results contrast with the extensive genome variability of rotavirus strains observed in urban areas.


The filum terminale of the frog spinal cord, a non transformed preparation: I. Morphology and uptake of gamma-aminobutyric acid.
The filum terminale of the frog spinal cord is a rather pure glial cell preparation, largely devoid of neuronal elements. gamma-Aminobutyric acid (GABA) is taken up by the frog filum terminale (FT) via a Na+-dependent, ouabain-inhibited, saturable high affinity transport system with a Km of 2.7 x 10(5) M. The rate of the FT GABA uptake is significantly greater than the velocities observed in the spinal cord. In fact, the Vmax increases caudally beyond the level of the last root, and is maximal in the FT per se. beta-Alanine is a competitive inhibitor of the FT high affinity transport system for GABA (Ki 11.1 x 10(-5) M). In addition to GABA, the FT also takes up beta-alanine, glycine, glutamate and aspartate at rates significantly higher than those shown by the spinal cord of the frog. Light and electron microscope level radioautography clearly shows that GABA uptake occurs primarily in the glial cells and also in ependymal cells present in the FT. In that the FT contains few ependymal cells and a large number of glia, it is fair to state that most of the GABA accumulated by the FT reflects the glial transport of this amino acid. Unlike the adult frog, the spinal cord of the tadpole does not show any regional differences in the rate of GABA transport during early development. However, during later developmental stages, the rates of GABA transport increase in the caudal portion of the tadpole cord as compared to the more rostral areas. Close to metamorphosis, the terminal portion of the tadpole cord, which is destined to become the filum terminals of the frog, accumulates GABA at rates not greatly different from those observed in the FT of the adult frog. Therefore, the tadpole spinal cord is a useful preparation in which to study the dynamic properties of normal non-transformed glia as influenced by a changing neuronal population, whereas the frog FT is a unique preparation for the study of some properties of normal glia largely in the absence of neurons.


The utilization of intraoperative contralateral ankle images for syndesmotic reduction.
To evaluate the variability in ankle syndesmotic morphology on contralateral ankle fluoroscopic images and the reductions obtained utilizing these images. A retrospective cohort study was performed at a level one trauma center including 46 adult patients undergoing operative fixation of malleolar ankle fractures that also had anteroposterior (AP) and lateral fluoroscopic images of the uninjured contralateral ankle intraoperatively. Contralateral and post-fixation fluoroscopic images were used to measure the tibiofibular clear space (TFCS) as a proportion of the superior clear space (SCS) on mortise images and the posterior tibiofibular distance (PTFD) as a proportion of the lateral superior clear space (LSCS) on lateral images. Differences between contralateral and post-fixation ankle measurements were compared between those patients with syndesmotic injuries and those without (control group). The mean TFCS/SCS and PTFD/LSCS ratios measured on contralateral ankle images were 1.2 (95% confidence interval (CI) 1.1 to 1.3; range 0.7 to 1.8) and 1.8 (95% CI 1.5 to 2; range 0.5 to 3.4). The mean difference between the contralateral and post-fixation TFCS/SCS and PTFD/LSCS in patients with and without syndesmotic fixation was 0.07 vs. 0.13 (F-ratio 0.3, p = 0.5) and -0.2 vs 0.5 (F ratio 5.2, p= 0.02). Contralateral syndesmotic measurements varied widely and the utilization of these images allowed for syndesmotic reductions with similar measurements. Intraoperative contralateral ankle images should be considered to assess syndesmotic reduction.


Relationship between glucocorticoid receptor and response to glucocorticoid therapy in ulcerative colitis.
To clarify the relationship between the glucocorticoid receptor and the effectiveness of glucocorticoid therapy in patients with ulcerative colitis, we investigated the number and apparent dissociation constant of glucocorticoid receptor in peripheral blood mononuclear leukocytes of patients with ulcerative colitis. Eleven patients with ulcerative colitis (5 who responded to intravenous glucocorticoids and 6 who did not) and ten control subjects were studied. The number and apparent dissociation constant of glucocorticoid receptor were measured using a whole-cell binding assay. Results were expressed as a median (interquartile range). The number of glucocorticoid receptors from the six nonresponders, five responders, and ten healthy controls were 4922 (range, 4484-5643), 3413 (range, 3183-4450), and 3610 (range, 2594-3979) binding sites/cell, respectively. The apparent dissociation constant of the glucocorticoid receptors from the nonresponders, responders, and healthy controls were 7.03 (range, 5.66-10), 4.27 (range, 4-5.13), and 6.18 (range, 5.86-6.74) nM, respectively. Nonresponders had a significant increase both in the number of binding sites and in the apparent dissociation constant compared with responders (P = 0.045; P = 0.029). The increased number and apparent dissociation constant of glucocorticoid receptor are closely associated with the effectiveness of glucocorticoid therapy. The measurement of the number and apparent dissociation constant of glucocorticoid receptor may be useful in predicting response to glucocorticoids.


Induction of dental pulp stem cell differentiation into odontoblasts by electroporation-mediated gene delivery of growth/differentiation factor 11 (Gdf11).
The long-term goal of dental treatment is to preserve teeth and prolong their function. In dental caries an efficient method is to cap the exposed dental pulp and conserve the pulp tissue with reparative dentin. We examined whether growth/differentiation factor 11 (GDF11), a morphogen could enhance the healing potential of pulp tissue to induce differentiation of pulp stem cells into odontoblasts by electroporation-mediated gene delivery. Recombinant human GDF11 induced the expression of dentin sialoprotein (Dsp), a differentiation marker for odontoblasts, in mouse dental papilla mesenchyme in organ culture. The Gdf11 cDNA plasmid which was transferred into mesenchymal cells derived from mouse dental papilla by electroporation, induced the expression of Dsp. The in vivo transfer of Gdf11 by electroporation stimulated the reparative dentin formation during pulpal wound healing in canine teeth. These results provide the scientific basis and rationale for gene therapy for endodontic treatments in oral medicine and dentistry.


Patterns and disparities in prescribing of opioids and benzodiazepines for older adults in North Carolina.
We characterized real-world prescribing patterns of opioids and benzodiazepines (BZDs) for older adults to explore potential disparities by race and sex and to characterize patterns of co-prescribing. A retrospective evaluation was conducted using electronic health data for adults ≥65 years old who presented to one of 15 primary care practices between 2019 and 2020 (n = 25,141). Chronic opioid and BZD users had ≥4 prescriptions in the year prior, with at least one in the last 90 or 180 days, respectively. We compared demographic characteristics between all older adults versus chronic opioid and BZD users. We used logistic regression to identify characteristics (age, sex, race, Medicaid use, fall history) associated with opioid and BZD co-prescribing. We identified 833 (3.3%) chronic opioid and 959 chronic BZD users (3.8%) among all older adults seen in these practices. Chronic opioid users were less likely to be Black (12.7% vs. 14.3%) or other non-White race (1.4% vs. 4.3%), but more likely to be women (66.8% vs. 61.3%). A similar trend was observed for BZD users, with less prescribing among Black (5.4% vs. 14.3%) and other races (2.2% vs. 4.3%) older adults and greater prescribing among women (73.6% vs. 61.3%). Co-prescribing was observed among 15% of opioid users and 13% of BZD users. Co-prescribing was largely driven by the presence of relevant co-morbid conditions including chronic pain, anxiety, and insomnia rather than demographic characteristics. We observed notable disparities in opioid and BZD prescribing by sex and race among older adults in primary care. Future research should explore if such patterns reflect appropriate prescribing or are due to disparities in prescribing driven by biases related to perceived risks for misuse.


Amplification and expression of the epidermal growth factor receptor gene during the progression of neuroepithelial tumours in vivo.
The epidermal growth factor receptor (EGFR) gene is homologous to the oncogene c-erbB. The occurrence of amplification and rearrangements at the EGFR gene locus is associated with malignancy in neuroepithelial tumours. Sixteen neuroepithelial tumours from eight patients with recurrence of their neoplasms were analysed for changes at the EGFR gene locus and for expression of EGFR. Ten tumours from five patients lacked changes at the EGFR gene locus. Three of eight individuals showed EGFR gene amplifications in both tumours with a higher grade of amplification in the second tumour. In addition to amplification, a rearrangement was found in both tumours of the first patient. In the second case an amplification of chromosome-7-specific c-met sequences was found in the regrown tumour, suggesting that a polysomy 7 was at least partly responsible for the higher copy number of the EGFR sequences. In both tumours of the third patient with EGFR gene amplification different alleles were amplified. In contrast to the findings at the DNA level the EGFR expression, analysed by immunohistochemical techniques, showed a more heterogeneous pattern after tumour progression.


Modeling and efficiency analysis of blockchain agriculture products E-commerce cold chain traceability system based on Petri net.
The cold chain supply chain of e-commerce has the characteristics of long chain, dispersed production, heterogeneous information sources, etc., which is easy to cause the upstream and downstream information of the supply chain to be broken and opaque. Traditional traceability data is stored in each node enterprise, and there are problems such as low cooperation trust and poor authenticity in the upstream and downstream data transmission process of the supply chain, resulting in consumers' trust crisis on the authenticity of traceability information. Blockchain traceability system through the establishment of multi-party participation, joint maintenance of distributed database, and the use of cryptography and consensus mechanism to establish trust relationships, with data can not be tampered with, sharing of high credibility. On the basis of stochastic Petri net theory, this study constructed a blockchain e-commerce cold chain traceability model centering on the actual application of blockchain technology in logistics traceability to improve the reliability and validity of e-commerce cold chain traceability. Correlation matrix and invariants were used to analyze the validity of the model, and an isomorphic Markov chain was constructed to analyze the effectiveness evolution of the model. This study aims to deepen the understanding of the cold chain traceability system of blockchain e-commerce from the three aspects of the best optimization link, the best synergism scale, and the adaptive ability of the system to provide reference for the improvement of cold chain traceability ability by blockchain technology.


Symptomatic sinus bradycardia in infants with structurally normal hearts.
Sixteen infants, ages 6 weeks to 23 months, were evaluated because of syncopal attacks (n = 6), apneic episodes (n = 3), or a combination of syncope, apnea, or "convulsions" (n = 7). Comprehensive metabolic and neurologic investigations yielded negative results in 15 infants; in one, an abnormal EEG was recorded. Severe sinus bradycardia, complete sinus arrest, junctional escape rhythm, or ventricular escape rhythm was found in four patients, and permanent multiprogrammable pacemakers were implanted. Follow-up for 6 to 24 months with ventricular demand pacing showed complete cessation of attacks in two infants and marked improvement in two.


Hydraulics and gas exchange recover more rapidly from severe drought stress in small pot-grown grapevines than in field-grown plants.
Modifications of plant hydraulics and shoot resistances (Rshoot) induced by water withholding followed by rewatering, and their relationships with plant water status, leaf gas exchange and water use efficiency at the leaf level, were investigated in pot-grown and field-grown, own-rooted Syrah grapevines in an arid climate. Water stress induced anisohydric behavior, gradually reducing stomatal conductance (gs) and leaf photosynthesis (A) in response to decreasing midday stem water potential (Ψs). Water stress also rapidly increased intrinsic water-use efficiency (A/gs); this effect persisted for many days after rewatering. Whole-plant (Kplant), canopy (Kcanopy), shoot (Kshoot) and leaf (Kleaf) hydraulic conductances decreased during water stress, in tune with the gradual decrease in Ψs, leaf gas exchange and whole plant water use. Water-stressed vines also had a lower Ψ gradient between stem and leaf (ΔΨl), which was correlated with lower leaf transpiration rate (E). E and ΔΨl increased with increasing vapour pressure deficit (VPD) in non-stressed control vines but not in stressed vines. Perfusion of xylem-mobile dye showed that water flow to petioles and leaves was substantially reduced or even stopped under moderate and severe drought stress. Leaf blade hydraulic resistance accounted for most of the total shoot resistance. However, hydraulic conductance of the whole root system (Kroot) was not significantly reduced until water stress became very severe in pot-grown vines. Significant correlations between Kplant, Kcanopy and Ψs, Kcanopy and leaf gas exchange, Kleaf and Ψs, and Kleaf and A support a link between water supply, leaf water status and gas exchange. Upon re-watering, Ψs recovered faster than gas exchange and leaf-shoot hydraulics. A gradual recovery of hydraulic functionality of plant organs was also observed, the leaves being the last to recover after rewatering. In pot-grown vines, Kcanopy recovered rather quickly following restoration of Ψs, although gas exchange recovery did not directly depend on recovery of Kcanopy. In field-grown vines, recovery of water status, gas exchange and hydraulic functionality was slower than in pot-grown plants, and low gs after rewatering was related to sustained decreased Kplant, Kcanopy and Kshoot and lower water transport to leaves. These results suggest that caution should be exercised when scaling up conclusions from experiments with small pot-grown plants to field conditions.


The Influence of Chimeric Antigen Receptor Structural Domains on Clinical Outcomes and Associated Toxicities.
Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of B cell malignancies, improving patient survival and long-term remission. Nonetheless, over 50% of patients experience severe treatment-related toxicities including cytokine release syndrome (CRS) and neurotoxicity. Differences in severity of toxic side-effects among anti-CD19 CARs suggest that the choice of costimulatory domain makes a significant contribution to toxicity, but comparisons are complicated by additional differences in the hinge and transmembrane (TM) domains of the most commonly used CARs in the clinic, segments that have long been considered to perform purely structural roles. In this perspective, we examine clinical and preclinical data for anti-CD19 CARs with identical antigen-binding (FMC63) and signalling (CD3ζ) domains to unravel the contributions of different hinge-TM and costimulatory domains. Analysis of clinical trials highlights an association of the CD28 hinge-TM with higher incidence of CRS and neurotoxicity than the corresponding sequences from CD8, regardless of whether the CD28 or the 4-1BB costimulatory domain is used. The few preclinical studies that have systematically varied these domains similarly support a strong and independent role for the CD28 hinge-TM sequence in high cytokine production. These observations highlight the value that a comprehensive and systematic interrogation of each of these structural domains could provide toward developing fundamental principles for rational design of safer CAR-T cell therapies.


National and provincial burden of varicella disease and cost-effectiveness of childhood varicella vaccination in China from 2019 to 2049: a modelling analysis.
In China, varicella is the third most frequently reported vaccine-preventable infectious disease after tuberculosis and influenza, and imposes a heavy burden on families and society. To inform future immunization policy, we investigated disease burden of varicella in China and explored cost-effectiveness of different varicella vaccination strategies at national and provincial levels. A dynamic transmission model was developed to assess disease burden of varicella and the impact of varicella vaccination in China. A cost-effectiveness analysis of three alternative vaccination strategies in China's National Immunization Program (NIP) compared with no vaccination was conducted. Scenario analyses and sensitivity analyses were performed to check the robustness of the results. It was estimated that 3.35 million new varicella cases occurred in 2019, more than three times of 982 thousand cases officially reported from National Notifiable Infectious Disease Surveillance System (NNIDSS). The under-reported rate was approximately 71%. The economic analysis revealed that from the societal perspective, the incremental cost-effectiveness ratio (ICER) for one dose of varicella vaccination in NIP was US$ 2357 per QALY at the national level and it was cost-effective in 22 of 31 provinces. The ICER for one dose varicella vaccination plus a mass catch-up for unvaccinated children aged 2-11 years old would be US$ -5260 per QALY, cost-saving at the national level. The one dose plus mass catch-up NIP strategy was also cost-saving in 24 of the 31 provinces. Varicella incident cases were substantially under-reported in China. Varicella vaccination in the NIP could significantly contribute to reducing the burden of varicella disease. From the societal perspective, including varicella vaccination into China's NIP was highly cost-effective at the national level and in most provinces. Bill & Melinda Gates Foundation.


False Negative Inferior Petrosal Sinus Sampling in Young-Onset Cushing Disease: What Happens Next.
False negative results during inferior petrosal sinus sampling (IPSS) may complicate the diagnostic evaluation of patients with ACTH-dependent Cushing syndrome (CS). The management of these patients can be confusing for clinicians and lead to delayed management. We studied patients with young-onset (<21yo) CD who underwent IPSS during their diagnostic evaluation. For all patients, diagnosis of CD was eventually confirmed based on histologic evaluation of a resected pituitary tumor or remission after transsphenoidal surgery (TSS). We recorded a rare incidence of false negative IPSS results in 5 out of the 142 IPSS procedures (3.5%), performed in 4 unique patients. Patients with negative IPSS did not differ in demographic (age and sex) or biochemical (diurnal ACTH/cortisol or 24hour urinary free cortisol) data from the remaining. Additional workup was performed in three of the four patients including evaluation for ectopic sources of CS and repeat IPSS. Two of these patients also received medical treatment for suppression of cortisol production. One patient decided to proceed with pituitary exploration without additional evaluation. All patients finally underwent surgery and achieved remission. In patients with CD, IPSS may rarely lead to false negative results. Management of these patients usually includes screening for ectopic sources of ACTH/CRH secretion, repeating IPSS if ectopic workup is negative, and considering medical management until final diagnosis of the source of hypercortisolism is made.


Some perspectives on intervention strategies for persons with developmental disorders.
We present a view of language that crosses modal considerations (e.g., speech vs. augmentative systems) and places language within an interaction framework. We emphasize the need to consider normal social, cognitive, and linguistic development in selecting program guidelines for developmentally delayed persons. We address the child's linguistic code not as a set of phonetic, syntactic, and semantic features that can be trained in isolation, but as a means by which he can exercise the various pragmatic uses of communication. In effect, our interest has thus expanded from the child alone to the child as one member of a communicating dyad. Programming in the areas of mother's verbal input, expanding children's language skills, training in augmentative systems--all reflect an overriding objective of optimizing the language-user's ability to successfully participate in interactions with other persons in his/her environment.


Early-Age Onset Colorectal Neoplasia in Average-Risk Individuals Undergoing Screening Colonoscopy: A Systematic Review and Meta-Analysis.
Incidence and mortality associated with early-age onset colorectal cancer (EAO-CRC) is increasing, prompting professional society recommendations to lower the screening age in average-risk individuals. The yield of screening individuals younger than 50 years is not known. A systematic review of 3 databases from inception through July 2020 was performed in all languages that reported colonoscopy findings in average-risk individuals younger than 50 years. The primary outcomes were EAO colorectal neoplasia (CRN) and advanced colorectal neoplasia (aCRN) prevalence. Subgroup analyses were performed based on sex, geographic location, time period, and age, including comparison with those aged 50-59 years. Generalized linear mixed model with random intercept logistic regression and fixed subgroup effects were performed. Of 10,123 unique articles, 17 studies published between 2002 and 2020, including 51,811 average-risk individuals from 4 continents, were included. The pooled rate of EAO-CRN was 13.7% (95% confidence interval [CI], 0.112%-0.168%) and EAO-aCRN was 2.2% (95% CI, 0.016%-0.031%). Prevalence of CRC was 0.05% (95% CI, 0.00029%-0.0008%). Rates of EAO-CRN were higher in men compared with women (relative risk, 1.71%; 95% CI, 1.49%-1.98%), and highest in the United States (15.6%; 95% CI, 12.2%-19.7%) compared with Europe (14.9%; 95% CI, 6.9%-29.3%), East Asia (13.4%; 95% CI, 10.3%-17.2%), and the Middle East (9.8%; 95% CI, 7.8%-12.2%) (P = .04) The rate of EAO-CRN in age groups 45-49 years and 50-59 years was 17.8% (95% CI, 14.5%-21.6%) and 24.8% (95% CI, 19.5%-30.8%), respectively (P = .04). The rate of EAO-aCRN in age group 45-49 years was 3.6% (95% CI, 1.9%-6.7%) and 4.2% (95% CI, 3.2%-5.7%), respectively (P = .69). The rate of aCRN in individuals aged 45-49 years was similar to the rate observed in individual aged 50-59 years, suggesting that expanding screening to this population could yield a similar impact on colorectal cancer risk reduction.


Physiological mechanisms of the tolerance response to manganese stress exhibited by Pinus massoniana, a candidate plant for the phytoremediation of Mn-contaminated soil.
Manganese (Mn) pollution in soil, especially around mining areas, is a serious environmental problem worldwide. Generally, plant remediation technology needs to select species with high Mn tolerance, and exploring the Mn tolerance mechanism of tree species with high ecological and economic benefits is of considerable significance for the effective identification and efficient utilization of Mn phytoremediation species. Masson pine (Pinus massoniana) is one of the main afforestation tree species, exhibiting high ecological and economic value in subtropical areas and also a plant with high Mn accumulation. To reveal the mechanisms governing the tolerance of this species for Mn stress, the morphological, physiological, and biochemical responses of seedlings grown in sand cultures under different Mn stress (0.0009~30 mmol·L-1) were analyzed. The results showed that despite the chlorosis of leaves under high Mn stress (30 mmol·L-1), the height of plant seedling, the diameter of ground and the root morphology was not significantly inhibited (p < 0.05), and a high level of Mn accumulated (translocation factor = 1.10). With increasing Mn concentration, malondialdehyde (MDA), soluble protein, and soluble sugar increased, and superoxide dismutase (SOD) and catalase (CAT) increased at first and later decreased. Under Mn stress, net photosynthetic rate, transpiration rate, stomatal conductance, total chlorophyll, chlorophyll a, and carotenoids increased first and subsequently decreased, and intercellular CO2 concentration and chlorophyll b decreased, but chlorophyll fluorescence characteristics did not change significantly. Taken together, these results indicate that Masson pine can tolerate Mn stress by increasing its antioxidant enzyme activity and non-enzyme metabolite content. In addition, Masson pine can maintain photosynthesis by changing its gas exchange parameters, photosynthetic pigment content, and chlorophyll fluorescence, which is another important mechanism for coping with high Mn concentrations in the environment. In conclusion, the above results show that Masson pine can be effectively used for phytoremediation of Mn-contaminated soil.


Regulation of the cellular localization and function of human transient receptor potential channel 1 by other members of the TRPC family.
Members of the Canonical Transient Receptor Potential (TRPC) family of ionic channels are able to form homo- and heterotetrameric channels. Depending on the study, TRPC1 has been detected on both the surface and inside the cell, probably in the endoplasmic reticulum (ER). Likewise, TRPC1 has been described both as a store-operated channel and as one unable to function when forming a homotetramer. It is possible that the apparent differences in the expression and function of TRPC1 are due to its association with other proteins, possibly from the same TRPC family. In the present study we used confocal microscopy and a fluorescently tagged TRPC1 to examine the localization of this protein when co-expressed with other members of the TRPC family. Whole-cell and single channel electrophysiological recordings were conducted to study the function of TRPC1 expressed alone or co-expressed with other members of the TRPC family. A FRET-based calcium sensor fused to TRPC1 was used to assess the functionality of the intracellular TRPC1. Our results showed that TRPC4 and TRPC5 were able to increase the amount of membrane-expressed TRPC1 as evaluated by confocal microscopy and patch clamp recordings. The FRET-based calcium sensor fused to TRPC1 strongly suggests that this protein forms ER-expressed functional homotetrameric channels activated by agonists coupled to the IP(3) cascade. These results indicate that TRPC1 is a multifunctional protein able to form intracellular calcium release channels when expressed alone, and plasma membrane channels when co-expressed with TRPC4 or TRPC5, but not TRPC3 or TRPC6. Both (ER and plasma membrane) forms of the channel are activated upon addition of agonists coupled to the IP(3) cascade.


Laser treatment in twin-to-twin transfusion syndrome.
Twin-to-twin transfusion syndrome (TTTS) is a severe fetal condition that has regained attention since surgical endoscopic treatment proved beneficial in a randomized controlled trial. Our objective is to review published series of cases treated with fetoscopic surgery. Diagnostic criteria, surgical technique, and perinatal outcome of series of TTTS cases treated by laser were reviewed. Over 1300 cases from 17 publications have been included, with a median perinatal survival rate of 57% (50-100%); brain lesions were present in 2-7% of the survivors at the age of 1-6 months. The percutaneous technique has gained wide acceptance, with an acceptable risk of maternal morbidity but a significant risk of miscarriage or preterm rupture of the membranes, presenting in 6.8-23% and 5-30%, respectively. The conclusion is that standardization of the technique and stability to improvement of the initial results should broaden the use of this technique. The overall survival rate at birth was 66% (1894/2869). However, variations in survival rates between centres and inconsistency in the reporting of complications call for more homogeneity in the pre- and post-operative assessment.


Comparison of the biologic activity of porcine and semisynthetic human insulins using the glucose-controlled insulin infusion system in insulin-dependent diabetes.
Semisynthetic human insulin is prepared from porcine pancreas by chemical methods involving the substitution of porcine B-30 alanine with threonine. To compare the effectiveness of porcine and semisynthetic human insulins, eight insulin-dependent diabetic patients were evaluated during two separate periods using a glucose-controlled insulin infusion system. During each 36-h period, patients received either porcine or semisynthetic human insulin. Patients ingested mixed meals. The mean daily insulin requirements for porcine and semisynthetic human insulins were 84 +/- 9 U and 85 +/- 6 U (+/- SEM), respectively (P = NS). Mean blood glucose values were similar at 95 +/- 1 mg/dl for porcine and 101 +/- 3 mg/dl with semisynthetic human insulin (P = NS). Prior metabolic control or insulin antibody levels did not correlate with intravenous insulin requirements. These studies indicate that semisynthetic human insulin is as effective as porcine insulin in maintaining near-normal blood glucose control in short-term intravenous studies using artificial pancreas techniques in insulin-dependent diabetes.


Experimental study on the fluid mechanics of blood sucking in the proboscis of a female mosquito.
Female mosquitoes are known to have a magnificent micro-scale pumping system that can transport small quantities of blood very effectively. To understand the dynamic characteristics of blood flow inside female mosquitoes, the measurement technique that is capable of measuring instantaneous flow fields of a biological sample at micrometer scales is required. In this study, the blood-sucking flow inside a female mosquito's food canal was measured in vivo using a micro particle image velocimetry (micro-PIV) velocity field measurement technique with high-temporal resolution. The volumetric flow rate (Q) and the time-averaged feeding speed (V) based on the diameter of the food canal (D) was found to be 5.751 x 10(-3) mm3/s and 0.416 cm/s, respectively. Spectral analysis on the velocity waveform shows a clear peak at 6.1 Hz, indicating distinct pulsatile blood-sucking characteristics. The Womersley number (alpha) was about 0.117 and the velocity profile of the blood flow inside the proboscis has a parabolic Hagen-Poiseuille flow pattern when alpha is much smaller than 1.


Adenocarcinoma of the urethra: A rare subtype of urethral cancer.
Urethral adenocarcinoma (UA) is a rare type of urethral cancer with a poor prognosis. We present a case of UA of intestinal subtype in a 57-year-old patient who initially had lower urinary tract symptoms and was subsequently found to have a urethral lesion in a urethral diverticulum on pelvic MRI which was confirmed on biopsy. She had neoadjuvant chemotherapy followed by open anterior pelvic exenteration, complete urethrectomy and ileal conduit urinary diversion. She required adjuvant chemotherapy for local invasion and a metastasis in the uterus but developed progressive metastatic disease and succumbed to the disease 13-months after surgery.


Ultrasound guidance improves a continuous popliteal sciatic nerve block when compared with nerve stimulation.
Continuous sciatic nerve blockade at the popliteal level effectively alleviates postoperative pain after major foot and ankle surgery. No randomized controlled trials have previously compared the success rate of continuous sciatic nerve sensory blockade between ultrasound and nerve stimulation guidance. In the current study, we tested the hypothesis that ultrasound-guided catheter placement improves the success rate of continuous sciatic nerve sensory blockade compared with catheter placement with nerve stimulation guidance. After research ethics committee approval and informed consent, 100 patients scheduled for elective major foot and ankle surgery were randomly allocated to popliteal catheter placement either with ultrasound or nerve stimulation guidance. The primary outcome was the success rate of sensory block the first 48 postoperative hours. Successful sensory blockade was defined as sensory loss in both the tibial and common peroneal nerve territories at 1, 6, 24, and 48 hrs postoperatively. The ultrasound group had significantly higher success rate of sensory block compared with the nerve stimulation group (94% versus 79%, P=0.03). Ultrasound compared with nerve stimulation guidance also entails reduced morphine consumption (median of 18 mg [range, 0-159 mg] versus 34 mg [range, 0-152 mg], respectively, P=0.02), fewer needle passes (median of 1 [range, 1-6] versus 2 [range, 1-10], respectively, P=0.0005), and greater patient satisfaction (median numeric rating scale 9 [range, 5-10] versus 8 [range, 3-10)] respectively, P=0.0006) during catheter placement. Ultrasound guidance used for sciatic catheter placement improves the success rate of sensory block, number of needle passes, patient satisfaction during catheter placement, and morphine consumption compared with nerve stimulation guidance.


[Conservative treatment options for arthritis of the ankle : What is possible, what is effective?]
In this article the causes of arthritis in the region of the ankle are introduced and the conservative treatment options are described and discussed more extensively. The risks of treatment with nonopioid analgesics (NOPA) are presented in detail. The topical use of nonsteroidal anti-inflammatory drugs (NSAID) should always be considered in the clinical routine. If contraindications for oral NSAIDs are present, intra-articular treatment is a meaningful option. The best evidence is currently available for viscosupplementation but the study situation for the use of platelet-rich plasma (PRP) is still not sufficiently comprehensive and there are only a few case reports on the use of mesenchymal stem cells..


Combination treatment of stroke with sub-therapeutic doses of Simvastatin and human umbilical cord blood cells enhances vascular remodeling and improves functional outcome.
Human umbilical cord blood cells (HUCBCs) have been employed as a restorative treatment for experimental stroke. In this study, we investigated whether transplantation of sub-therapeutic doses of HUCBCs and Simvastatin enhances cerebral vascular remodeling after stroke. Adult male Wistar rats (n=34) were subjected to transient middle cerebral artery occlusion (MCAo) and treated with: phosphate-buffered solution (PBS, gavaged daily for 7 days); Simvastatin (0.5mg/kg, gavaged daily for 7 days); HUCBCs (1×10(6), injected once via tail vein); and combination Simvasatin with HUCBCs, starting at 24h after MCAo. There was no significant difference between Simvastatin- or HUCBC-monotherapy and MCAo-alone group. Combination treatment 24h post-stroke significantly increased the perimeter of von Willebrand factor (vWF)-positive vessels, the diameter and density of alpha smooth muscle actin (αSMA)-positive arteries, and the percentage of 5-bromodeoxyuridine (BrdU)-positive endothelial cells (ECs) in the ischemic boundary zone (IBZ) compared with MCAo-alone or HUCBC-monotherapy 14 days after MCAo (p<0.05, n=8/group); Combination treatment significantly increased the densities of vWF-vessels and αSMA-arteries as well as the densities of BrdU-ECs and BrdU-positive smooth muscle cells (SMCs) in vascular walls in the IBZ compared with Simvastatin-monotherapy. Moreover, the increased BrdU-ECs and BrdU-SMCs were significantly correlated with neurological functional outcome 14 days after MCAo. Combination treatment also significantly increased the expression of Angiopoietin-1 (Ang1), Tie2 and Occludin in the IBZ (p<0.05, n=8/group). The in vitro experiments showed that combination treatment and Ang1 significantly increased capillary-like tube formation and arterial cell migration; anti-Ang1 significantly reduced combination treatment-induced tube-formation and artery cell migration (p<0.05, n=6/group). These findings indicated that a combination of sub-therapeutic doses of Simvastatin and HUCBCs treatment of stroke increases Ang1/Tie2 and Occludin expression in the ischemic brain, amplifies endogenous angiogenesis and arteriogenesis, and enhances vascular remodeling which in concert may contribute to functional outcome after stroke.


Role of FGFR3 in Urothelial Carcinoma.
This study was undertaken to analyze the immunohistochemical expression of fibroblast growth factor receptor (FGFR3) in urothelial carcinoma and correlate its expression with the pathological stage, recurrence and other clinicopathological parameters. A retrospective study was undertaken on paraffin blocks of 55consecutiveurothelial carcinoma specimens in 28 months received in Sri Ramachandra Medical College, Chennai, India. Blocks with the sections containing the tumor and adjacent normal epithelium were chosen for the immunohistochemical (IHC) study of FGFR3. IHC expression of FGFR3 in high grade (HG) invasive urothelial carcinoma was positive in 18% cases, 66.7% of HG non-invasive urothelial and 82.6% of low grade (LG) non-invasive urothelial carcinomas. The FGFR3 expression was presented in 78.1% of non-invasive carcinoma. In case of invasive urothelial carcinoma, the FGFR3 positivity was observed in 18.2% of tumors (P<0.05).FGFR3 expression in LG tumors was positive in 82.6 % of the cases whereas 32.3% of HG cases were positive for FGFR3 (P<0.05).FGFR3 was expressed in 14.3 % of HG invasive tumors which recurred. HG non-invasive tumors were positive for FGFR3 in 80% of the cases. LG non-invasive tumors were positive for FGFR3 in 72.7% of cases (P<0.05). The expression of FGFR3 is higher in low grade, non-invasive tumors and recurrent non-invasive tumors. The targeted therapy for FGFR3 may be used as one of the modes of treatment for urothelial carcinoma. It can also be used as a marker to determine the grade in difficult cases and the risk of recurrence.


Ultrasound Elastography in the Differentiation of Simple Cyst and Type I Hydatid Cyst of the Liver.
Hydatid cyst (HC) is a parasitic disease that is endemic particularly to the sheep-breeding regions of the world, our country included. Given their propensity to materialize most commonly in the liver, our study evaluates the value of ultrasound elastography in the differential diagnosis of simple cyst and type I HCs of the liver.The study involved a total of 73 cysts (22 simple cysts, 51 type I HCs) that were removed using the puncture aspiration injection reaspiration technique between 2016 and 2018. All measurements were made using a Siemens ACUSON S2000 (Siemens Healthcare, Erlangen, Germany) device with a 4-MHZ 4C1 convex probe, an acoustic radiation force impulse elastography procedure, and a Virtual Touch IQ option. The difference between the mean shearwave elastography (SWE) values of both groups was analyzed with an independent t test.Of the 70 patients involved in the study, 29 were female and 41 were male, with a mean ± SD age of 38.85 ± 17.62 years (range, 5-82 years). Upon the examination of the 22 simple cysts and the 51 HCs, the mean ± SD SWE values were found to be 2.6 ± 0.96 (0.96-4.25) and 2.8 ± 1.69 (0.66-4.84), respectively. No statistically significant difference was identified between the SWE values of type I HCs and simple cysts (P > 0.005).Although HCs and simple cysts had similar radiological appearances, and a relative difference was noted in the differentiation of the elastographic measurements, this difference was not statistically significant. Accordingly, more comprehensive and various studies are needed.


[Observations on malaria vectors in Mozambique. I. The status of Anopheles populations before the start of mosquito control].
The basic status parameters of populations of the main malaria vectors (Anopheles arabiensis and An. funestus) in the vicinity of the city of Maputo, Mozambique, were considered, such as mosquito density and its seasonal variation, female biting activity rate, degree of mosquito-man contact, degree of exophilia and endophagy, physiological age of females, duration of gonotrophic cycle, sporozoite index, vectorial capacity, entomological inoculation rate.


Six-minute walk test in managing and monitoring sarcoidosis patients.
To describe the value and limitations of using the 6-min test in assessing patients with sarcoidosis. Static lung function studies and chest roentgenogram do not correlate well with the symptoms of sarcoidosis patients. In particular, dyspnea is a common complaint of sarcoidosis patients, which may be due to multiple factors including lung function, muscle strength, cardiac disease, and fatigue as a result of the disease. The 6-min walk distance has been the focus of studies in other interstitial lung diseases. Its use and limitations in sarcoidosis are described. The 6-min walk distance can be a useful test in assessing sarcoidosis patients. Reduction of 6-min walk distance, however, can be due to multiple factors.


Possible activation of an intramyocardial inflammatory process ( Staphylococcus aureus)after treatment with infliximab in a boy with Crohn disease.
In an 11-year old boy with Crohn disease, long-term therapy with prednisolone was decided to be augmented by infliximab, a monoclonal antibody to tumour necrosis factor alpha. The patient, who was in a stable clinical condition with low signs of inflammation at that time, deteriorated 3 days after the first dose of 200 mg infliximab with fever, nausea, myalgia and signs of cardiac failure. Echocardiography demonstrated destruction of the aortic valve with third grade insufficiency. In the blood culture, a susceptible strain of Staphylococcus aureus was isolated. Antibiotic therapy resulted in rapid improvement, but the aortic valve had to be replaced by a homograft due to massive insufficiency. At surgery, there were no signs of endocarditic vegetations, the aortic ring and the right coronary aortic cusp had been destroyed by a massive intramyocardial abscess, leading from close beneath the aortic ring in the direction of the right atrium. The size of the process suggested chronic infection or reinfection after several weeks. As clinical and laboratory signs as well as echocardiographic changes pointed to a dramatic flare-up shortly after the administration of infliximab, we suggest that this chronic inflammatory process was activated by infliximab. when using infliximab, special awareness of potential risks is necessary in patients with chronic infections or in a state of immunodeficiency.


Biorelevant in vitro Tools and in silico Modeling to Assess pH-Dependent Drug-drug Interactions for Salts of Weak Acids: Case Example Potassium Raltegravir.
Early assessment of pH-dependent drug-drug-interactions (DDIs) for salts of poorly soluble weakly acidic compounds offers various advantages for patient safety, the pharmaceutical industry, and regulatory bodies. Biorelevant media and tests reflecting physiological changes during acid-reducing agent (ARA) co-administration can be used to explore and predict the extent of the pH effect during therapy with ARAs. Solubility, one-stage and two-stage dissolution of tablets containing potassium raltegravir, the marketed salt form of this poorly soluble, weakly acidic drug, was investigated using biorelevant media specially designed to reflect administration without and during ARA co-therapy. The dissolution data were then converted into parameters suitable for input into an in silico model (Simcyp™) and the simulated plasma profiles were compared with available pharmacokinetic (PK) data from the literature. Dissolution of the potassium raltegravir formulation in media reflecting ARA co-administration, and thus elevated gastric pH, was faster and more complete than in experiments reflecting the low gastric pH observed in the absence of ARA co-administration. Simulations using data from dissolution experiments with ARA media appropriately bracketed the in vivo data for ARA co-administration in healthy volunteers. Dissolution data from in vitro experiments in biorelevant media reflecting physiological changes due to ARA co-administration provide valuable information about potassium raltegravir's behavior during concomitant ARA therapy. The approach may also be suitable for salts forms of other poorly soluble, weakly acidic drugs.


Pulmonary arterial hypertension induced by distention of the main pulmonary artery in conscious newborn, young, and adult sheep.
Distention of the main pulmonary artery by balloon inflation in sheep results in presumably reflex elevation of pulmonary arterial pressure and resistance distal to the balloon. This response to main pulmonary artery distention is significantly greater in newborn lambs than in older lambs or adult sheep. In several of the newborn lambs, pulmonary artery pressure was raised to suprasystemic levels. Further, in some of the newborn animals, these increases in pulmonary artery pressure and resistance were sustained after deflation of teh balloon for periods up to 2 hr. The functional significance of this pulmonary hypertension reflex was not elucidated. However, the data strongly suggest that this reflex may contribute to the maintenance of high pulmonary vascular resistance during fetal and early neonatal life.


[Systemic lupus erythematosus].
Systemic lupus erythematosus (SLE) is the classical systemic autoimmune disease. Its prevalence is slightly below 1:1,000 in women and 10-fold lower in men. Typically, the disease manifests in women of childbearing age. While severe untreated SLE used to be a fatal disease, prognosis has improved stepwise with corticosteroids, cyclophosphamide and novel therapies. Deaths directly related to SLE are uncommon nowadays but infections, thromboses and accelerated atherosclerosis cause significant problems. The current review presents the state of the art in managing SLE patients.