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Drugs with a long residence time at their target sites are often more efficacious in disease treatment. The mechanism, however, behind prolonged retention at the site of action is often difficult to understand for non-covalent agents. In this context, we focus on epichaperome agents, such as zelavespib and icapamespib, which maintain target binding for days despite rapid plasma clearance, minimal retention in non-diseased tissues, and rapid metabolism. They have shown significant therapeutic value in cancer and neurodegenerative diseases by disassembling epichaperomes, which are assemblies of tightly bound chaperones and other factors that serve as scaffolding platforms to pathologically rewire protein–protein interactions. To investigate their impact on epichaperomes in vivo, we conducted pharmacokinetic and target occupancy measurements for zelavespib and monitored epichaperome assemblies biochemically in a mouse model. Our findings provide evidence of the intricate mechanism through which zelavespib modulates epichaperomes in vivo. Initially, zelavespib becomes trapped when epichaperomes bound, a mechanism that results in epichaperome disassembly, with no change in the expression level of epichaperome constituents. We propose that the initial trapping stage of epichaperomes is a main contributing factor to the extended on-target residence time observed for this agent in clinical settings. Zelavespib's residence time in tumors seems to be dictated by target disassembly kinetics rather than by frank drug–target unbinding kinetics. The off-rate of zelavespib from epichaperomes is, therefore, much slower than anticipated from the recorded tumor pharmacokinetic profile or as determined in vitro using diluted systems. This research sheds light on the underlying processes that make epichaperome agents effective in the treatment of certain diseases. [ABSTRACT FROM AUTHOR]

Background: Microscopic colitis (MC) causes chronic diarrhea. It has two histologic subtypes: lymphocytic colitis (LC) and collagenous colitis (CC). Little is known about the natural progression of disease with time and with treatment. Objectives: We aimed to assess histological changes over time. Design: We designed a retrospective study including adults diagnosed with MC from January 1992 to January 2020 at Mayo Clinic. Methods: Pathology reports were reviewed until 31 October 2020. Histological assessments at least 8 weeks apart were considered as adequate follow-up. Histological change from one subtype to the other and resolution were tracked with univariate and multivariable Cox proportional hazards models. Results: Overall, 416 patients with a median age at diagnosis of 63.9 years with >1 histopathological assessment were identified. Histology at initial diagnosis was CC in 218 (52.4%) patients and LC in 198 (47.6%). No medications were associated with a histological change. However, histological resolution was more likely with the use of aspirin [hazard ratio (HR): 2.10, 95% confidence interval (CI): 1.34–3.31, p = 0.001) and proton-pump inhibitors (PPIs; HR: 2.01, 95% CI: 1.34–3.02, p = 0.001). Histological resolution was more likely with budesonide treatment (HR: 1.86, 95% CI: 1.16–3.00, p = 0.010) and less likely with mesalamine (HR: 0.40, 95% CI: 0.19–0.83, p = 0.014), compared to medications such as prednisone, loperamide, and bismuth. Patients with CC were less likely to change their histology compared to patients with LC (HR: 0.24, 95% CI: 0.14–0.42, p < 0.001). There was no difference in histological resolution between the two subtypes (HR: 0.70, 95% CI: 0.47–1.05, p = 0.084). Conclusion: Patients with LC have a higher chance of changing their histology as compared to CC. However, histological resolution was associated with the use of PPIs and aspirin, and treatment with budesonide. [ABSTRACT FROM AUTHOR]

The increasingly appreciated prevalence of complicated stressor‐to‐phenotype associations in human disease requires a greater understanding of how specific stressors affect systems or interactome properties. Many currently untreatable diseases arise due to variations in, and through a combination of, multiple stressors of genetic, epigenetic, and environmental nature. Unfortunately, how such stressors lead to a specific disease phenotype or inflict a vulnerability to some cells and tissues but not others remains largely unknown and unsatisfactorily addressed. Analysis of cell‐ and tissue‐specific interactome networks may shed light on organization of biological systems and subsequently to disease vulnerabilities. However, deriving human interactomes across different cell and disease contexts remains a challenge. To this end, this opinion article links stressor‐induced protein interactome network perturbations to the formation of pathologic scaffolds termed epichaperomes, revealing a viable and reproducible experimental solution to obtaining rigorous context‐dependent interactomes. This article presents our views on how a specialized 'omics platform called epichaperomics may complement and enhance the currently available conventional approaches and aid the scientific community in defining, understanding, and ultimately controlling interactome networks of complex diseases such as Alzheimer's disease. Ultimately, this approach may aid the transition from a limited single‐alteration perspective in disease to a comprehensive network‐based mindset, which we posit will result in precision medicine paradigms for disease diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory condition resulting in the formation of fibrofatty plaques within the intimal layer of arterial walls. The identification of resident stem cells in the vascular wall has led to significant investigation into their contributions to health and disease, as well as their therapeutic potential. Of these, mesenchymal stem cells (MSCs) are the most widely studied in human clinical trials, which have demonstrated a modulatory role in vascular physiology and disease. This review highlights the most recent knowledge surrounding the cell biology of MSCs, including their origin, identification markers and differentiation potential. The limitations concerning the implementation of MSC therapy are considered and novel solutions to overcome these are proposed. Mesenchymal stem cells have been shown to have paracrine effects that affect the onset and progression of atherosclerotic disease. Notable protective effects include a reduction in serum lipids, plaque size and endothelial dysfunction, as well as an increase in plaque stability and overall anti-inflammatory immunomodulation. Created with BioRender.com. [ABSTRACT FROM AUTHOR]

Induction of posterior vitreous detachment (PVD) by pharmacologic vitreolysis has been largely attempted through the use of enzymatic reagents. Ocriplasmin has been the only FDA-approved clinical reagent so far. Several adverse effects of ocriplasmin have emerged, however, and the search for alternative PVD-inducing reagents continues. Since i) collagen forms an important structural component of the vitreous, and ii) strong vitreo-retinal adhesions exist between the cortical vitreous and the internal limiting membrane (ILM) of the retina, an effective PVD-inducing reagent would require both, vitreous liquefaction, and concurrent dehiscence of vitreoretinal adhesion, without being toxic to retinal cells. We designed a combination of two reagents to achieve these two objectives; a triple helix-destabilizing collagen binding domain (CBD), and a fusion of RGD (integrin-binding) tripeptide with CBD (RCBD) to facilitate separation of posterior cortical vitreous from retinal surface. Based on in vitro, ex-vivo, and in vivo experiments, we show that a combination of CBD and RCBD displays potential for safe pharmacologic vitreolysis. Our findings assume significance in light of the fact that synthetic RGD-containing peptides have already been used for inhibition of tumor cell invasion. Proteins such as variants of collagen binding domains could have extended therapeutic uses in the future. [ABSTRACT FROM AUTHOR]

The authors report a case of successful management of right side hemidystonia with gamma knife radiosurgery. A 24-year-old male with a history of birth asphyxia subsequently developed worsening right-sided torsional hemidystonia which failed to respond to the medical management. MRI of the brain was unremarkable. Stereotactic gamma knife radiosurgery (GKRS) was performed to create a lesion in the left posteroventral globus pallidum. The patient gradually improved over a course of 18 months without any complication. He obtained 61% improvement in dystonia rating scale. Radiosurgical pallidotomy is often viewed with suspicion and functional neurosurgeons show reluctance in preferring it to stereotactic radio frequency lesioning or stimulation surgery. The authors would like to highlight the chances of not only control, but also cure of the disease with this cost-effective treatment modality. [ABSTRACT FROM AUTHOR]

Lateral abdominal wall defects, while rare, present a more challenging problem than commonly encountered ventral defects due to the complexity of the anatomy, physiologic forces, and impact of muscle denervation. The lateral abdominal wall encompasses a large surface area ranging from the costal margin superiorly to the iliac crest inferiorly and from the linea semilunaris anteriorly to the paraspinous musculature posteriorly. The ratio of muscle to fascia/aponeurosis is much higher, which makes repair through muscle tissue versus fascia less secure. Furthermore, these defects are subject to asymmetric forces caused by the independent contraction of anterior and posterior muscle units, which lead to unbalanced strain and hernia progression. These features necessitate the use of wide underlay mesh load bearing repairs supported by the static pillars of the abdominal wall. Management can be further complicated when defects extend beyond the defined boundaries, requiring surgical repair to be adapted based on the border structures involved. Primary fascial coaptation may not be as easily accomplished, and therefore careful planning is important to ensure stable coverage of exposed mesh. [ABSTRACT FROM AUTHOR]

The recreational use of cannabis has sharply increased in recent years in parallel with its legalization and decriminalization in several countries. Commonly, the traditional cannabis has been replaced by potent synthetic cannabinoids and cannabimimetics in various forms. Despite overwhelming public perception of the safety of these substances, an increasing number of serious cardiovascular adverse events have been reported in temporal relation to recreational cannabis use. These have included sudden cardiac death, vascular (coronary, cerebral and peripheral) events, arrhythmias and stress cardiomyopathy among others. Many of the victims of these events are relatively young men with few if any cardiovascular risk factors. However, there are reasons to believe that older individuals and those with risk factors for or established cardiovascular disease are at even higher danger of such events following exposure to cannabis. The pathophysiological basis of these events is not fully understood and likely encompasses a complex interaction between the active ingredients (particularly the major cannabinoid, Δ9-tetrahydrocannabinol), and the endo-cannabinoid system, autonomic nervous system, as well as other receptor and non-receptor mediated pathways. Other complicating factors include opposing physiologic effects of other cannabinoids (predominantly cannabidiol), presence of regulatory proteins that act as metabolizing enzymes, binding molecules, or ligands, as well as functional polymorphisms of target receptors. Tolerance to the effects of cannabis may also develop on repeated exposures at least in part due to receptor downregulation or desensitization. Moreover, effects of cannabis may be enhanced or altered by concomitant use of other illicit drugs or medications used for treatment of established cardiovascular diseases. Regardless of these considerations, it is expected that the current cannabis epidemic would add significantly to the universal burden of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

With an estimated prevalence of 5.8 million in the USA and over 23 million people worldwide, heart failure (HF) is growing in epidemic proportions. Despite the use of guideline-directed medical therapies such as angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, angiotensin receptor blockers, and mineralocorticoid receptor antagonists for chronic systolic HF for almost two decades, HF remains a leading cause of morbidity, mortality, and health care expenditures. The Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial provided compelling evidence for the cardiovascular and mortality benefit of sacubitril/valsartan when compared to enalapril in patients with heart failure and reduced ejection fraction (HFrEF). Sacubitril/valsartan performed better than enalapril across various HFrEF patient characteristics and showed substantial benefit in patients with other common comorbidities. Following the trial, the US Food and Drug Administration approved this drug for the treatment of HF. Various international HF consensus guidelines endorse sacubitril/valsartan as a class I recommendation for the management of symptomatic HFrEF. Although this high-quality clinical study is the largest and the most globally represented trial in HFrEF patients, concerns have been raised regarding the generalizability of the trial results in real-world HF population. The gaps in US Food and Drug Administration labeling and guideline recommendations might lead to this medication being used in a larger population than it was studied in. In this review, we will discuss the current role of sacubitril/valsartan in the management of HF, concerns related to PARADIGM-HF and answers, shortcomings of this novel drug, effects on patient characteristics, real-world eligibility, and the role of ongoing and further investigations to clarify the profile of sacubitril/valsartan in the management of HF. [ABSTRACT FROM AUTHOR]

Tricuspid regurgitation (TR) presents as either primary valve pathology or secondary to pulmonary or left-sided heart disease. Severe TR portends a worse prognosis independent of age, right ventricular size and function, severe left ventricular dysfunction, and increased pulmonary arterial pressures. Surgical treatment for TR has mostly been limited to patients undergoing mitral valve repair since those at high surgical risk are not candidates for traditional TR surgery. For these patients, minimally invasive techniques could be of great benefit, yet these techniques have been slow to develop because of the various anatomic and physiological aspects of the tricuspid valve apparatus. Several promising new techniques are currently undergoing clinical investigation, including caval valve implantation, percutaneous tricuspid annuloplasty techniques (Trialign, TriCinch, Cardioband), edge-to-edge repair with the MitraClip system, the FORMA device, and the GATE tricuspid Atrioventricular Valved Stent. Further evaluation of their safety and long-term efficacy is warranted prior to commercial approval and widespread adoption. [ABSTRACT FROM AUTHOR]

Background and Aims: Caudal analgesia is a good, reliable, and easy method to provide intraoperative and postoperative analgesia for infra-umbilical surgeries in children. Many additives are being used in combination with local anesthetics in caudal block to prolong the postoperative analgesia (clonidine, midazolam, ketamine, fentanyl, and dexmedetomidine). The purpose of this study was to compare the intraoperative hemodynamics, postoperative analgesia, postoperative rescue analgesic requirement, postoperative sedation and side-effects of clonidine and midazolam used as adjuvants to bupivacaine for caudal analgesia. Material and Methods: Following approval from Institutional Ethical Research Committee, 75 American Society of Anesthesiologists I and II patients aged between 1 and 7 years undergoing various elective infra-umbilical surgical procedures were included in this study. The patients were randomly allocated into three groups of 25 patients each. Group B received 1 ml/kg 0.25% bupivacaine in normal saline, Group BC received 1 ml/kg 0.25% bupivacaine + 1 µg/kg clonidine in normal saline, and Group BM received 1ml/kg 0.25% bupivacaine + 30 µg/kg midazolam in normal saline. The various parameters studied were intraoperative hemodynamic changes, duration of postoperative analgesia, postoperative sedation, postoperative analgesic requirement, and incidence of side-effects. Results: All the groups were similar with respect to patient and block characteristics. The hemodynamic parameters before and after administering caudal analgesia were also comparable. The mean duration of analgesia was 724.80 ± 60.29 min in Group BC, 605.40 ± 82.37 min in Group BM and 295.00 ± 41.78 min in Group B. Thus, the duration of analgesia was significantly prolonged in Group BC compared to Groups BM and B. The FLACC pain score was higher in Group B at the end of 4th, 8th and 12th h compared with Group BC and Group BM. Furthermore at the end of 12th h, pain scores were significantly higher in Group BM compared to Group BC. Only 1 child in Group BC received three rescue medications compared to 15 (60%) children in Group B and 7 (28%) children in Group BM. None of the groups were treated for bradycardia or hypotension and no significant sedation was noted. Conclusion: This study showed that the addition of both clonidine (1 µg/kg) and midazolam (30 µg/kg) with bupivacaine administered caudally significantly increase the duration of postoperative analgesia with minimal side-effects in children. The use of clonidine as an additive to bupivacaine in caudal epidural is a superior choice to midazolam as it reduces the demand of postoperative rescue analgesics significantly. [ABSTRACT FROM AUTHOR]

Background: To evaluate results of a technique for treating neglected epiphyseal injuries of the distal radius with ulnar impaction.Materials and Methods: This retrospective study involved six cases (four males; two females), all of whom sustained the primary injury during childhood (range 9-12 years of age). All presented with wrist deformity and ulnar-sided wrist pain. They were managed with osteotomy of the distal radius, osteotomy and shortening of the ulna, harvesting the bone grafts, and distal radioulnar joint (DRUJ) reduction performed simultaneously through a dorsal midline approach. Mean follow-up was 30 months (range 24-36).Results: Deformity correction and pain relief was observed in all patients. Flexion arc increased from an average of 60° to 102.5°, supination from an average of 31.67° to 67.50°, and pronation from an average of 30.83° to 61.67°. The mean preoperative DASH score was 87.5, which improved to 18.72 postoperatively.Conclusion: Neglected epiphyseal injuries of the distal radius are difficult to manage and many variations are described for handing each of the associated problems. Our technique provides an option for managing this injury with an easy surgical approach, single incision, and cost effectiveness. All the four components of the surgery, which include osteotomy of the distal radius, osteotomy of the ulna, harvesting the bone grafts, and DRUJ reduction were done through a single incision and in a single sitting. Level of evidence IV. [ABSTRACT FROM AUTHOR]

Background: Due to increase in road traffic and sports injuries, tears of anterior cruciate ligament (ACL) and the posterior cruciate ligament (PCL) of the knee are common. Magnetic resonance imaging (MRI) is emerging as an important tool of diagnosis and evaluation of these injuries. Methods: We carried out a prospective study on role of MRI on ten patients who had undergone ACL or PCL repair over a period of six months. In this report we present three illustrative cases to capture the spectrum of findings in our series to underline the role of MRI in management of such injuries and discuss the modalities of the procedure. Results: In our series, as demonstrated by the cases, MRI had an important role in diagnosis and evaluation of injuries to the cruciate ligaments. Conclusion: MRI can play an important role, particularly in tertiary centres, in diagnosis and evaluation of reconstructed ACL and PCL ligaments of the knee joint. [ABSTRACT FROM AUTHOR]

Introduction: Intertrochanteric fractures are common in elderly population and pose a significant financial burden to the society. Anatomically contoured proximal femur locking compression plate (PFLCP) is the latest addition in the surgeons' armamentarium to deal with these fractures. It creates an angular stable construct, which will theoretically lessen the risk of failure by screw cut-out and varus collapse, the common mode of DHS failure. We compared DHS with PFLCP in AO type 31A1 and 31A2 intertrochanteric fractures. Materials and Methods: A randomized prospective study was carried out between June 2011 and June 2013. 26 cases each of DHS and PFLCP were included. Results: Functional and radiological outcome was similar in both groups. Conclusion: Both DHS and PFLCP are good choices for stable intertrochanteric fractures, and both lead to excellent functional outcomes, but non-union might be more common with PFLCP. [ABSTRACT FROM AUTHOR]

Purpose: To compare two commonly used methods of temporary hemiepiphysiodesis (staples and figure of eight plate) in the management of coronal plane deformities of the knee in skeletally immature children. Methods: This prospective study was conducted between November 2012 and November 2015. A total of 40 patients with 67 affected knee joints, having at least 1 year of skeletal growth remaining, were included in the study. Angular correction was measured by recording the mechanical lateral distal femoral angle (mLDFA), mechanical medial proximal tibial angle (mMPTA), and anatomical tibio-femoral angle (TFA) (for the overall alignment of lower limbs). Implant removal was done after 5° of overcorrection was achieved. The rate of correction (° per month) and complications related to each technique were recorded. Results: The most common diagnosis was idiopathic genu valgum. The overall rate of correction (TFA) was 1.2° for staples and 1.4° for eight plate ( p = 0.70, not statistically significant). The correction in mLDFA was statistically better in the eight plate group, whereas an opposite trend was recorded in mMPTA. Implant-related complications were present in two cases of the staples group. Conclusion: Although the overall correction rate was similar in both groups, implant-related complications were lower with figure of eight plate. In idiopathic genu valgum (the most common diagnosis), the correction was statistically better in the eight plate group. We recommend figure of eight plate over staples in managing these deformities. [ABSTRACT FROM AUTHOR]

Aim: Platelet function is intricately linked to the pathophysiology of critical Illness, and some studies have shown that antiplatelet therapy (APT) may decrease mortality and incidence of acute respiratory distress syndrome (ARDS) in these patients. Our objective was to understand the efficacy of APT by conducting a meta-analysis.Materials and Methods: We conducted a meta-analysis using PubMed, Central, Embase, The Cochrane Central Register, the ClinicalTrials.gov Website, and Google Scholar. Studies were included if they investigated critically ill patients receiving antiplatelet therapy and mentioned the outcomes being studied (mortality, duration of hospitalization, ARDS, and need for mechanical ventilation).Results: We found that there was a significant reduction in all-cause mortality in patients on APT compared to control (odds ratio [OR]: 0.83; 95% confidence interval [CI]: 0.70-0.97). Both the incidence of acute lung injury/ARDS (OR: 0.67; 95% CI: 0.57-0.78) and need for mechanical ventilation (OR: 0.74; 95% CI: 0.60-0.91) were lower in the antiplatelet group. No significant difference in duration of hospitalization was observed between the two groups (standardized mean difference: -0.02; 95% CI: -0.11-0.07).Conclusion: Our meta-analysis suggests that critically ill patients who are on APT have an improved survival, decreased incidence of ARDS, and decreased need for mechanical ventilation. [ABSTRACT FROM AUTHOR]

Study Design: Retrospective study. Purpose: The aim of this study was to analyze various diagnostic tools, including GeneXpert, for the management of tuberculosis of the spine. Overview of Literature: Traditional diagnostic methods of microscopy, histology, and culture have low sensitivity and specificity for the management of tuberculosis of the spine. Methods: Of the 262 treated cases of spinal tuberculosis, data on 1 year follow-up was available for 217 cases. Of these, only 145 cases with a confirmed diagnosis were selected for retrospective analysis. Results: In 145 of the 217 patients (66.80%), diagnosis was confirmed on the basis of a culture. Of the 145 patients with a confirmed diagnosis, 98 (66.20%) patients were diagnosed on the basis of clinical presentation, whereas 123 (84.8%) exhibited a typical magnetic resonance imaging (MRI) picture. In 99 surgically treated patients, the diagnosis was confirmed on the basis of an intraoperative tissue biopsy. Among the 46 patients treated conservatively, 35 underwent a transpedicular biopsy, 4 patients underwent computed tomography-guided biopsy, 6 patients were diagnosed on the basis of material obtained from a cold abscess, and 1 patient underwent an open biopsy. The sensitivity of the culture for the detection of Mycobacterium tuberculosis was 66.80% (145/217) in our patients. Among the cases in which GeneXpert was used, the sensitivity for the detection of Mycobacterium tuberculosis was 93.4% (43/46). Moreover, the sensitivity of GeneXpert to detect rifampicin resistance was 100% (7/7) in our study. Conclusions: Majority of the patients with tuberculosis of the spine can be diagnosed on the basis of a typical radiological presentation via MRI. In our study, 84.8% cases exhibited typical MRI findings. For patients presenting with atypical MRI features, a rapid and accurate diagnosis is possible by combining GeneXpert with MRI. The combined use of MRI and GeneXpert is a rapid and highly sensitive tool to diagnose tuberculosis and rifampicin resistance in patients with tuberculosis of the spine. Furthermore, we achieved a 97.9% sensitivity for the detection of Mycobacterium tuberculosis and 100% sensitivity for the detection of rifampicin resistance in our study. [ABSTRACT FROM AUTHOR]

Tumefactive demyelinating (TD) lesions are extremely challenging lesions to diagnose during their histopathological examination and are often misdiagnosed as tumors. On the contrary, a glioblastoma multiforme is rarely misdiagnosed as a TD unless the two coexist. We present a case of a 60-year old man who was diagnosed as having tumefactive demyelination on a stereotactic biopsy. At autopsy, however, the lesion revealed a grade IV glioblastoma. The myelin loss along the periphery of the lesion was erroneously interpreted as TD during the histopathological examination. We have described the imaging, the biopsy, and the autopsy findings of this instructive case. It is pertinent to recognize its histology to prevent a misdiagnosis. [ABSTRACT FROM AUTHOR]

Introduction: The world of fashion is ever changing and this dynamics applies to dentistry. As dentistry and dental treatments have become necessary facet of a healthy life and therefore down the line fashion prospect of tooth jewellery are also getting fused into it. Aim: To assess the knowledge and practice of tooth jewellery among practicing dentists of Tricity, India. Materials and Methods: A descriptive, cross-sectional study was conducted among 310 dental practitioners in Tricity (Chandigarh, Mohali and Panchkula), India. A self-administered, close-ended questionnaire was distributed among all the dental practitioners in order to assess their knowledge and practice regarding tooth jewellery. Responses of the questionnaire was obtained on the dichotomous scale with Yes and No. Right answers were given a score of 2 whereas the wrong answers were given as score of 1. The data was analyzed using unpaired students t-test, one way ANOVA (analysis of variance) and multivariate logistic regression. Results: A significant difference was observed among the genders with males being three times more knowledgeable (OR=3.5, 95%CI: 0.8-2.8). It has been found that knowledge and practice scores of dental practitioners who spend more than 10 hours per day have two times more knowledge (OR= 2.3, 95%CI:0.08-1.1) than others. The dentists holding the masters degree were having three times more knowledge than the graduates' ones (OR= 2.3, 95%C.I:0.1-1.9). Conclusion: The present study concluded that dental practitioners had sufficient knowledge about tooth jewellery. Practice of tooth jewellery in the dental clinics was found to be adequate but it was also associated with some complications. To overcome this, it is advised that professional and government bodies should create strategies for enhancing and improving people's knowledge as well as make them aware of the pros and cons while using tooth jewellery which shall further enhance their smile. [ABSTRACT FROM AUTHOR]

Sepsis-associated encephalopathy (SAE) is characterized as brain dysfunction associated with sepsis. In this study we sought to investigate the effects of resveratrol in mice with SAE, as well as its effects in NLRP3 inflammasome and IL-1β, which were critical in the pathogenesis of SAE. SAE was induced in mice via cecal ligation and puncture (CLP), and resveratrol was administered at two doses after surgery. Spatial learning memory functions were evaluated by Morris water maze testing. Apoptosis in the hippocampus was quantified using TUNEL assay. Inflammation in the hippocampus was quantified by measuring the levels of microglial activation, NLRP3, and IL-1β. CLP mice treated with resveratrol demonstrated a better spatial memory during water maze training. The TUNEL assay demonstrated significantly attenuated rates of apoptosis, in resveratrol treated mice, while decreasing the number of iba-1 positive microglia in the hippocampus region. NLRP3 expression and IL-1β cleavage were well inhibited by resveratrol dose-dependently. The in vitro results showed that in the BV2 cell lines resveratrol prevents ATP induced NLRP3 activation and IL-1β cleavage, which were reversed by the sirtuin 1 inhibitor, nicotinamide. In conclusion, resveratrol improves the spatial memory in mice with SAE and inhibits the NLRP3/IL-1β axis in the microglia. [ABSTRACT FROM AUTHOR]

Tuberculosis never stops fascinating physicians. The burden of tuberculosis is a major cause of disability. While drugs are often blamed when patients develop new focal deficits on treatment, the deterioration in these patients can have a myriad of causes including the development of new tuberculomas. Recognizing the critically located tuberculomas as potential causes of vision loss is indispensable. Here, we report two patients with strategic tuberculomas leading to vision loss. In one patient, the cause of visual morbidity was compression of the optic pathways; in the other patient, cortical vision loss was noted due to strategic location of tuberculomas. [ABSTRACT FROM AUTHOR]

A 30-year-old male with bilateral acute visual loss presented with retinal edema in the posterior pole and peripapillary region with extensive retinal hemorrhages. Fluorescein angiography revealed delayed arterial filling in the right eye and absent arterial filling in the left eye, suggesting bilateral central retinal artery occlusion. Systemic evaluation revealed a history of chronic low-grade fever and generalized lymphadenopathy. HIV (ELISA) was positive, and other systemic comorbidities were ruled out. Cervical lymph node biopsy stained positive for acid-fast bacilli, with large areas of necrosis, palisaded by epithelioid cell granulomas, macrophages, and multinucleated giant cells, suggesting lymph node tuberculosis. Despite antiretroviral and antitubercular therapy, he developed optic atrophy at 4 weeks. [ABSTRACT FROM AUTHOR]

A young male presented with diminution of vision left eye, attributable to full-thickness macular hole, and submacular hemorrhage, following closed globe injury 2 weeks ago. The patient was managed successfully with 25-gauge vitrectomy, subretinal injection of tissue plasminogen activator and aspiration of liquefied blood through the macular hole, internal limiting membrane peeling, short-acting gas tamponade, and prone positioning. This resulted in good visual improvement, type 1 macular hole closure, and restoration of foveal architecture. The outcome and rationale of treatment in this unique scenario is discussed. [ABSTRACT FROM AUTHOR]

Background: Extra-articular proximal tibial fractures account for 5-11 % of all tibial shaft fractures. In recent years, closed reduction and minimally invasive plating and multidirectional locked intramedullary nailing have both become widely used treatment modalities for proximal and distal tibial metaphyseal fractures. This study was performed to compare plating and nailing options in proximal tibia extra-articular fractures. Materials and methods: This randomized prospective clinical study was conducted on 58 skeletally mature patients with a closed extra-articular fracture of the proximal tibia treated with minimally invasive proximal tibial plating (PTP) or intramedullary nailing (IMN) by trained surgeons at a tertiary trauma center. Results: Postoperative hospital stay ( p = 0.035), time to full weight-bearing, and union time ( p = 0.004) were significantly less in the IMN group than in the PTP group, but there was no clear advantage of either technique in terms of operative time ( p = 0.082), infection rate ( p = 0.738), range of motion of the knee ( p = 0.462), or degrees of malunion and nonunion. Conclusion: Both implants have shown promising results in extra-articular proximal tibial fractures, and provide rigid fixation that prevents secondary fracture collapse. Level of evidence: Level 2, randomized controlled trial. [ABSTRACT FROM AUTHOR]

Introduction: Optimizing methods for genital specimen collection to accurately characterize mucosal immune responses is a priority for the HIV prevention field. The menstrual cup (MC) has been proposed as an alternative to other methods including cervicovaginal lavage (CVL), but no study has yet formally compared these two methods. Methods: Forty HIV-infected, antiretroviral therapy-naïve women from the CAPRISA 002 acute HIV infection cohort study were randomized to have genital fluid collected using the MC with subsequent CVL, or by CVL alone. Qualitative data, which assessed levels of comfort and acceptability of MC using a 5-point Likert scale, was collected. Luminex multiplex assays were used to measure HIV-specific IgG against multiple gene products and 48 cytokines. Results: The majority (94%) of participants indicated that insertion, wearing and removal of the MC was comfortable. Nineteen MCs with 18 matching, subsequent CVLs and 20 randomized CVLs were available for analysis. Mucosal IgG responses against four HIV-antigens were detected in 99% of MCs compared to only 80% of randomized CVLs (p = 0.029). Higher specific antibody activity and total antibodies were observed in MCs compared to CVL (all p<0.001). In MCs, 42/48 (88%) cytokines were in the detectable range in all participants compared to 27/48 (54%) in CVL (p<0.001). Concentrations of 22/41 cytokines (53.7%) were significantly higher in fluid collected by MC. Both total IgG (r = 0.63; p = 0.005) and cytokine concentrations (r = 0.90; p<0.001) correlated strongly between MC and corresponding post-MC CVL. Conclusions: MC sampling improves the detection of mucosal cytokines and antibodies, particularly those present at low concentrations. MC may therefore represent an ideal tool to assess immunological parameters in genital secretions, without interfering with concurrent collection of conventional CVL samples. [ABSTRACT FROM AUTHOR]

Background-Regional variation in the incidence and outcomes of in-hospital cardiac arrest (IHCA) is not well studied and may have important health and policy implications. Methods and Results-We used the 2003 to 2011 Nationwide Inpatient Sample databases to identify patients ⩾18 years of age who underwent cardiopulmonary resuscitation (International Classification of Diseases, Ninth Edition, Clinical Modification procedure codes 99.60 and 99.63) for IHCA. Regional differences in IHCA incidence, survival to hospital discharge, and resource use (total hospital cost and discharge disposition among survivors) were analyzed. Of 838 465 patients with IHCA, 162 270 (19.4%) were in the Northeast, 159 581 (19.0%) were in the Midwest, 316 201 (37.7%) were in the South, and 200 413 (23.9%) were in the West. Overall IHCA incidence in the United States was 2.85 per 1000 hospital admissions. IHCA incidence was lowest in the Midwest and highest in the West (2.33 and 3.73 per 1000 hospital admissions, respectively). Compared with the Northeast, risk-adjusted survival to discharge was significantly higher in the Midwest (odds ratio, 1.33; 95% confidence interval, 1.31-1.36), South (odds ratio, 1.21; 95% confidence interval, 1.19-1.23), and West (odds ratio, 1.25; 95% confidence interval, 1.23-1.27). IHCA survival increased significantly from 2003 to 2011 in the United States and in all regions (all Ptrend<0.001). Total hospital cost was highest in the West, whereas discharge to skilled nursing facility and use of home health care among survivors was highest in the Northeast. Conclusions-We observed significant regional variation in IHCA incidence, survival, and resource use in the United States. This variation was explained only partially by differences in patient and hospital characteristics. Further studies are needed to identify other potential factors responsible for these regional differences to improve outcomes after IHCA. [ABSTRACT FROM AUTHOR]

Flavonoids and polyphenols are heterocyclic molecules that have been associated with beneficial effects on human health, such as reducing the risk of various diseases like cancer, diabetes, and cardiovascular and brain diseases. Protocatechuic acid (PCA) is a type of widely distributed naturally occurring phenolic acid. PCA has structural similarity with gallic acid, caffeic acid, vanillic acid, and syringic acid which are well-known antioxidant compounds. More than 500 plants contain PCA as active constituents imparting various pharmacological activity and these effects are due to their antioxidant activities, along with other possible mechanisms, such as anti-inflammatory properties and interaction with several enzymes. Over the past two decades, there have been an increasing number of publications on polyphenols and flavonoids, which demonstrate the importance of understanding the chemistry behind the antioxidant activities of both natural and synthesized compounds, considering the benefits from their dietary ingestion as well as pharmacological use. This work aims to review the pharmacological effects of PCA molecules in humans and the structural aspects that contribute to these effects. [ABSTRACT FROM AUTHOR]

We present the case of a 72-year-old female with a major depressive episode who developed hyponatremia associated with bupropion. In reviewing the literature, there are only a few case reports which pertain to this topic. The clinical symptoms of hyponatremia can be misinterpreted as a worsening of the primary psychiatric illness and can lead to potentially serious consequences if not fully evaluated. We recommend that clinicians should be well aware of this side effect and that sodium levels should be checked within the first 2 weeks after initiating treatment in patients, especially those with additional risk factors for hyponatremia, such as older age, female sex, diuretic use, low BMI, and unexplained mental status changes at any time during treatment with antidepressants. The risk for hyponatremia associated with mirtazapine appears to be low and its use can be helpful in patients who have developed hyponatremia induced by other antidepressants and who experienced symptoms of weight loss and insomnia. [ABSTRACT FROM AUTHOR]

Acute fibrinous and organizing pneumonia (AFOP) is a rare disease characterized by bilateral basilar infiltrates and histological findings of organizing pneumonia and intra‑alveolar fibrin in the form of “fibrin balls.” Here, we report a 43‑year‑old female with complaints of fever, dry cough, and shortness of breath with hypoxemia. High‑resolution computed tomography thorax revealed diffuse confluent consolidation in bilateral lung zones. Bronchoscopy and transbronchial biopsy revealed features of AFOP. With prednisolone treatment, there was an improvement in her condition. AFOP is a rare disease and should be taken into consideration and differential diagnosis of severe acute pneumonias with no significant comorbidities. [ABSTRACT FROM AUTHOR]

Background: The gene of tryptophan hydroxylase is widely recognized as a major candidate gene in many psychiatric disorders. However, no study has been done which investigates tryptophan hydroxylase 2 gene polymorphism in anxiety and depressive disorders in Kashmiri population (India). Objectives: To study tryptophan hydroxylase 2 (TPH2) C 11993 A gene polymorphism in anxiety and depressive disorders. Method: Sixty patients of depression disorder, 60 patients of anxiety disorder and 40 unrelated healthy volunteers (control) were studied in a case control design. Polymorphism was determined using polymerase chain reaction (PCR) and agarose gel electrophoresis after digestion with HAP II enzyme. Genotypes and allele frequencies were compared using Chi-square tests, Fischer's exact test, odds ratio, 95% confidence interval (C.I) and p-value of <0.05 was considered to be statistical significant. Results: The mean age ± SD of anxiety, depression and control group was 32.73±10.99, 32.20±10 and 29.75±10.12 respectively and the difference was found to be statistically non significant (p=0.349).The mean HAM-A (Hamilton rating scale for anxiety) score and HAM-D (Hamilton rating scale for depression) score was high in both groups (anxiety and depression) and found to be statistically significant (p=0.001).Depression group had AA genotype (55.2%) than control (37.5%) and was found to be statistically non significant (p=0.890).Comparison of allelic frequency revealed no association of A allele in anxiety group (76.67%) compared with control (75.5%) and was found to be statistically non significant (p= 0.866), OR 1.09 (0.56-2.11). Conclusion: TPH2C 11993 A gene was not found to be associated with major depressive disorder (MDD) and anxiety disorder in Kashmiri population. [ABSTRACT FROM AUTHOR]

Objective: Suicidal thoughts and behaviors (STBs) are prevalent among youth with psychotic disorders (PD) relative to the general population. Recent research now suggests that STBs may present during the prodromal phase of the disease, or the clinical high risk (CHR) state. While this knowledge is important for the development of suicide prevention strategies in adolescent and adult populations, it remains unclear whether risk for suicide extends to children with or at risk for psychosis. The current study is an extension of previous work assessing STBs in youth across the psychosis continuum. We examine STBs in 37 CHR and PD children ages 7–13 years old, and further explore the prodromal symptom correlates of STB severity among CHR children. Results: CHR and PD children endorsed STBs with a frequency and severity similar to what is observed in older CHR and PD populations. A number of children had never previously vocalized their suicidal plans or intent. Among CHR children, Social Anhedonia and Odd Behavior or Appearance were significantly correlated with STB severity. These findings underscore the importance of screening for STBs even in young children presenting with psychotic symptoms. [ABSTRACT FROM AUTHOR]

Background: Management of metastatic bone disease of the extremities (MBD-E) is challenging, and surgical directions pose significant implications for overall patient morbidity and mortality. Recent literature reviews on the surgical management of MBD-E present a paucity of high-level evidence and global inconsistencies in study design. In order to steer productive research, a scoping review was performed to map and assess critical knowledge gaps.Methods: The Arksey and O'Malley framework for scoping studies was followed. A comprehensive literature search identified a large body of literature pertaining to the surgical management of MBD-E. Study data and meta-data was extracted and presented using descriptive analytics and a thematic framework. Literature gaps were identified and analyzed.Results: Three hundred eighty five studies from 1969 to 2017 were included. Studies were categorized into 11 separate themes, with the majority (63%) falling into the "surgical fixation strategies" theme, followed by "complications" at 7% and "prognosis and survival" at 6.2%. Less than 3% of studies were categorized in "patient related outcomes" or "epidemiology" themes. 89% of studies were retrospective and only 6 studies were of level 1 or 2 evidence. We identified a temporal increase in publication by decade, and all studies published on interventional radiology techniques or economic analyses were published after 2007 or 2009, respectively. 64.9% of studies were published in Europe and 20.3% were published in North America. Average patient age was 62 (± 5.2 years), and breast was the most common primary tumour (28%), followed by lung (17%) and kidney (15%). In terms of surgical location, 75% of operations involved the femur, followed by the humerus at 22% and tibia at 3%.Conclusions: We present a descriptive overview of the current published literature on the surgical management of MBD-E. Critical knowledge gaps have been identified through the development of a thematic framework. Consolidation of literary gaps must involve bolstered efforts towards patient and family-engaged research initiatives and assessment of patient-related surgical outcomes. Multi-disciplinary engagement in developing prospective research will also help guide evidence-based personalized practice for these patients. By building on existing comprehensive patient databases and registries, knowledge on survival and prognostic parameters can be greatly improved. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the case of 65-year-old African-American female who was diagnosed with lung adenocarcinoma and has been subjected to pemetrexed and carboplatin medication.

Thrombopoietin (TPO), a hematopoietic growth factor produced predominantly by the liver, is essential for thrombopoiesis. Prevailing theory posits that circulating TPO levels are maintained through its clearance by platelets and megakaryocytes via surface c-Mpl receptor internalization. Interestingly, we found a two- to threefold decrease in circulating TPO in GPIbα-/- mice compared with wild-type (WT) controls, which was consistent in GPIbα-deficient human Bernard-Soulier syndrome (BSS) patients. We showed that lower TPO levels in GPIbα-deficient conditions were not due to increased TPO clearance by GPIbα-/- platelets but rather to decreased hepatic TPO mRNA transcription and production. We found that WT, but not GPIbα-/-, platelet transfusions rescued hepatic TPO mRNA and circulating TPO levels in GPIbα-/- mice. In vitro hepatocyte cocultures with platelets or GPIbα-coupled beads further confirm the disruption of platelet-mediated hepatic TPO generation in the absence of GPIbα. Treatment of GPIbα-/- platelets with neuraminidase caused significant desialylation; however, strikingly, desialylated GPIbα-/- platelets could not rescue impaired hepatic TPO production in vivo or in vitro, suggesting that GPIbα, independent of platelet desialylation, is a prerequisite for hepatic TPO generation. Additionally, impaired hepatic TPO production was recapitulated in interleukin-4/GPIbα--transgenic mice, as well as with antibodies targeting the extracellular portion of GPIbα, demonstrating that the N terminus of GPIbα is required for platelet-mediated hepatic TPO generation. These findings reveal a novel nonredundant regulatory role for platelets in hepatic TPO homeostasis, which improves our understanding of constitutive TPO regulation and has important implications in diseases related to GPIbα, such as BSS and auto- and alloimmune-mediated thrombocytopenias. [ABSTRACT FROM AUTHOR]