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Unanticipated pathogenic risk and emerging transmittable diseases can result from interspecies exchanges of viruses among animals and humans. The emergence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing coronavirus disease-19 (COVID-19) pandemic has recently exemplified this mechanism. Cough, fever, fatigue, headache, sputum production, hemoptysis, dyspnea, diarrhea, and gastrointestinal disorders are the characteristic features of the disease. The most prevalent and serious manifestation of the infection tends to be pneumonia. The new strains of SARS-CoV-2 with more infectivity have been emerging at regular intervals. There is currently no World Health Organization-approved particular drug for COVID-19. Besides, developing novel antivirals would take much time. Thus, repurposing the application of natural products can provide alternatives and can facilitate medication against COVID-19 as well as can slow down the aggressive progression of the disease before the arrival of approved drugs. Probiotics have long been known for their positive effects on the gut microbiome and impact on immune responses. Particularly, their involvement against viral diseases, especially those of the upper and lower respiratory tract, is of current interest for their prospective application against COVID-19. In this review, we comprehensively address the mode of action of probiotics and their possible intervention against coronavirus diseases correlating with their efficacy against viral diseases. In this regard, we explored recently published relevant research and review articles in MEDLINE/PubMed related to COVID-19 and the effects of probiotics on viral infections., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Tzu Chi Medical Journal.)

Cardiovascular disease including stroke is a major complication that tremendously increases the morbidity and mortality in patients with diabetes mellitus (DM). DM poses about four times higher risk for stroke. Cardiometabolic risk factors including obesity, hypertension, and dyslipidaemia often co-exist in patients with DM that add on to stroke risk. Because of the strong association between DM and other stroke risk factors, physicians and diabetologists managing patients should have thorough understanding of these risk factors and management. This review is an evidence-based approach to the epidemiological aspects, pathophysiology, diagnostic work up and management algorithms for patients with diabetes and stroke., Competing Interests: Conflict-of-interest statement: None.

Progressive neurological signs and symptoms, in immunocompromised individuals, could be due to progressive multifocal leukoencephalopathy (PML). We report the case of a patient who present a stroke unit with symptoms that were consistent initially with a posterior circulation stroke. Prior chemotherapy with Rituximab, for a lymphoma, had predisposed the patient to infection with the JC virus. Physicians need to be aware of the condition, and patients need to aware of these risks of chemotherapy., (© The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

G-protein-coupled receptor (GPCR) kinases (GRKs) bind to and phosphorylate GPCRs, initiating the process of GPCR desensitization and internalization. GRK4 is implicated in the regulation of blood pressure, and three GRK4 polymorphisms (R65L, A142V, and A486V) are associated with hypertension. Here, we describe the 2.6 Å structure of human GRK4α A486V crystallized in the presence of 5'-adenylyl β,γ-imidodiphosphate. The structure of GRK4α is similar to other GRKs, although slight differences exist within the RGS homology (RH) bundle subdomain, substrate-binding site, and kinase C-tail. The RH bundle subdomain and kinase C-terminal lobe form a strikingly acidic surface, whereas the kinase N-terminal lobe and RH terminal subdomain surfaces are much more basic. In this respect, GRK4α is more similar to GRK2 than GRK6. A fully ordered kinase C-tail reveals interactions linking the C-tail with important determinants of kinase activity, including the αB helix, αD helix, and the P-loop. Autophosphorylation of wild-type GRK4α is required for full kinase activity, as indicated by a lag in phosphorylation of a peptide from the dopamine D1 receptor without ATP preincubation. In contrast, this lag is not observed in GRK4α A486V. Phosphopeptide mapping by mass spectrometry indicates an increased rate of autophosphorylation of a number of residues in GRK4α A486V relative to wild-type GRK4α, including Ser-485 in the kinase C-tail., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Present study attempted to assess the level of microbiological contamination in oral herbal medicines, frequently used for medications, through conventional cultural and biochemical tests along with the antibiogram of the isolates. Moreover, the anti-bacterial potential of the herbal medicines was also aimed to be checked by the agar well diffusion method and minimum inhibitory concentration (MIC) assay. Out of 10 categories of liquid oral herbal medicine samples (n = 50) studied, all were found to be contaminated with bacteria (10(3)-10(5) cfu/mL), specifically with Staphylococcus spp. in 8 samples; while 2 samples harbored Klebsiella spp. Fungal presence was observed only in one sample. Study of antibiogram revealed Klebsiella spp. to be strongly resistant against penicillin G and erythromycin, whereas S. aureus possessed 80% sensitivity. The in vitro anti-bacterial activity was observed in 7 samples. Of them, one sample was found to exhibit the activity against almost all the test bacteria and another was found effective against 5 out of 8 test bacteria. Five samples showed the activity within a minor range while 3 samples were devoid of such trait. Samples 2 and 4 were found to stall the bacterial growth below 10 mg/mL of concentration in MIC test. Overall, the prevalence of specific pathogens was not so significant in the samples studied as well as only one drug-resistant isolate was identified. Besides, the anti-bacterial trait of 5 samples indicated that most of herbal medicines might be considered effective for medication.

The principal obstacles in the treatment of tuberculosis (TB) are delayed and inaccurate diagnosis which often leads to the onset of the drug resistant TB cases. To avail the appropriate treatment of the patients and to hinder the transmission of drug-resistant TB, accurate and rapid detection of resistant isolates is critical. Present study was designed to demonstrate the efficacy of molecular techniques inclusive of line probe assay (LPA) and GeneXpert MTB/RIF methods for the detection of multi-drug resistant (MDR) TB. Sputum samples from 300 different categories of treated and new TB cases were tested for the detection of possible mutation in the resistance specific genes (rpoB, inhA and katG) through Genotype MTBDRplus assay or LPA and GeneXpert MTB/RIF tests. Culture based conventional drug susceptibility test (DST) was also carried out to measure the efficacy of the molecular methods employed. Among 300 samples, 191 (63.7%) and 193 (64.3%) cases were found to be resistant against rifampicin in LPA and GeneXpert methods, respectively; while 189 (63%) cases of rifampicin resistance were detected by conventional DST methods. On the other hand, 196 (65.3%) and 191 (63.7%) isolates showed isoniazid resistance as detected by LPA and conventional drug susceptibility test (DST), respectively. Among the drug resistant isolates (collectively 198 in LPA and 193 in conventional DST), 189 (95.6%) and 187 (96.9%) were considered to be MDR as examined by LPA and conventional DST, respectively. Category-II and -IV patients encountered higher frequency of drug resistance compared to those from category-I and new cases. Considering the higher sensitivity, specificity and accuracy along with the required time to results significantly shorter, our study supports the adoption of LPA and GeneXpert assay as efficient tools in detecting drug resistant TB in Bangladesh.

Plants have long been used as herbal medicines in many countries. However, microbial contamination of these medicines may affect human health. Present study was performed to assess the pathogenic proliferation in the locally available commercial herbal oral medicines. The pathogenic load was compared with the microbiological standard given by the British Pharmacopoeia. Out of 85 oral liquid samples, 2 were found to be highly contaminated with a total aerobic bacterial load of 1.24 x 10(5) cfu/ml, 10 samples were contaminated with fungi (1.2 x 10(4)-6.3 x 10(4) cfu/ml). Tests for specific pathogens were carried out. One sample showed contamination by coliforms but none of the samples were contaminated by Salmonella spp. and Shigella spp. Among 40 semisolid samples, one showed to be contaminated with bacteria (1.93 x 10(5) cfu/g) and 5 samples consisted of fungal load ranging between 1.5 x 10(4)-2.2 x 10(4) cfu/g. The presence of bacteria and fungi in these samples thus suggest the fact that aseptic handling is necessary during processing of oral herbal medicines.

Objective: Tuberculosis (TB) caused by Mycobacterium tuberculosis has been identified as a re-emerging infectious disease with public health importance globally. Exploitation of new laboratory techniques for precise identification of mycobacteria in clinical specimens is of great importance to improve the diagnosis as part of the global TB control efforts., Methods: The current study was conducted for the evaluation of BACTEC MGIT 960 method in comparison with Lowenstein-Jensen (LJ) culture and light emitting diode (LED) fluorescence microscopy for isolation of mycobacteria among TB suspects from Bangladesh. A total of 421 specimens were tested with these methods., Results: Among the tested samples, 3.6% (n=15) were LED fluorescence microscopy positive; while 18 (4.2%) and 45 (10.6%) were recovered from LJ and MGIT 960 culture. The relative positivity found through MGIT 960 system were 60% and 66.7% higher than that of LJ culture and LED fluorescence microscopy, respectively. Recovery rate of Mycobacterium tuberculosis complex ([MTC], 21 by MGIT and 16 by LJ culture) and non-tubercular mycobacteria ([NTM], 24 by MGIT and 2 by LJ culture) by MGIT 960 was 24% and 96% greater, respectively than LJ culture. Moreover, MGIT 960 was found to be highly sensitive (100%), specific (93.3%), accurate (93.6%) and a more rapid method in detecting mycobacteria when compared with LJ culture., Conclusion: Extended recovery of NTM and MTC through MGIT 960 urged frequent application of this method to detect mycobacteria more effectively and rapidly., (Copyright © 2013 Asian-African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.)

The present study was an attempt to establish a suitable method for the effective diagnosis of extra-pulmonary tuberculosis in Bangladesh. In this regard, detection of Mycobacterium tuberculosis from 390 different extra-pulmonary specimens was performed by Bright-Field microscopy, light-emitting diode fluorescence microscopy and Lowenstein-Jensen culture methods, followed by an extensive comparison among these methods. M. tuberculosis was detected in 53 cases through the conventional Lowenstein-Jensen culture method; 49 cases were detected under Bright-Field microscope, whereas the light-emitting diode fluorescence microscopy detected 64 cases. Out of 53 culture-positive isolates, 12 were found to be multi-drug resistant. Light-emitting diode fluorescence microscopy was found to be more sensitive and effective than both the Bright-Field microscopy and the Lowenstein-Jensen culture methods. Incidentally, light-emitting diode fluorescence microscopy appeared imperative to detecting the multi-drug resistant tuberculosis., (Copyright © 2012 Asian-African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.)

The receptor tyrosine kinase c-Met is implicated in oncogenesis and is the target for several small molecule and biologic agents in clinical trials for the treatment of cancer. Binding of the hepatocyte growth factor to the cell surface receptor of c-Met induces activation via autophosphorylation of the kinase domain. Here we describe the structural basis of c-Met activation upon autophosphorylation and the selective small molecule inhibiton of autophosphorylated c-Met. MK-2461 is a potent c-Met inhibitor that is selective for the phosphorylated state of the enzyme. Compound 1 is an MK-2461 analog with a 20-fold enthalpy-driven preference for the autophosphorylated over unphosphorylated c-Met kinase domain. The crystal structure of the unbound kinase domain phosphorylated at Tyr-1234 and Tyr-1235 shows that activation loop phosphorylation leads to the ejection and disorder of the activation loop and rearrangement of helix αC and the G loop to generate a viable active site. Helix αC adopts a orientation different from that seen in activation loop mutants. The crystal structure of the complex formed by the autophosphorylated c-Met kinase domain and compound 1 reveals a significant induced fit conformational change of the G loop and ordering of the activation loop, explaining the selectivity of compound 1 for the autophosphorylated state. The results highlight the role of structural plasticity within the kinase domain in imparting the specificity of ligand binding and provide the framework for structure-guided design of activated c-Met inhibitors.

Phosphoinositide-dependent kinase 1 (PDK1) is a critical activator of multiple prosurvival and oncogenic protein kinases and has garnered considerable interest as an oncology drug target. Despite progress characterizing PDK1 as a therapeutic target, pharmacological support is lacking due to the prevalence of nonspecific inhibitors. Here, we benchmark literature and newly developed inhibitors and conduct parallel genetic and pharmacological queries into PDK1 function in cancer cells. Through kinase selectivity profiling and x-ray crystallographic studies, we identify an exquisitely selective PDK1 inhibitor (compound 7) that uniquely binds to the inactive kinase conformation (DFG-out). In contrast to compounds 1-5, which are classical ATP-competitive kinase inhibitors (DFG-in), compound 7 specifically inhibits cellular PDK1 T-loop phosphorylation (Ser-241), supporting its unique binding mode. Interfering with PDK1 activity has minimal antiproliferative effect on cells growing as plastic-attached monolayer cultures (i.e. standard tissue culture conditions) despite reduced phosphorylation of AKT, RSK, and S6RP. However, selective PDK1 inhibition impairs anchorage-independent growth, invasion, and cancer cell migration. Compound 7 inhibits colony formation in a subset of cancer cell lines (four of 10) and primary xenograft tumor lines (nine of 57). RNAi-mediated knockdown corroborates the PDK1 dependence in cell lines and identifies candidate biomarkers of drug response. In summary, our profiling studies define a uniquely selective and cell-potent PDK1 inhibitor, and the convergence of genetic and pharmacological phenotypes supports a role of PDK1 in tumorigenesis in the context of three-dimensional in vitro culture systems.

Introduction: Cerebral misery perfusion represents a failure of cerebral autoregulation. It is an important differential diagnosis in post-stroke patients presenting with collapses in the presence of haemodynamically significant cerebrovascular stenosis. This is particularly the case when cortical or internal watershed infarcts are present. When this condition occurs, further investigation should be done immediately., Case Presentation: A 50-year-old Caucasian man presented with a stroke secondary to complete occlusion of his left internal carotid artery. He went on to suffer recurrent seizures. Neuroimaging demonstrated numerous new watershed-territory cerebral infarcts. No source of arterial thromboembolism was demonstrable. Hypercapnic blood-oxygenation-level-dependent-contrast functional magnetic resonance imaging was used to measure his cerebrovascular reserve capacity. The findings were suggestive of cerebral misery perfusion., Conclusions: Blood-oxygenation-level-dependent-contrast functional magnetic resonance imaging allows the inference of cerebral misery perfusion. This procedure is cheaper and more readily available than positron emission tomography imaging, which is the current gold standard diagnostic test. The most evaluated treatment for cerebral misery perfusion is extracranial-intracranial bypass. Although previous trials of this have been unfavourable, the results of new studies involving extracranial-intracranial bypass in high-risk patients identified during cerebral perfusion imaging are awaited.Cerebral misery perfusion is an important and under-recognized condition in which emerging imaging and treatment modalities present the possibility of practical and evidence-based management in the near future. Physicians should thus be aware of this disorder and of recent developments in diagnostic tests that allow its detection.

p70 ribosomal S6 kinase (p70S6K) is a downstream effector of the mTOR signaling pathway involved in cell proliferation, cell growth, cell-cycle progression, and glucose homeostasis. Multiple phosphorylation events within the catalytic, autoinhibitory, and hydrophobic motif domains contribute to the regulation of p70S6K. We report the crystal structures of the kinase domain of p70S6K1 bound to staurosporine in both the unphosphorylated state and in the 3'-phosphoinositide-dependent kinase-1-phosphorylated state in which Thr-252 of the activation loop is phosphorylated. Unphosphorylated p70S6K1 exists in two crystal forms, one in which the p70S6K1 kinase domain exists as a monomer and the other as a domain-swapped dimer. The crystal structure of the partially activated kinase domain that is phosphorylated within the activation loop reveals conformational ordering of the activation loop that is consistent with a role in activation. The structures offer insights into the structural basis of the 3'-phosphoinositide-dependent kinase-1-induced activation of p70S6K and provide a platform for the rational structure-guided design of specific p70S6K inhibitors.

Prostasin (also called channel activating protease-1 (CAP1)) is an extracellular serine protease implicated in the modulation of fluid and electrolyte regulation via proteolysis of the epithelial sodium channel. Several disease states, particularly hypertension, can be affected by modulation of epithelial sodium channel activity. Thus, understanding the biochemical function of prostasin and developing specific agents to inhibit its activity could have a significant impact on a widespread disease. We report the expression of the prostasin proenzyme in Escherichia coli as insoluble inclusion bodies, refolding and activating via proteolytic removal of the N-terminal propeptide. The refolded and activated enzyme was shown to be pure and monomeric, with kinetic characteristics very similar to prostasin expressed from eukaryotic systems. Active prostasin was crystallized, and the structure was determined to 1.45 A resolution. These apoprotein crystals were soaked with nafamostat, allowing the structure of the inhibited acyl-enzyme intermediate structure to be determined to 2.0 A resolution. Comparison of the inhibited and apoprotein forms of prostasin suggest a mechanism of regulation through stabilization of a loop which interferes with substrate recognition.

The p90 ribosomal S6 kinases (RSKs) also known as MAPKAP-Ks are serine/threonine protein kinases that are activated by ERK or PDK1 and act as downstream effectors of mitogen-activated protein kinase (MAPK). RSK1, a member of the RSK family, contains two distinct kinase domains in a single polypeptide chain, the regulatory C-terminal kinase domain (CTKD) and the catalytic N-terminal kinase domain (NTKD). Autophosphorylation of the CTKD leads to activation of the NTKD that subsequently phosphorylates downstream substrates. Here we report the crystal structures of the unactivated RSK1 NTKD bound to different ligands at 2.0 A resolution. The activation loop and helix alphaC, key regulatory elements of kinase function, are disordered. The DFG motif of the inactive RSK1 adopts an "active-like" conformation. The beta-PO(4) group in the AMP-PCP complex adopts a unique conformation that may contribute to inactivity of the enzyme. Structures of RSK1 ligand complexes offer insights into the design of novel anticancer agents and into the regulation of the catalytic activity of RSKs.

Inclusion body myositis (IBM), a condition characterised by progressive muscle weakness and inclusion bodies visible on muscle biopsy, is the most common type of myopathy in patients over 50 years of age. However, it is not only under diagnosed but frequently misdiagnosed as polymyositis and hence wrongly treated with steroids. In the evaluation of progressive weakness in older Caucasian males, IBM should be an important diagnostic consideration. Treatment-resistant 'polymyositis' in patients over 50 years of age is often IBM. If there is no histological confirmation, the diagnostic criteria allow for a category of 'possible IBM'. Sometimes, the diagnosis is missed because of the slow progression of the disease and a lack of suspicion on the part of physicians. The following case report and literature review will explore many of these issues.

Cervicocerebral arterial dissections (CAD) are an important cause of strokes in younger patients accounting for nearly 20% of strokes in patients under the age of 45 years. Extracranial internal carotid artery dissections comprise 70%-80% and extracranial vertebral dissections account for about 15% of all CAD. Aetiopathogenesis of CAD is incompletely understood, though trauma, respiratory infections, and underlying arteriopathy are considered important. A typical picture of local pain, headache, and ipsilateral Horner's syndrome followed after several hours by cerebral or retinal ischaemia is rare. Doppler ultrasound, MRI/MRA, and CT angiography are useful non-invasive diagnostic tests. The treatment of extracranial CAD is mainly medical using anticoagulants or antiplatelet agents although controlled studies to show their effectiveness are lacking. The prognosis of extracranial CAD is generally much better than that of the intracranial CAD. Recurrences are rare in CAD.

Background: Iron deficiency anaemia (IDA) is a recognised feature of coeliac disease in adults and can be its only presentation., Objective: To determine the yield of routine distal duodenal biopsies in diagnosing coeliac disease in adult and elderly patients with IDA whose endoscopy revealed no upper gastrointestinal cause of iron deficiency., Study Design: Prospective study in a teaching hospital endoscopy unit., Method: Altogether 504 consecutive patients with IDA, aged 16-80 years, attending for endoscopy were included in this study. At least two distal duodenal biopsies were taken if endoscopy revealed no cause of iron deficiency., Result: In nine (1.8%) patients duodenal biopsies revealed typical histological features of coeliac disease. Of these, five patients were above 65 years old., Conclusion: In adult and elderly patients undergoing endoscopy for IDA, the endoscopist should take distal duodenal biopsies to exclude coeliac disease if no upper gastrointestinal cause of anaemia is found. Coeliac disease is not an uncommon cause of IDA in patients >65 years of age and a history of chronic diarrhoea increases diagnostic yield in this age group.

Background: Unsedated oesophagogastroduodenoscopy (OGD) is considered by most endoscopists to be a quick, safe, and well tolerated procedure. Older patients are said to tolerate it better than younger patients. However, patients' perception of the discomfort for the unsedated OGD has not been well studied., Objective: This study was undertaken to compare (1) patients' perception of discomfort with the endoscopist's perception of patients' discomfort for the unsedated OGD, (2) tolerability between older (> or =75 years) and younger (<75 years) patients., Design and Subjects: A total of 130 consecutive patients attending a day case endoscopy unit were recruited for the study. The patients and endoscopist recorded their assessment using a visual analogue scale (VAS). The results were analysed using non-parametric tests. Thirty patients were excluded from the study based on exclusion criteria. Sixty three (57%) patients were aged > or =75 years and 37 (43%) were <75 years., Results: A significant difference was noted between patients' perception of the discomfort and the endoscopist's assessment of the patient's discomfort as suggested by the overall higher VAS scores for patients (median 4.9, SD 2.6) than those of the endoscopist (median 2.2, SD 1.2), giving a significant difference in median VAS score of 3.4 (p<0.001). Older and younger patients had similar scores, with median (SD) VAS scores of 4.8 (2.5) for > or =75 years and 4.9 (2.8) for <75 years. The endoscopist's median scores for these two groups were 2.2 (1.2) and 2.1 (1.3), respectively., Conclusions: Patients' discomfort during OGD performed without sedation was greatly underestimated by the endoscopist. There was no significant difference in acceptability between old and the young patients.

Parkinson's disease is often recognised as a motor disease characterised by rest tremor, rigidity, bradykinesia, and postural disturbances. However, there are several non-motor aspects of the disease that are of at least equal importance in the management of patients with Parkinson's disease. They include depression, cognitive impairment, anxiety, and psychosis among others. It is important to recognise them, as they are common and they contribute significantly to patients' morbidity, quality of life, and institutionalisation to long term care homes. In addition to the disease duration and severity, other factors including drugs may contribute to their occurrence. Pathogenesis of these aspects is not fully understood, though there has been a significant increase in the knowledge in recent years. Management of these aspects involves a multidisciplinary approach.

Acute confusional states in the older patient often have a remediable cause. Every effort should be made to ascertain the cause so that appropriate treatment can be given and future episodes prevented. A patient is described who presented with recurrent episodes of acute psychosis after ingestion of Atropa belladonna (deadly nightshade).

Background: In a retrospective case-note and computer database analysis we assessed the outcome of very elderly patients (> or = 75 years old) with end-stage renal disease (ESRD) on renal replacement therapy (RRT)., Methods: Fifty-eight individuals aged 75 or over (group 1) commenced RRT between 1 January 1991 and 31 December 1995. Comparisons were made with other patients commencing RRT who were divided into two groups: group 2 (201 individuals 65-74 years old) and group 3 (379 patients <65 years old). All subjects were followed up until the point of assessment (30 June 1998), the time of death, or withdrawal from dialysis. Survival rates in the three groups were compared using Kaplan-Meier method. The number of hospital admissions, length of in-patient stay, and complications rate on RRT were assessed for group 1., Results: One-year survival rates in groups 1, 2 and 3 were 53.5, 72.6, and 90.6% respectively and the 5-year survival rates were 2.4, 18.8, and 61.4% respectively. The very elderly spent 20% of their time in hospital, 46% had two co-morbid factors at the outset, and 26% developed multiple complications while on RRT. Withdrawal from dialysis remained the most common cause of death in this group of individuals (38%), followed by cardiovascular causes (24%) and infections (22%)., Conclusion: Very elderly ESRD patients on RRT have a very poor outcome and, since they are the largest growing group of RRT patients, this has important implications for future health policies.