Anti-tumor necrosis factor treatment restores the gut barrier in Crohn's disease

OBJECTIVES: A primary defect of the tight junctions and, hence, increased intestinal epithelial permeability has been proposed as a basic pathogenic event in Crohn's disease. Challenge of the mucosal immune system by the commensal gut flora would then result in chronic inflammation. Alternatively, increased permeability could be the result of inflammation. Our aim was to study intestinal permeability in refractory Crohn's disease before and after treatment with monoclonal chimeric antibodies directed against tumor necrosis factor (TNF) to investigate whether the abnormal permeability persists after control of inflammation. MErHODS: Twenty-three patients with active Crohn's disease were evaluated before and 4 wk after a single infusion of 5 mg/kg infliximab. Intestinal permeability was studied by measurement of urinary excretion of 51Cr-EDTA after oral intake. RESULTS: The increased permeation of 51Cr-EDTA through the small intestine (1.63% interquartile range [IQR] 1.06-2.07) and the overall permeation (3.27% IQR 2.40-4.38) before therapy decreased significantly after infliximab infusion to values (1.04% IQR 0.74-1.54 and 2.42% IQR 2.03-2.80, respectively) in the range of those found in normal volunteers (1.12% IQR 0.85-1.58 and 2.28% IQR 1.88-2.86, respectively). CONCLUSION: Inhibiting the proinflammatory cytokine tumor necrosis factor dramatically reduces gut inflammation and largely restores the gut barrier in Crohn's disease. Our data confirm the central role of TNF in gut barrier modulation in inflammatory conditions in vivo.     

Recent developments and controversies in transcatheter aortic valve implantation

Interventional cardiology has been revolutionised by transcatheter aortic valve implantation (TAVI), which has become established as the benchmark treatment for severe aortic stenosis in patients at high risk for surgical aortic valve replacement (AVR). Increased procedural familiarity and progression in device technology has enabled improvements to be made in complication rates, which have led to a commensurate expansion in the use of TAVI; it is now a viable alternative to AVR in patients at intermediate surgical risk, and has been used in cohorts such as those with bicuspid aortic valves or pure, severe aortic regurgitation. Given the rapid expansion in the use of TAVI, including cohorts of younger patients with fewer co‐morbidities, attention must be paid to further reducing remaining complications, such as cardiac tamponade or stroke. To this end, novel techniques and devices have been devised and trialled, with varying levels of success. Furthermore, significant work has gone into refining the technique with exploration of alternative imaging modalities, as well as alternative access routes to provide greater options for patients with challenging vascular anatomy. Whilst significant progress has been made with TAVI, areas of uncertainty remain such as the management of concomitant coronary artery disease and the optimum post‐procedure antiplatelet regimen. As such, research in this field continues apace, and is likely to continue as use of TAVI becomes more widespread. This review provides a summary of the existing evidence, as well as an overview of recent developments and contentious issues in the field of TAVI.     

Electrophysiologic severity of carpal tunnel syndrome in diabetic patients of the Saudi population

Objectives:To study the frequency of multiple vascular risk factors and electrophysiological severity of carpal tunnel syndrome (CTS) in Saudi diabetic patients.Methods:This retrospective cross-sectional study was conducted in Neurology Department, King Fahd Hospital of University, Al-Khobar, Kingdom of Saudi Arabia from April 2017 to March 2018 and included 200 patients with CTS. Body parameters, such as blood pressure (BP), weight, height, and body mass index (BMI), along with laboratory and median nerve electrophysiological parameters, of diabetic and non-diabetic patients were compared, and a p-value<0.05 was considered significant.Results:Frequency of hypertension (HTN) and obesity was significantly higher in diabetic patients (p<0.05). Mean median nerve sensory amplitude (MNSA) was lower in diabetic patients (p<0.05).Non-recordable nerves, as well as bilateral and extremely severe CTS (p<0.05), were more frequently seen in diabetic patients. Age, BMI, systolic BP, low serum high density lipoprotein (HDL), high triglycerides, high fasting blood sugar, and high glycated hemoglobin (Hba1c) levels, known to affect the electrophysiological severity of CTS, had a statistically significant association with diabetes.Conclusion:Diabetes mellitus (DM) and obesity are the most commonly identified risk factors of CTS. Dyslipidemia, HTN and obesity are more frequently seen in diabetic patients with CTS. These concurrent risk factors are confounding the electrophysiological severity of CTS in these patients. Further larger-scale studies with the control of confounding factors are recommended.

Carpal tunnel syndrome (CTS) is known to have a frequent nerve entrapment syndrome and encompasses 45% of non-traumatic nerve lesions.1,2 Carpal tunnel syndrome can result in various problems, including pain and paresthesia in the median nerve distribution, swelling, and in severe cases weakness of the thumb and lateral 3 fingers.3 It affects the daily life activities, such as holding and gripping things by hand, brushing teeth, and driving.4 Carpal tunnel syndrome can be associated with any risk factor that causes pressure on the median nerve inthe wrist, including coexisting comorbidities and working conditions of the individuals.5 Some common conditions that can lead to CTS includes obesity, DM, oral contraceptives, smoking, corticosteroid use, pregnancy, hypothyroidism, rheumatoid arthritis, osteoarthritis, and wrist fracture.6The prevalence of CTS in diabetic patients is 14% without diabetic neuropathy and 30% with diabetic neuropathy.7 Literature has shown a high incidence of CTS in pre-diabetic states.8 Some researchers have also found a relationship between duration of diabetes, Hba1c, and micro vascular complications.9 Although type 2 diabetes is more frequently diagnosed among CTS patients, some studies had reported that the association between diabetes and CTS represents a confusion bias, most likely due to the strong relationship between obesity and type 2 diabetes.10 It has been shown that age, BMI, and other vascular risk factors, including metabolic syndrome, could affect the electrophysiological severity of CTS. Elevated low density lipoprotein (LDL) cholesterol and hyperglycemia were reported as independent risk factors for CTS in some studies.8,11,12 Similarly, obesity, elevated triglycerides, elevated LDL cholesterol and hypertension were shown to be strongly associated with CTS.13 In the study conducted by Balci et al,14 75% of the CTS patients were found to have metabolic syndrome, and the electrophysiological parameters (median nerve sensory onset latency, sensory conduction velocity, sensory amplitude, distal motor latency, motor conduction velocity, and motor amplitude) were worse in patients with metabolic syndrome. Gül et al,15 similarly showed that severity of CTS was even more severe in patients with metabolic syndrome than in those with diabetes.The aim of the present study was to study the frequency of multiple vascular risk factors, such as HTN, dyslipidemia and obesity in CTS patients, and to compare the electrophysiological severity of CTS in Saudi diabetic and non diabetic patients. This population is facing a high burden of multiple vascular risk factors, which are also affecting the severity of CTS.     

Antiinfectives targeting enzymes and the proton motive force

There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5–2 μg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance.There is a need for new antibiotics, due to the increase in drug resistance (1, 2). For example, some studies report that by 2050, absent major improvements in drug discovery and use, more individuals will die from drug-resistant bacterial infections than from cancer, resulting in a cumulative effect on global gross domestic product of as much as 100 trillion dollars (3, 4). To discover new drugs, new targets, leads, concepts, and implementations are needed (5, 6).Currently, one major cause of death from bacterial infections is tuberculosis (TB) (7), where very highly drug-resistant strains have been found (8). Therapy is lengthy, even with drug-sensitive strains, and requires combination therapies with four drugs. Two recent TB drugs/drug leads (9–11) are TMC207 [bedaquiline (1); Sirturo] and SQ109 (2) (Fig. 1). Bedaquiline (1) targets the Mycobacterium tuberculosis ATP synthase (9) whereas SQ109 (2) has been proposed to target MmpL3 (mycobacterial membrane protein large 3), a trehalose monomycolate transporter essential for cell wall biosynthesis (12). SQ109 (2) is a lipophilic base containing an adamantyl “headgroup” connected via an ethylene diamine “linker” to a geranyl (C₁₀) “side chain,” and in recent work (13), we synthesized a series of 11 analogs of SQ109 (2) finding that the ethanolamine (3) was more potent than was SQ109 (2) against M. tuberculosis H37Rv [0.063 vs. 0.25 μg/mL minimal inhibitory concentration (MIC)], and that at least one protonatable nitrogen in the linker was essential for activity. The latter observation suggested to us that SQ109 (2) and ethanolamine (3) might have activity as uncouplers, collapsing the proton motive force (PMF; ∆P) used to drive ATP synthesis, because we had observed similar uncoupling effects for lipophilic bases, US Food and Drug Administration (FDA)-approved drugs, in trypanosomatid parasites (14, 15). The PMF is given by Mitchell (16, 17): ∆P = ∆ψ − Z∆pH, where ∆ψ is the electrical or membrane potential component of ∆P, ∆pH is the transmembrane pH gradient, and Z is 2.303RT/F where R is the gas constant, T is temperature (in kelvins), and F is the Faraday constant.Open in a separate windowFig. 1.Structures of inhibitors/uncouplers and other compounds of interest. Common or previously used names are indicated.We found with SQ109 and its analogs that the most potent M. tuberculosis cell growth inhibitors investigated did indeed collapse pH gradients and ∆ψ, as also observed with the lipophilic bases amiodarone (4) (14) and dronedarone (5) (15), antiarrhythmia drugs, in trypanosomatid parasites (18), and SQ109 (2) also acts as an uncoupler in Trypanosoma cruzi (19). Amiodarone (4) and dronedarone (5) had little uncoupling activity against host cells. In related work, Li et al. (20) found that other TB drug leads, BM212 (6), THPP-2 (7), Ro 48-8071 (8), the urea AU1235 (9), and the indolecarboxamide 2418 (10), most of which had been proposed to target MmpL3, likewise had activity as uncouplers, collapsing pH gradients, and in some cases were active against the nonreplicative bacteria found under hypoxic conditions. Several of these compounds also have enzyme targets. For example, SQ109 (2), ethanolamine (3), and Ro 48-8071 (8) have been found (13, 20) to inhibit enzymes involved in menaquinone biosynthesis, particularly the prenyl transferase 1,4-dihydroxy-2-naphthoate octaprenyltransferase (MenA) and human oxidosqualene cyclase (OSC) (21), and bedaquiline (1) is a potent ATP synthase inhibitor, indicating the possibility of multitarget activity for such compounds. These results are of interest because they show that several recently discovered M. tuberculosis drug leads can act as uncouplers in addition to targeting one or more enzymes that are essential for bacterial cell growth, with membrane targeting being of particular interest because it might be expected to be less susceptible to the development of resistance than is purely enzyme targeting, and SQ109 (2) does indeed have a low frequency of resistance in M. tuberculosis (∼2.55 × 10⁻¹¹) (22). Targeting membrane lipids is also a reason for the low frequency of resistance found with, for example, amphotericin [which binds to ergosterol in fungi and protozoa (23)], as well as the recently discovered teixobactin, which binds to lipid II/III (24).In other work by Goldman (25), it has been pointed out that most of the new TB drug leads that have been discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼ 5.7) bases with membrane targets, which suggested to us the possibility that these drug leads might function by targeting the PMF, as well as membrane proteins. Although targeting the PMF might be expected to be purely mitotoxic, Stock et al. (26) have shown that compounds with logP > 6 have generally low mitotoxicity, which is due, they proposed, to low membrane permeability attributable to accumulation in lipophilic membranes.Perhaps the most well-known uncoupler is 2,4-dinitrophenol (DNP; 11). DNP functions as a protonophore, a proton-translocating molecule, and analogs such as niclosamide (12) and nitazoxanide (13) [active form, tizoxanide (14)] are used clinically: niclosamide (12) to treat tapeworm infections (27) and nitazoxanide (13) to treat infections due to Giardia lamblia (28) and Cryptosporidium parvum. Nitazoxanide (13) has also been in clinical trials for the treatment of Helicobacter pylori and Clostridium difficile infections. Interestingly, SQ109 (2) has similar activity against both organisms (29), and with H. pylori, SQ109 (2) once again has a very low (≈10⁻¹²) frequency of resistance (29). In addition, nitazoxanide (13) has been found to kill both replicating and nonreplicating M. tuberculosis (30–33), and Nathan and coworkers (30, 31) were unable to develop resistant colonies using up to 10¹² cfu, proposing a dual “PMF + unknown target” mechanism of action. Niclosamide (12) has been proposed as a lead for the treatment of type II diabetes (34), and it is also an inhibitor of breast cancer stem-like cells (35) and an inhibitor of Pseudomonas aeruginosa quorum sensing (36). There has also been very recent interest in the development of DNP analogs such as DNP methyl ether (37), for treating diabetes, and of controlled-release DNP formulations (38) as mild hepatic mitochondrial uncouplers for treating hypertriglyceridemia, insulin resistance, hepatic steatosis, and diabetes. Niclosamide (12) and tizoxanide (14) are both FDA-approved, and closantel (15) is an anthelmintic uncoupler in veterinary use, and all could provide leads for new and improved inhibitors that target other pathogens. There has also been considerable renewed interest (39) in the use of pyrazinoic acid (16), which functions, at least in part, as a protonophore uncoupler, for treating TB (39, 40), stimulating our interest in discovering new TB drug leads with uncoupler activity.In this work, we carried out three main types of investigation. First, we investigated the uncoupling effects of 21 compounds (primarily known drugs or drug leads) on uncoupling (∆pH/∆ψ collapse) in bacterial inverted membrane vesicles (IMVs) and in porcine mitochondria. Second, we investigated drug–membrane interactions using differential scanning calorimetry (DSC) and electron paramagnetic resonance (EPR) spectroscopy. Third, we used molecular dynamics (MD) structure-based in silico screening and structure-similarity searches to find prenyl synthase inhibitors with uncoupler activity, leading finally to a consideration of the future prospects for discovering new “enzyme + uncoupler” antiinfective drug leads.     

Online binary decision decoding using functional near-infrared spectroscopy for the development of brain–computer interface

In this paper, a functional near-infrared spectroscopy (fNIRS)-based online binary decision decoding framework is developed. Fourteen healthy subjects are asked to mentally make “yes” or “no” decisions in answers to the given questions. For obtaining “yes” decoding, the subjects are asked to perform a mental task that causes a cognitive load on the prefrontal cortex, while for making “no” decoding, they are asked to relax. Signals from the prefrontal cortex are collected using continuous-wave near-infrared spectroscopy. It is observed and verified, using the linear discriminant analysis (LDA) and the support vector machine (SVM) classifications, that the cortical hemodynamic responses for making a “yes” decision are distinguishable from those for making a “no” decision. Using mean values of the changes in the concentration of hemoglobin as features, binary decisions are classified into two classes, “yes” and “no,” with an average classification accuracy of 74.28 % using LDA and 82.14 % using SVM. These results demonstrate and suggest the feasibility of fNIRS for a brain–computer interface.     

Development of a Computerised Antithrombotic Risk Assessment Tool (CARAT) to optimise therapy in older persons with atrial fibrillation

Aim: To develop and evaluate a novel Computerised Antithrombotic Risk Assessment Tool (CARAT) to aid clinicians' decision making regarding the risk–benefit of antithrombotic therapy in older patients. Methods: CARAT was developed in an iterative process involving multidisciplinary feedback and computerisation of previously trialled algorithms. Hospital‐based clinicians then applied the tool to patient cases, to evaluate its usability. Results: Overall, 94% of clinicians (n= 27 yielding 216 responses) were satisfied with CARAT's format. Most (72%) clinician responses agreed with CARAT recommendations; over two‐thirds agreed with estimates of stroke and bleeding risk. However, geriatricians were 3.5 times more likely to disagree with CARAT recommendations than cardiologists, particularly in cases of high fall risk. Overall, 63% responded that CARAT was at least ‘somewhat useful’ for clinical practice; 22% indicating it was ‘very useful’. Conclusion: CARAT has potential as a useful decision‐support tool to assist clinicians in decision making regarding appropriate antithrombotic therapy in older patients.     

Duct-to-mucosa versus invagination pancreaticojejunostomy after pancreaticoduodenectomy: a meta-analysis

Background Postoperative pancreatic fistula remains one of the most common and troublesome complications following pancreaticoduodenectomy. No consensus exists regarding the optimal pancreaticojejunostomy reconstruction technique to reduce this complication. We aimed to perform a systematic review comparing two commonly used techniques of pancreaticojejunostomy reconstruction （duct-to-mucosa versus invagination）, by meta-analysis and assessment of evidence quality. Methods Databases searched including The Cochrane Library, Medline, PubMed, Embase, etc. Randomized controlled trials （RCTs） comparing duct-to-mucosa and invagination pancreaticojejunostomy were included. Outcomes of interest were pancreatic fistula rate, mortality, morbidity, reoperation and hospital stay. Pooled estimates were expressed as risk ratio （RR） or mean difference. Results From 321 identified abstracts, four RCTs （467 patients; duct-to-mucosa： 232; invagination： 235） were included. Pancreatic fistula rate （RR, 0.74; 95% confidence interval （C/）： 0.24-2.28; P=0.60）, mortality （RR, 1.18; 95% CI： 0.39- 3.54; P=0.77）, morbidity （RR, 0.91; 95% CI： 0.69-1.21; P=0.53）, reoperation （RR, 1.09; 95% CI： 0.54-2.22; P=-0.81） and hospital stay （mean difference, -1.78; 95% CI： -4.60-1.04; P=0.22） were similar between techniques. Conclusions Duct-to-mucosa and invagination pancreaticojejunostomy are comparable with regards to assessed parameters. High-quality, large-volume, multi-center RCTs with standard outcome definitions are required.     

Osteosarcoma metastatic to adrenal gland diagnosed by fine-needle aspiration

Osteosarcoma, a primary malignant tumor of the long bones, frequently metastasizes to the lungs. We report an unusual case of osteosarcoma metastatic to the right adrenal gland in a 37-yr-old male who presented 8 yr after remission with an adrenal mass. A preoperative diagnosis was made by fine-needle aspiration (FNA) biopsy. FNA biopsy revealed pleomorphic oval cells with prominent nucleoli, spindle cells, and giant tumor cells. Diagnostic osteoid was readily seen on smears and was also detected by polarization of cell-block section. Immunocytochemical stains revealed positivity of tumor cells for vimentin and osteonectin. Cytokeratin stains were negative. The cytologic diagnosis of metastatic Osteosarcoma was made, which was later confirmed upon resection of tumor by histology. Although the role of FNA in the diagnosis of primary bone tumors, including osteogenic sarcoma (OGS), remains controversial, this case, however, demonstrates the value of FNA biopsy combined with immunocytochemistry performed on the aspirated material in diagnosing osteosarcoma from an unusual location such as the adrenal gland.