Randomised controlled trial of tourniquet associated pain generated in lower limb after exsanguination by Esmarch bandage versus limb elevation.

BACKGROUND: Tourniquets are common adjuncts in the operating theatre but can be associated with post-operative pain. This study was designed to compare what effect pre-tourniquet Esmarch bandage exsanguination has on pain, compared to pre-tourniquet exsanguination by elevation alone. METHODS: 52 volunteers (104 lower limbs) were included in this study with each volunteer acting as their own matched control. The primary outcome was patient reported pain, measured in both legs simultaneously using area under curve. Secondary outcomes were pain score during inflation and deflation, cumulative pain score, duration of recovery and blood pressure during testing. RESULTS: Pain after Esmarch was superior to elevation as measured by area under pain curve (68.9 SD 26.1 vs 77.2 SD 27.3, p = 0.0010), independent of leg dominance. Cumulative pain scores demonstrated the same superiority after inflation (50.7 SD 17.1 vs 52.9 SD 17.0, p = 0.026) but not after deflation (p = 0.59). Blood pressure was not significantly different. Time to full recovery of the lower limb was the same for both groups-7.6 min (SD 2.1 min, p = 0.80). CONCLUSION: Previous studies describe a positive effect on pain when Esmarch bandage was used prior to tourniquet inflation for upper limb. Our findings suggest the same benefit from Esmarch when it was used on lower limbs-particularly during inflation of tourniquet. In addition to pain profiles, surgeon preference and patient factors need to be considered when deciding between elevation and Esmarch bandage.

Specific inhibition of NADPH oxidase 2 modifies chronic epilepsy.

Recent work by us and others has implicated NADPH oxidase (NOX) enzymes as main producers of reactive oxygen species (ROS) following a brain insult such as status epilepticus, contributing to neuronal damage and development of epilepsy. Although several NOX isoforms have been examined in the context of epilepsy, most attention has focused on NOX2. In this present study, we demonstrate the effect of gp91ds-tat, a specific competitive inhibitor of NOX2, in in vitro epileptiform activity model as well as in temporal lobe epilepsy (TLE) model in rats. We showed that in in vitro seizure model, gp91ds-tat modulated Ca2+ oscillation, prevented epileptiform activity-induced ROS generation, mitochondrial depolarization, and neuronal death. Administration of gp91ds-tat 1 h after kainic acid-induced status epilepticus significantly decreased the expression of NOX2, as well as the overall NOX activity in the cortex and the hippocampus. Finally, we showed that upon continuous intracerebroventricular administration to epileptic rats, gp91ds-tat significantly reduced the seizure frequency and the total number of seizures post-treatment compared to the scrambled peptide-treated animals. The results of the study suggest that NOX2 may have an important effect on modulation of epileptiform activity and has a critical role in mediating seizure-induced NOX activation, ROS generation and oxidative stress in the brain, and thus significantly contributes to development of epilepsy following a brain insult.

Spatial, temporal, and cell-type-specific expression of NADPH Oxidase isoforms following seizure models in rats.

The NADPH Oxidase (NOX) enzymes are key producers of reactive oxygen species (ROS) and consist of seven different isoforms, distributed across the tissues and cell types. The increasing level of ROS induces oxidative stress playing a crucial role in neuronal death and the development of epilepsy. Recently, NOX2 was reported as a primary source of ROS production, activated by NMDA receptor, a crucial marker of epilepsy development. Here, we demonstrate spatial, temporal, and cellular expression of NOX2 and NOX4 complexes in in-vitro and in-vivo seizure models. We showed that the expression of NOX2 and NOX4 was increased in the initial 24 h following a brief seizure induced by pentylenetetrazol. Interestingly, while this elevated level returns to baseline 48 h following seizure in the cortex, in the hippocampus these levels remain elevated up to one week following the seizure. Moreover, we showed that 1- and 2- weeks following status epilepticus (SE), expression of NOX2 and NOX4 remains significantly elevated both in the cortex and the hippocampus. Furthermore, in in-vitro seizure model, NOX2 and NOX4 isoforms were overexpressed in neurons and astrocytes following seizures. These results suggest that NOX2 and NOX4 in the brain have a transient response to seizures, and these responses temporally vary depending on, seizure duration, brain region (cortex or hippocampus), and cell types.

Inguinoscrotal herniation of the bladder: A rare case of obstructive uropathy.

Inguinoscrotal herniation of the bladder is a rare presentation of inguinal hernia that can result in significant complications if untreated. We describe a case of an elderly male with a delayed presentation of bladder herniation resulting in severe acute kidney injury requiring urgent placement of nephrostomy tubes. Ultimately surgery is required for definitive management.

Cytomorphological Patterns of Nerve Aspirates in Pure Neuritic Leprosy-A Single Centre Cross-Sectional Observational Study.

BACKGROUND: Pure neuritic leprosy (PNL) poses a diagnostic challenge because of absence of skin patches, inconclusive skin biopsies and nerve conduction studies. Nerve biopsy though the diagnostic gold standard, is invasive, requires expertise, and may not be feasible in all cases. Fine needle aspiration cytology (FNAC) of accessible thickened nerves can be utilized as a minimally invasive diagnostic modality in PNL. This study was carried out to describe cytomorphological patterns of nerve aspirates in patients of PNL for diagnosis and classification of leprosy and study its advantage, if any, over skin biopsy. METHODS: Twenty-seven treatment naive clinically diagnosed patients of PNL were included in this cross-sectional study carried out from January 2017 to December 2018 at a tertiary care centre in Western India. FNAC was done from a clinically involved nerve and aspirates were evaluated for cytomorphological characteristics and the presence of Acid-Fast Lepra bacilli. RESULTS: Nerve aspirates were diagnostic in 10 (37%) patients while 17 (63%) aspirates showed non-specific or no inflammation. Of the diagnostic aspirates, six (22.2%) were classified as tuberculoid leprosy, three (11.1%) as lepromatous and one (3.7%) as borderline leprosy. Mycobacterium leprae were demonstrated among three (11.1%) of these aspirates. In comparison, only three (11.1%) skin biopsies were diagnostic of leprosy with features of indeterminate spectrum. Remaining 24 skin biopsies showed normal histology in 20 (74.1%) cases to perivascular lymphocytic infiltrate in four (14.8%) cases. CONCLUSION: Our study demonstrates that FNAC of clinically thickened nerves has a better diagnostic yield than skin biopsy in PNL and shows all spectrums of leprosy. It also offers the advantage of sampling major nerve trunks without the fear of residual neurological deficit. However, most of the smears were paucicellular and a negative aspirate does not rule out leprosy.

Chronic graft-versus-host disease in pancreas after kidney transplant recipients - An unrecognized entity.

Graft-versus-host disease (GVHD), a common complication after peripheral blood stem cell or bone marrow transplantation, rarely occurs in kidney and pancreas transplant recipients. The true incidence may be confounded by the rarity of the disorder, with a resultant lack of appreciation of the diagnosis as a potential cause of common clinical manifestations such as cytopenias and immune dysfunction. Reports of GVHD in kidney and pancreas transplant recipients almost uniformly describe patients in the early posttransplant period (days to months) with the typical manifestations of acute GVHD involving the skin, liver, and intestines. In contrast, reports of solid organ transplant recipients with clinical features more consistent with chronic GVHD (cGVHD) are lacking, raising concern of underrecognition of this severe complication. Occurrence later after transplant may be even more likely to result in lack of recognition. We report 2 cases of possible cGVHD occurring in recipients of pancreas after kidney transplantation, which were diagnosed at 5.5 and 42 months after pancreas transplant. Both patients presented with severe pancytopenia, multiple opportunistic infections, and features suggestive of cGVHD. Transplant professionals should be aware of the possibility of acute and cGVHD in pancreas after kidney transplant recipients and be able to recognize the clinical manifestations.

Direct physical interaction of active Ras with mSIN1 regulates mTORC2 signaling.

BACKGROUND: The mechanistic (or mammalian) target of rapamycin (mTOR), a Ser/Thr kinase, associates with different subunits forming two functionally distinct complexes, mTORC1 and mTORC2, regulating a diverse set of cellular functions in response to growth factors, cellular energy levels, and nutrients. The mechanisms regulating mTORC1 activity are well characterized; regulation of mTORC2 activity, however, remains obscure. While studies conducted in Dictyostelium suggest a possible role of Ras protein as a potential upstream regulator of mTORC2, definitive studies delineating the underlying molecular mechanisms, particularly in mammalian cells, are still lacking. METHODS: Protein levels were measured by Western blotting and kinase activity of mTORC2 was analyzed by in vitro kinase assay. In situ Proximity ligation assay (PLA) and co-immunoprecipitation assay was performed to detect protein-protein interaction. Protein localization was investigated by immunofluorescence and subcellular fractionation while cellular function of mTORC2 was assessed by assaying extent of cell migration and invasion. RESULTS: Here, we present experimental evidence in support of the role of Ras activation as an upstream regulatory switch governing mTORC2 signaling in mammalian cancer cells. We report that active Ras through its interaction with mSIN1 accounts for mTORC2 activation, while disruption of this interaction by genetic means or via peptide-based competitive hindrance, impedes mTORC2 signaling. CONCLUSIONS: Our study defines the regulatory role played by Ras during mTORC2 signaling in mammalian cells and highlights the importance of Ras-mSIN1 interaction in the assembly of functionally intact mTORC2.

Immune-mediated tuberculous uveitis - A rare association with papulonecrotic tuberculid.

The tuberculids are a group of distinct clinicopathological form of skin lesions representing hypersensitivity reaction to hematogenous dissemination of Mycobacterium tuberculosis or its antigen from an underlying active or a silent focus of tuberculosis elsewhere in the body in an individual with a strong antituberculous cell-mediated immunity and by definition do not show bacilli on special stains and are culture-negative. Ocular involvement can occur in tuberculosis, both due to direct invasion by the bacilli as well as an immune-mediated reaction; however, immune-mediated tuberculous uveitis occurring as a hypersensitivity response in association with PNT has hardly been reported in the literature. Here we report one such rare case.

The Substantial Loss of Nephrons in Healthy Human Kidneys with Aging.

Nephron number may be an important determinant of kidney health but has been difficult to study in living humans. We evaluated 1638 living kidney donors at Mayo Clinic (MN and AZ sites) and Cleveland Clinic. We obtained cortical volumes of both kidneys from predonation computed tomography scans. At the time of kidney transplant, we obtained and analyzed the sections of a biopsy specimen of the cortex to determine the density of both nonsclerotic and globally sclerotic glomeruli; the total number of glomeruli was estimated from cortical volume×glomerular density. Donors 18-29 years old had a mean 990,661 nonsclerotic glomeruli and 16,614 globally sclerotic glomeruli per kidney, which progressively decreased to 520,410 nonsclerotic glomeruli per kidney and increased to 141,714 globally sclerotic glomeruli per kidney in donors 70-75 years old. Between the youngest and oldest age groups, the number of nonsclerotic glomeruli decreased by 48%, whereas cortical volume decreased by only 16% and the proportion of globally sclerotic glomeruli on biopsy increased by only 15%. Clinical characteristics that independently associated with fewer nonsclerotic glomeruli were older age, shorter height, family history of ESRD, higher serum uric acid level, and lower measured GFR. The incomplete representation of nephron loss with aging by either increased glomerulosclerosis or by cortical volume decline is consistent with atrophy and reabsorption of globally sclerotic glomeruli and hypertrophy of remaining nephrons. In conclusion, lower nephron number in healthy adults associates with characteristics reflective of both lower nephron endowment at birth and subsequent loss of nephrons.