TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions

TAR DNA-binding protein 43 (TDP-43) is a major pathological protein of sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Thus, TDP-43 defines a novel class of neurodegenerative diseases called TDP-43 proteinopathies. We performed ubiquitin and TDP-43 immunohistochemistry on 193 cases of familial and sporadic FTLD with or without MND. On selected cases, immunoelectron microscopy and biochemistry were performed. Clinically defined frontotemporal dementias (FTDs) included four groups: 1) familial FTD with mutations in progranulin (n = 36), valosin-containing protein (n = 5), charged multivesicular body protein 2B (n = 4), and linked to chromosome 9p (n = 7); 2) familial cases of FTD with unknown gene association (n = 29); 3) sporadic FTD (n = 72); and 4) familial and sporadic FTD with MND (n = 40). Our studies confirm that the spectrum of TDP-43 proteinopathies includes most cases of sporadic and familial FTLD-U with and without MND and expand this disease spectrum to include reported families with FTD linked to chromosome 9p but not FTD with charged multivesicular body protein 2B mutations. Thus, despite significant clinical, genetic, and neuropathological heterogeneity of FTLD-U, TDP-43 is a common pathological substrate underlying a large subset of these disorders, thereby implicating TDP-43 in novel and unifying mechanisms of FTLD pathogenesis.     

Pharmacological evaluation of the efficacy of <Emphasis Type="Italic">Dysoxylum binectariferum</Emphasis> stem bark and its active constituent rohitukine in regulation of dyslipidemia in rats

The antidyslipidemic effect of the ethanolic extract of Dysoxylum binectariferum stem bark and its major active constituent rohitukine was evaluated in a high fat diet (HFD)-fed dyslipidemic rat model. Chronic feeding of ethanolic extract (200 mg/kg) in HFD-fed rats showed significant lipid lowering activity. The bioassay guided fractionation of ethanolic extract resulted in the identification of known alkaloid rohitukine as major active constituent. Rohitukine (50 mg/kg) significantly decreased the plasma levels of total cholesterol (24 %), phospholipids (25 %), triglycerides (27 %), very low density lipoprotein (27 %) and low density lipoprotein (32 %) accompanied with an increase in high density lipoprotein (21 %). The present study demonstrated that ethanolic extract of Dysoxylum binectariferum stem bark and its major constituent rohitukine both have antidyslipidemic as well as antioxidant potentials. The antidyslipidemic activity of rohitukine can be correlated to its effect on enzymes involved in lipid metabolism.     

Therapeutic targets for altering mitochondrial dysfunction associated with diabetic retinopathy

Introduction: Retinopathy remains as one of the most feared blinding complications of diabetes, and with the prevalence of this life-long disease escalating at an alarming rate, the incidence of retinopathy is also climbing. Although the cutting edge research has identified many molecular mechanisms associated with its development, the exact mechanism how diabetes damages the retina remains obscure, limiting therapeutic options for this devastating disease.

Areas covered: This review focuses on the central role of mitochondrial dysfunction/damage in the pathogenesis of diabetic retinopathy, and how damaged mitochondria initiates a self-perpetuating vicious cycles of free radicals. We have also reviewed how mitochondria could serve as a therapeutic target, and the challenges associated with the complex double mitochondrial membranes and a well-defined blood-retinal barrier for optimal pharmacologic/molecular approach to improve mitochondrial function.

Expert opinion: Mitochondrial dysfunction provides many therapeutic targets for ameliorating the development of diabetic retinopathy including their biogenesis, DNA damage and epigenetic modifications. New technology to enhance pharmaceuticals uptake inside the mitochondria, nanotechnology to deliver drugs to the retina, and maintenance of mitochondrial homeostasis via lifestyle changes and novel therapeutics to prevent epigenetic modifications, could serve as some of the welcoming avenues for a diabetic patient to target this sight-threatening disease.     

Lipid based nanocarriers: a translational perspective

Over the recent couple of decades, pharmaceutical field has embarked most phenomenal noteworthy achievements in the field of medications as well as drug delivery. The rise of Nanotechnology in this field has reformed the existing drug delivery for targeting, diagnostic, remedial applications and patient monitoring. The convincing usage of nanotechnology in the conveyance of medications that prompts an extension of novel lipid-based nanocarriers and non-liposomal systems has been discussed. Present review deals with the late advances and updates in lipidic nanocarriers, their formulation strategies, challenging aspects, stability profile, clinical applications alongside commercially available products and products under clinical trials. This exploration may give a complete idea viewing the lipid based nanocarriers as a promising choice for the formulation of pharmaceutical products, the challenges looked by the translational process of lipid-based nanocarriers and the combating methodologies to guarantee the headway of these nanocarriers from bench to bedside.     

Surgical management of a large retinal cyst in X-linked retinoschisis with internal drainage: Report of an unusual case

Although X-linked retinoschisis is a common retinal degeneration condition, the presence of a large retinal cyst obscuring the visual axis in an infant is a rare presentation. Herein, we describe such a case of a child who presented to us with the diagnosis of retinal detachment in both the eyes. However, following multimodal imaging and electrophysiology, the child was found to have bilateral juvenile retinoschisis with a large retinoschisis cyst involving the visual axis seen intraoperatively in the left eye. A limbal approach followed by lensectomy was used to excise the inner retinal layer of the cyst. The intracystic fluid was then drained and the stretched retinal vessels were endocauterized and severed without causing any iatrogenic outer retinal breaks and retinal detachment. The correct diagnosis and meticulous preoperative planning of the surgical procedure helped us manage this challenging case with a favorable anatomical and functional outcome.     

A knowledge based interpretation system for EMG abnormalities

The conventional method of diagnosis in electromyography is complex and time consuming, not only due to the large number of parameters, to be considered for diagnosis, but also because of the usual procedure of evaluating the different parameters of EMG signal by visual scanning of the plotted signal. So there is a clear need to make use of computer aided decision support system. In the present work an attempt has been made in the direction of integration into one automated system, the qualitative knowledge of the physician, with possibly sophisticated signal analysis tools which must replace the visual scanning. A software program (in Turbo-C) on a PC-AT has been developed to evaluate the different parameters of MUAP's (motor unit action potential) in a EMG signal. Then an Expert system (in Turbo-Prolog) has been implemented for diagnostic purposes of different muscular abnormalities by making a knowledge base from the different parameters involved in the decision making procedure of clinical electromyography. A hybrid model of rule and frame based Expert system is implemented. An attempt has been made for making a complete system, i.e., for recording, analysis and decision making for diagnosis.     

Primary vs delayed primary closure in patients undergoing lower limb amputation following trauma: A randomised control study

Lower limb crush injury is a major source of mortality and morbidity in trauma patients. Complications, especially surgical site infections (SSIs) are a major source of financial burden to the institute and to the patient as it delays rehabilitation. As such, every possible attempt should be made to reduce any complications. We, thus, aimed to compare the outcomes in early vs delayed closure of lower extremity stumps in cases of lower limb crush injury requiring amputation, so as to achieve best possible outcome. A randomised controlled study was conducted in the Division of Trauma Surgery & Critical Care at Jai Prakash Narayan Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi from 1 September 2018 to 30 June 2019 and included patients undergoing lower limb amputation below hip joint. Patients were randomised in two groups, in one group amputation stump was closed primarily, while in the second group delayed primary closure of stump was performed. We compared rate of SSI, length of hospital stay, and number of surgeries in both the groups. Fifty‐six patients with 63 amputation stumps were recruited in the study. Mean age of patients in the study was 34 years, of which about 95% patients were males. The most common mechanism of injury was road traffic injury in 66% of patients. Mean injury severity score was 12.28 and four patients had diabetes preoperatively. Total 63 extremities were randomised with 30 cases in group I and 33 cases in group II as per computer‐generated random number. Above knee amputations was commonest (57.14%) followed by below knee amputations (33.3%). Two patients died in the current study. In group I, In‐hospital infection was detected in 7 cases (23.3%) and in group II 9 cases (27.3%) had SSI during hospital admission (P > .05). Mean hospital stay in group I was 10.32 ± 7.68 days and in group II was 11 ± 8.17 days (P > .05). Road traffic injuries and train‐associated injuries are a major cause of lower limb crush injuries, leading to limb loss. Delayed primary closure of such wounds requires extra number of surgical interventions than primary closure. There is no difference in extra number of surgical interventions required in both the groups. Thus, primary closure can be safely performed in patients undergoing lower limb amputations following trauma, provided that a good lavage and wound debridement is performed.     

Chronic Pancreatitis with Benign Biliary Obstruction: Management Issues

Background

Benign biliary obstruction (BBO) is an important complication in patients with advanced chronic pancreatitis (CP). Its presentation varies from an incidental finding to overt jaundice. Thus it presents certain management issues. The present study was therefore performed to analyze the clinical presentation and management of biliary obstruction in patients with CP.

Methods

Retrospective analysis was performed from a prospectively collected database of 155 CP patients managed at our institute from October 2003 to June 2012.

Results

Among 43 (28 %) CP patients with biliary obstruction, 3 patients had evidence of malignancy on follow-up examination and were excluded from the final analysis. The various presentations include chronic nonprogressive elevation of serum alkaline phosphatase (SAP) (n = 15), a progressive increase in SAP with episodes of jaundice (n = 17), and persistent jaundice (n = 8). Of 15 patients with chronic nonprogressive elevation of SAP, 5 were managed conservatively, and the remaining 10 underwent only a pancreatic drainage procedure. During a median follow-up of 41 months (range 11–90 months), none of the 15 patients developed complications related to biliary obstruction. All patients with progressive increase in SAP levels and persistent jaundice underwent the biliary drainage procedure [choledochojejunostomy (CDJ, n = 20) and choledochoduodenostomy (CDD, n = 3)]. During a median follow-up of 30 months (range 10–89 months), two patients died of unrelated causes and two patients had an asymptomatic elevation of SAP.

Conclusions

BBO is common in patients with CP; however, biliary drainage is not indicated for chronic nonprogressive elevation of SAP. In patients with a progressive increase in SAP or persistent jaundice, both CDJ and CDD provide effective biliary drainage.