Carbonic anhydrases as disease markers

Introduction: The physiologic importance of fast CO₂/HCO₃^? interconversion in various tissues requires the presence of carbonic anhydrase (CA, EC 4.2.1.1). Fourteen CA isozymes are present in humans, all of them being used as biomarkers.

Area covered: A great number of patents and articles were focused on the use of CA isozymes as biomarkers for various diseases and syndromes in the recent years, in an ascending trend over the last decade. The review highlights the most important studies related with each isozyme and covers the most recent patent literature.

Expert opinion: The CAs biomarker research area expanded significantly in recent years, shifting from the predominant use of CA IX and CA XII in cancer diagnostic, staging, and prognosis towards a wider use of CA isozymes as disease biomarkers. CA isozymes are currently used either alone, in tandem with other CA isozymes and/or in combination with other proteins for the detection, staging, and prognosis of a huge repertoire of human dysfunctions and diseases, ranging from mild transformation of the normal tissues to extreme shifts in tissue organization and function. The techniques used for their detection/quantitation and the state-of-the-art in each clinical application are presented through relevant clinical examples and corresponding statistical data.     

A pediatric case series of abdominal epilepsy

Background

Abdominal epilepsy (AE) is an infrequent cause of recurrent abdominal pain in children. It is characterized by paroxysmal episodes of abdominal pain, a variety of other abdominal complaints, electroencephalogram abnormalities, and response to anti-epileptic agents. We described the clinical profile of six patients with AE.

Methods

We conducted a retrospective survey of AE in children from the records of the hospital. The diagnosis of AE was dependent on recurrent abdominal symptoms, subtle central nervous system abnormalities, electroencephalogram abnormalities and response to anticonvulsant agents.

Results

The six patients were diagnosed with AE. The incidence of the disease was 0.07% in all admissions to the pediatric ward. Recurrent pain was common in all patients except two who had additional recurrent vomiting. In this series, the boy to girl ratio (1:2) was unequal.

Conclusion

High suspicion is required for the diagnosis of AE after exclusion of other possible causes.     

Identification of 5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine as novel orally bioavailable and metabolically stable antimalarial compound for further exploration

Malaria continues to be a significant public health problem threatened by the emergence and spread of resistance to artemisinin-based combination therapies and marked half a million deaths in 2016. A new imidazopyridine chemotype has been envisaged through scaffold-hopping approach combined with docking studies for putative-binding interactions with Plasmodium falciparum phosphatidylinositol-4-kinase (PfPI4K) target. The docking results steered to the synthesis of compound 1 [5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine] followed by the in vitro screening for antiplasmodial activity and ADME-PK studies. Combined with potent antimalarial activity of compound 1 (Pf3D7 IC₅₀ = 29 nM) with meager in vitro intrinsic clearance, moderate plasma-protein binding, and acceptable permeability, compound 1 displayed sustained exposure and high oral bioavailability in mice and can thus have the potential as next generation PI4K inhibitor for in vivo studies.     

Role of different receptors and actin filaments on Salmonella Typhimurium invasion in chicken macrophages

Bacterial attachment to host cell is the first event for pathogen entry. The attachment is mediated through membrane expressed adhesins present on the organism and receptors on the cell surface of host. The objective of this study was to investigate the significance of Fc receptors (FcRs), actin filament polymerization, mannose receptors (MRs), carbohydrate moieties like N-linked glycans and sialic acid on chicken macrophages for invasion of S. Typhimurium. Opsonisation of S. Typhimurium resulted in three folds more invasion in chicken monocyte derived macrophages. Cytochalasin D, an inhibitor of actin filament polymerization prevented uptake of S. Typhimurium. Pre-incubation of macrophages with cytochalasin D, showed severe decrease (28 folds) in S. Typhimurium invasion. Next we attempted to analyse the role of carbohydrate receptors of macrophages in S. Typhimurium invasion. Treatment of macrophages with methyl α-d-mannopyranoside, PNGase F and neuraminidase, showed 2.5, 5 and 2.5 folds decrease in invasion respectively. Our data suggest that deglycosylation of N-linked glycans including sialic acid by PNGase F is more effective in inhibition of S. Typhimurium invasion than neuraminidase which removes only sialic acid. These findings suggested FcRs, actin filament polymerization, MRs, N-linked glycans and sialic acid may act as gateway for entry of S. Typhimurium.     

Renal aquaporin-4 associated pathology in TG-26 mice

Human immunodeficiency virus-associated nephropathy (HIVAN) is a leading cause of end-stage renal disease in HIV patients, which is characterized by glomerulosclerosis and renal tubular dysfunction. Aquaporin-4 (AQP-4) is a membrane bound water channel protein that plays a distinct role in water reabsorption from renal tubular fluid. It has been proven that failure of AQP-4 insertion into the renal tubular membrane leads to renal dysfunction. However, the role of AQP-4 in HIVAN is unclear. We hypothesize that impaired water reabsorption leads to renal injury in HIVAN, where AQP-4 plays a crucial role. Renal function is assessed by urinary protein and serum blood urea nitrogen (BUN). Kidneys from HIV Transgenic (TG26) mice (HIVAN animal model) were compared to wild type mice by immunostaining, immunoblotting and quantitative RT-PCR. TG26 mice had increased proteinuria and BUN. We found decreased AQP-4 levels in the renal medulla, increased endothelin-1, endothelin receptor A and reduced Sirtuin1 (SIRT-1) levels in TG26 mice. Also, oxidative and endoplasmic reticulum stress was enhanced in kidneys of TG26 mice. We provide the first evidence that AQP-4 is inhibited due to induction of HIV associated stress in the kidneys of TG26 mice which limits water reabsorption in the kidney which may be one of the cause associated with HIVAN, impairing kidney physiology. AQP-4 dysregulation in TG26 mice suggests that similar changes may occur in HIVAN patients. This work may identify new therapeutic targets to be evaluated in HIVAN.     

Analysis of 88 nephrectomies in a rural tertiary care center of India

Nephrectomy is not an uncommon surgery in day-to-day practice of urology. Trauma is the most common cause of emergency nephrectomy. On the other hand, elective nephrectomy is done for both benign and malignant diseases of the kidney. This study has been performed to know the different causes of nephrectomy in a rural, tertiary care center of India. In our series, we have studied all the elective nephrectomies done in our hospital during a period of eight years. We have analyzed 88 cases of nephrectomies regarding their age, sex, laterality of disease, and histopathologic report of the nephrectomy specimens. Out of 88 cases, 61 were males and 27 were females. In our series, 62.5% cases of nephrectomies were done for benign causes and 37.5% cases for malignant causes. Among the benign causes, neglected pelviureteric junction obstruction was the leading cause, followed by calculus disease resulting in obstruction. On the other hand, renal cell carcinoma was the most common malignant pathology requiring nephrectomy.     

Extra corporeal carbon dioxide removal: A reliable modality in refractory hypercapnia to prevent invasive ventilation

Extracorporeal carbon dioxide removal (ECCO2R) is a valid alternative to consider in hypercapnic respiratory failure in chronic obstructive pulmonary disease (COPD) patients to avoid invasive ventilation when noninvasive ventilation fails. Here we report a similar case, after obtaining informed consent, where a patient suffering from severe hypercapnic respiratory failure due to COPD, was selected for ECCO2R and improved remarkably.