Secretory factors in the retrocerebral endocrine-aortal complex of the water-bug, Sphaerodema annulatum (Heteroptera: Belostomatidae)

A histological study of the retrocerebral endocrine-aortal complex of Sphaerodema annulatum, employing conventional neurosecretory stains, reveals the presence of three qualitatively different secretory factors—one present in the corpora cardiaca (CC) and the other two distributed in the corpora allata (CA), aorta wall and nerves going to the pericardial cells. For reasons discussed in the paper, the factor present in the CC is regarded as an indigenous secretion produced by their own intrinsic secretory cells, and the remaining two as cerebral in origin, produced by two tinctorially different neurosecretory cell types.     

Factors influencing the basal and recombinant human thyrotropin-stimulated serum thyroglobulin in patients with metastatic thyroid carcinoma

The serum thyroglobulin (Tg) level is the most sensitive marker for detecting residual thyroid carcinoma. We hypothesized that the basal and TSH-stimulated Tg levels in patients with metastatic thyroid carcinoma would reflect tumor volume, histological subtype, and location of metastatic lesions. A retrospective review of 417 thyroid cancer survivors undergoing evaluation for residual disease with the assistance of recombinant human TSH (rhTSH) was performed. In 169 patients with metastatic disease, we found that the basal Tg level directly correlated with the number of lesions, and that it was highest in patients with follicular and lowest in those with papillary thyroid carcinoma. The basal Tg level was highest in patients with bone metastases and lowest in those with cervical metastases. The fold increase in the serum Tg after rhTSH treatment was highest in papillary thyroid carcinoma and lowest in Hurthle cell carcinoma. The fold increase in Tg was not influenced by tumor volume or by the site of metastatic lesions. Multivariate analysis showed multiple interactions between factors, but did not identify one factor that significantly influenced basal Tg or fold increase. We conclude that the location and volume of metastases influence basal Tg, but not its responsiveness to rhTSH, whereas the histological type of carcinoma influences both basal Tg and responsiveness to rhTSH.     

Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1α Inhibitory Activity

Amino-quinazoline BRaf kinase inhibitor 2 was identified from a library screen as a modest inhibitor of the unfolded protein response (UPR) regulating potential anticancer target IRE1α. A combination of crystallographic and conformational considerations were used to guide structure-based attenuation of BRaf activity and optimization of IRE1α potency. Quinazoline 6-position modifications were found to provide up to 100-fold improvement in IRE1α cellular potency but were ineffective at reducing BRaf activity. A salt bridge contact with Glu651 in IRE1α was then targeted to build in selectivity over BRaf which instead possesses a histidine in this position (His539). Torsional angle analysis revealed that the quinazoline hinge binder core was ill-suited to accommodate the required conformation to effectively reach Glu651, prompting a change to the thienopyrimidine hinge binder. Resulting analogues such as 25 demonstrated good IRE1α cellular potency and imparted more than 1000-fold decrease in BRaf activity.     

Averting transmission: A pivotal target to manage amoebiasis

Amoebiasis is a parasitic infectious disease caused by the enteric protozoan Entamoeba histolytica, a leading basis of deaths accounted to parasites, succeeding malaria and schistosomiasis. Conventional treatment methodologies used to deal with amoebiasis mainly rely on the administration of anti‐amoebic compounds and vaccines but are often linked with substantial side‐effects on the patient. Besides, cases of development of drug resistance in protozoans have been recorded, contributing further to the reduction in the efficiency of the treatment. Loopholes in the efficacious management of the disease call for the development of novel methodologies to manage amoebiasis. A way to achieve this is by targeting the essential metabolic processes of ‘encystation’ and ‘excystation’, and the associated biomolecules, thus interrupting the biphasic life cycle of the parasite. Technologies like the CRISPR‐Cas9 system can efficiently be exploited to discover novel and essential molecules that regulate the protozoan's metabolism, while efficiently manipulating and managing the known drug targets, leading to an effective halt and forestall to the enteric infection. This review presents a perspective on these essential metabolic processes and the associated molecules that can be targeted efficaciously to prevent the transmission of amoebiasis, thus managing the disease and proving to be a fruitful endeavour.     

Putative roles of a proline–glutamic acid-rich protein (PE3) in intracellular survival and as a candidate for subunit vaccine against Mycobacterium tuberculosis

The proline–glutamic acid (PE) protein family of Mycobacterium tuberculosis (Mtb) plays diverse roles in the pathogenesis and modulation of host immune responses. The uniqueness of conserved regions of PE proteins may be useful to test and validate their corresponding functions. Hence, the present study has been undertaken to demonstrate the role of PE3 (Rv0159c) for persistence, host immune response and immunoprophylaxis. We have expressed Mtb-specific PE3 gene in M. smegmatis (MS) and used the strain to infect J774A.1 macrophage cells and BALB/c mice. It was observed that during the infection, the MS expressing PE3 showed higher bacterial load when compared to infection with wild-type MS. In hypoxic condition, the expression level of PE3 gene was induced in Mtb, which further showed its relevance in the cell survival during hypoxia-induced persistence. The expression level of PE3 in Mtb was markedly induced during chronic stage of murine infection, which reiterated its importance in mycobacterial persistence in the host. The immunization of mice with recombinant PE3 protein stimulated the secretion of TNF, IL-6 and IL-2 cytokines and generated strong protective immunity against challenge with live mycobacteria, which was evidenced by decreased viable bacilli in the lungs, histopathological changes and increased survival of PE3 immunized mice. Conclusively, the results indicated that PE3 plays significant roles in mycobacterial persistence during infection, modulate host immune response and hence could be a prospective candidate for the development of subunit vaccine against tuberculosis.     

Tissue specific expression of sialic acid metabolic pathway: role in GNE myopathy

Journal of Muscle Research and Cell Motility - GNE myopathy is an adult-onset degenerative muscle disease that leads to extreme disability in patients. Biallelic mutations in the rate-limiting...     

Evolution of β-catenin-independent Wnt–GSK3–mTOR signalling in regulation of energy metabolism in isoproterenol-induced cardiotoxicity model

Inflammation Research - Isoproterenol (ISO) is widely used agent to study the effects of interventions which could prevent or attenuate the development of myocardial infarction. The sequence of...     

Diagnosis and management of hemorrhagic complications of percutaneous transhepatic biliary drainage: a primer for residents

Hemorrhagic complications are uncommon after percutaneous transhepatic biliary drainage. The presenting features include bleeding through or around the drainage catheter, hematemesis or melena. Diagnosis requires cholangiography, CT angiography or conventional angiography. Minor venous hemorrhage is managed by catheter repositioning, clamping or upgrading to a larger bore catheter. Major vascular injuries require percutaneous or endovascular procedures like embolization or stenting. A complete knowledge of these complications will direct the interventional radiologist to take adequate precautions to reduce their incidence and necessary steps in their management. This review presents and discusses various hemorrhagic complications occurring after percutaneous transhepatic biliary drainage along with their treatment options and suggests a detailed algorithm.     

Treatment of neglected femoral neck fracture

Intra-capsular femoral neck fractures are seen commonly in elderly people following a low energy trauma. Femoral neck fracture has a devastating effect on the blood supply of the femoral head, which is directly proportional to the severity of trauma and displacement of the fracture. Various authors have described a wide array of options for treatment of neglected/nonunion (NU) femoral neck fracture. There is lack of consensus in general, regarding the best option. This Instructional course article is an analysis of available treatment options used for neglected femoral neck fracture in the literature and attempt to suggest treatment guides for neglected femoral neck fracture. We conducted the “Pubmed” search with the keywords “NU femoral neck fracture and/or neglected femoral neck fracture, muscle-pedicle bone graft in femoral neck fracture, fibular graft in femoral neck fracture and valgus osteotomy in femoral neck fracture.” A total of 203 print articles were obtained as the search result. Thirty three articles were included in the analysis and were categorized into four subgroups based on treatment options. (a) treated by muscle-pedicle bone grafting (MPBG), (b) closed/open reduction internal fixation and fibular grafting (c) open reduction and internal fixation with valgus osteotomy, (d) miscellaneous procedures. The data was pooled from all groups for mean neglect, the type of study (prospective or retrospective), classification used, procedure performed, mean followup available, outcome, complications, and reoperation if any. The outcome of neglected femoral neck fracture depends on the duration of neglect, as the changes occurring in the fracture area and fracture fragments decides the need and type of biological stimulus required for fracture union. In stage I and stage II (Sandhu''s staging) neglected femoral neck fracture osteosynthesis with open reduction and bone grafting with MPBG or Valgus Osteotomy achieves fracture union in almost 90% cases. However, in stage III with or without AVN, the results of osteosynthesis are poor and the choice of treatment is replacement arthroplasty (hemi or total).     

Cellular requirements for tumor-specific immunity elicited by heat shock proteins: tumor rejection antigen gp96 primes CD8+ T cells in vivo.

Purified preparations of 96-kDa heat shock proteins (gp96) have been previously shown to elicit tumor-specific immunity to the tumor from which gp96 is obtained but not to antigenically distinct chemically induced tumors. The cellular requirements of gp96-elicited immunity have been examined. It is observed that depletion of CD8+, but not CD4+, T cells in the priming phase abrogates the immunity elicited by gp96. The CD8+ T cells elicited by immunization with gp96 are active at least up to 5 weeks after immunization. Depletion of macrophages by treatment of mice with carrageenan during the priming phase also results in loss of gp96-elicited immunity. In the effector phase, all three compartments, CD4+ and CD8+ T cells and macrophages, are required. Immunity elicited by whole irradiated tumor cells shows a different profile of cellular requirements. In contrast to immunization with gp96, depletion of CD4+, but not CD8+, T cells during priming with whole tumor cells abrogates tumor immunity. Further, ablation of macrophage function during priming or effector phases has no effect on tumor immunity elicited by whole cells. Our results suggest the existence of a macrophage-dependent and a macrophage-independent pathway of tumor immunity. Our observations also show that in spite of exogenous administration, vaccination with gp96 preparations elicits a CD8+ T-cell response in vivo, and it is therefore a useful method of vaccination against cancer and infectious diseases.