Role of Glutathione-S-Transferases in Gallbladder Cancer and Cholelithiasis Susceptibility and Meta-Analysis

Abstract

Glutathione-S-transferase T1 (GSTT1) and glutathione-S-transferase M1 (GSTM1) genes are associated with increase susceptibility to developing different types of cancers. The aim of present study was to investigate the role of genetic variants of GSTM1 and GSTT1 in gallbladder cancer (GBC) and cholelithiasis in Kashmir valley. Genotyping was done by multiplex polymerase chain reaction in 100 GBC, 100 cholelithiasis, and 150 controls adjusted by age and sex. We also performed a meta-analysis of published studies on GSTM1 and GSTT1 to evaluate the association between the GSTM1 and GSTT1 polymorphisms and GBC. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model. In the present study, no association was observed between GSTM1 null and GSTT1 null genotypes and GBC and cholelithiasis. Meta-analysis results showed that GSTM1 null genotype was associated with GBC risk (P?=?0.042). Subgroup analysis by ethnicity showed that GSTM1 null (P?=?0.024) and GSTT1 null genotype (P?=?0.037) were significantly associated with risk of GBC in Asians. This is the first study to investigate the role of genetic variants of GSTM1 and GSTT1 in GBC in Kashmir valley and cholelithiasis in the world.     

Spontaneous spinal epidural hemorrhage following disseminated intravascular coagulation resulting in paraplegia: a case report

Context: Spontaneous spinal epidural hemorrhage (SSEH) mostly presents as low back pain with or without a radiculopathy, and rarely with paraplegia or tetraplegia depending on the site and severity of spinal cord compression. We present here a case who had anemia and developed paraplegia following disseminated intravascular coagulation (DIC) due to a transfusion reaction.

Findings: A 65-year-old lady presented with sudden onset chest pain radiating to nape of the neck followed by loss of sensations and power in legs few hours after a blood transfusion. Her past history was negative for diabetes mellitus, hypertension, coronary artery disease, or a bleeding disorder. Her blood pressure was 90/57 mmHg and she had a normal pulse, respiratory rate, and temperature. On neurological examination, she had no motor power and unevokable muscle stretch reflexes in the lower limbs. The sensations were intact till T₃ dermatome. The laboratory evaluation was suggestive of DIC. The magnetic resonance imaging showed a non-enhancing abnormal signal intensity area in the posterior epidural space, extending from CV₄ to LV₄ causing cervico-dorsal cord compression associated with cord edema. Following diagnosis, urgent decompressive surgery was carried out due to deteriorating neurological status. The patient was transfused with five bags of red cell concentrate, two bags of platelets, and four bags of fresh frozen plasma during the operation. The patient regained consciousness following operation, however, the neurological status did not improve. She, unfortunately, died on the third post-op day due to cardiac arrest.

Conclusion: SSEH is a rare cause of paraplegia. Early radiological diagnosis is crucial for timely neurosurgical management and saving patient from permanent neurological deficit or a fatal outcome.     

ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-alpha/IL-6 in mice

BACKGROUND & AIMS: Tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 mediate hepatocyte proliferation in vivo, suggesting that local and systemic inflammatory reactions may trigger hepatic regeneration after major tissue loss. METHODS: Wild-type, intercellular adhesion molecule (ICAM)-1-/-, and neutropenic-induced mice were subjected to 70% hepatectomy. Three different approaches to block and/or deplete liver macrophages (Kupffer cells) were used. RESULTS: We found that liver from ICAM-1-deficient mice exhibited impaired regeneration after partial hepatectomy. This finding is associated with dramatic decrease in leukocyte recruitment and tissue TNF-alpha and IL-6 levels. All markers of hepatocyte proliferation were restored in ICAM-/- mice by injections of recombinant IL-6. Neutropenic animals and liver macrophage (Kupffer cell) depletion resulted in similar failure of regeneration with low levels of TNF-alpha and IL-6. CONCLUSIONS: The data suggest a novel pathway in which ICAM-1 binds to leukocytes after hepatectomy, triggering hepatocyte proliferation through Kupffer cell-dependent release of TNF-alpha and IL-6.     

One year of hepatitis B immunoglobulin plus tenofovir therapy is safe and effective in preventing recurrent hepatitis B infection post-liver transplantation

BACKGROUND:

Hepatitis B immunoglobulin (HBIG) given in combination with a nucleos(t)ide analogue has reduced the rate of recurrent hepatitis B virus (HBV) infection following liver transplantation (LT); however, the most effective protocol remains unclear.

OBJECTIVE:

To evaluate the use of tenofovir disoproxil fumarate (TDF) in combination with one year of low-dose HBIG.

METHODS:

Twenty-four adults who underwent LT for HBV-related liver disease at the University Health Network (Toronto, Ontario) and received TDF (± lamivudine) and one year of HBIG to prevent recurrent HBV infection from June 2005 to June 2011 were evaluated.

RESULTS:

The median length of follow-up post-LT was 29.1 months. Three patients died during the follow-up period. Patient survival was 100% and 84.1% at one and five years, respectively. None of the patients developed recurrent HBV infection. No significant adverse event was observed due to TDF administration; renal function pre- and post-LT were also acceptably preserved.

CONCLUSION:

The present study demonstrated that a short, finite course of low-dose HBIG combined with maintenance of long-term TDF staring before LT is cost-effective and safe. However, further prospective study involving a larger patient cohort with a longer followup period is required to confirm the results.     

Preconditioning, postconditioning, and remote conditioning in solid organ transplantation: basic mechanisms and translational applications

Ischemia and reperfusion (I/Rp) injury is inherent to solid organ transplantation and can result in primary nonfunction or delayed function of grafts, which is associated with a significant morbidity and mortality posttransplantation. It is also a major obstacle for the use of marginal grafts to increase the donor pool, as these grafts are prone to a higher degree of I/Rp injury. Pre-, post-, and remote conditioning are protective strategies against I/Rp injury, which can be applied in the transplant setting. These strategies hold the potential to reduce graft injury and to safely expand the donor pool. However, despite convincing experimental data, the protective effects of the "conditioning" protocols remain unclear, and only few have translated to clinical practice. This review summarizes pre-, post-, and remote conditioning strategies in clinical use in solid organ transplantation and discusses an overview of the mechanistic pathways involved in each strategy.     

In vitro study of chitosan-based multi-responsive hydrogels as drug release vehicles: a preclinical study

Systematic administration of painkillers and anti-inflammatory drugs is routinely employed to minimize pain and bodily disorders. Controlled drug delivery has the potential to improve the outcomes of disorders by providing sustained exposure to efficacious drug concentrations. Herein, we report the fabrication of multi-responsive hydrogels using reactive and functional polymers such as chitosan and polyvinyl pyrrolidone by varying the concentration of a cleavable crosslinker, tetraethyl orthosilicate. The swelling indices of the hydrogels were evaluated in distilled water, solutions with different pH values and different electrolytes. FTIR, WAXRD and TGA were conducted to investigate the structures, crystallinities and thermal stabilities of the prepared multi-responsive hydrogels, respectively. The ultimate tensile strength and elongations at break of the fabricated hydrogels were investigated to assess their mechanical stability. Optical microscopy, biodegradation, antimicrobial and cytotoxicity analyses were further carried out to verify the magnified crosslinked and porous structures, biodegradabilities, biocompatibilities and toxic behaviour of the as-prepared hydrogels, respectively. Drug release analysis was conducted to evaluate their release behaviour in PBS, SGF, SIF and electrolyte solutions. The overall results indicate the successful development of novel, non-toxic and sustained drug deliverable hydrogels, which can be considered as a paramount success towards the fabrication of controlled drug delivery systems.

Pictorial diagram of multi-responsive hydrogels for controlled drug release system.