Alpha 1 antitrypsin deficiency in children with chronic liver disease in North India

Objective

We attempted to determine the role of alpha-1-antitrypsin (AAT) deficient variants as an etiologic factor for chronic liver disease in North Indian children.

Design

This study investigated 1700 children (682 retrospectively and 1018 prospectively) (840 CLD, 410 neonatal cholestasis and 450 without liver disease) for AAT deficiency.

Setting

Tertiary referral center, All India Institute of Medical Sciences, New Delhi.

Patients

Of 1250 liver disease patients, 98 (7.8%) were suspected to be AAT deficient on the basis of screening tests (low serum AAT levels and/or absent/faint alpha-1-globulin band on serum agarose electrophoresis and/or diastase resistant PAS positive granules on liver biopsy).

Main outcome measures

AAT deficient Z or S allele in suspected patients.

Results

Z or S allele was not observed on phenotyping (1700 subjects), or with PCR-RFLP, SSCP and sequencing done in 50 of 98 suspected AAT deficient patients. A novel mutation G-to-A at position 333 in exon V was found in two siblings having positive immunohistochemistry for AAT on liver biopsy, both of whom had significant liver disease with portal hypertension.

Conclusion

In conclusion, AAT deficiency as an etiologic factor for chronic liver disease in childhood appeared to be uncommon in North India     

The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes

Approximately 5–10% of all pancreatic cancer patients carry a predisposing mutation in a known susceptibility gene. Since >90% of patients present with late stage disease, it is crucial to identify high risk individuals who may be amenable to early detection or other prevention. To explore the spectrum of hereditary pancreatic cancer susceptibility, we evaluated germline DNA from pancreatic cancer participants (n?=?53) from a large hereditary cancer registry. For those without a known predisposition mutation gene (n?=?49), germline next generation sequencing was completed using targeted capture for 706 candidate genes. We identified 16 of 53 participants (30%) with a pathogenic (P) or likely pathogenic (LP) variant that may be related to their hereditary pancreatic cancer predisposition; seven had mutations in genes associated with well-known cancer syndromes (13%) [ATM (2), BRCA2 (3), MSH2 (1), MSH6 (1)]. Many had mutations in Fanconi anemia complex genes [BRCA2 (3 participants), FANCF, FANCM]. Eight participants had rare protein truncating variants of uncertain significance with no other P or LP variants. Earlier age of pancreatic cancer diagnosis (57.5 vs 64.8 years) was indicative of possessing a P or LP variant, as was cancer family history (p values <0.0001). Our multigene panel approach for identifying known cancer predisposing genetic susceptibility in those at risk for hereditary pancreatic cancer may have direct applicability to clinical practice in cases with mutations in actionable genes. Future pancreatic cancer predisposition studies should include evaluation of the Fanconi anemia genes.     

Proteasome inhibition mediates p53 reactivation and anti-cancer activity of 6-Gingerol in cervical cancer cells

Human papilloma virus (HPV) expressing E6 and E7 oncoproteins, is known to inactivate the tumor suppressor p53 through proteasomal degradation in cervical cancers. Therefore, use of small molecules for inhibition of proteasome function and induction of p53 reactivation is a promising strategy for induction of apoptosis in cervical cancer cells. The polyphenolic alkanone, 6-Gingerol (6G), present in the pungent extracts of ginger (Zingiber officinale Roscoe) has shown potent anti-tumorigenic and pro-apoptotic activities against a variety of cancers. In this study we explored the molecular mechanism of action of 6G in human cervical cancer cells in vitro and in vivo. 6G potently inhibited proliferation of the HPV positive cervical cancer cells. 6G was found to: (i) inhibit the chymotrypsin activity of proteasomes, (ii) induce reactivation of p53, (iii) increase levels of p21, (iv) induce DNA damage and G2/M cell cycle arrest, (v) alter expression levels of p53-associated apoptotic markers like, cleaved caspase-3 and PARP, and (vi) potentiate the cytotoxicity of cisplatin. 6G treatment induced significant reduction of tumor volume, tumor weight, proteasome inhibition and p53 accumulation in HeLa xenograft tumor cells in vivo. The 6G treatment was devoid of toxic effects as it did not affect body weights, hematological and osteogenic parameters. Taken together, our data underscores the therapeutic and chemosensitizing effects of 6G in the management and treatment of cervical cancer.     

A case of acute epididymo-orchitis due to Pseudomonas aeruginosa presenting as ARDS in an immunocompetent host

Acute eididymo-orchitis is the most common cause of intrascrotal inflammation, and retrograde ascent of pathogens is the usual route of infection. Here we intend to present a case of young boy, not sexually active, suffering from acute epididymo-orchitis due to Pseudomonas aeruginosa presented with acute respiratory distress syndrome. Proper timely diagnosis of the primary cause and prompt treatment including support with non invasive ventilation lead to a favourable outcome in the same case.     

Alpha-1 antitrypsin deficiency among Indian children with liver disorders.

AIMS: To determine the frequency of alpha-1 antitrypsin (AAT) deficiency in children with chronic liver disease (CLD) and neonatal cholestasis syndrome (NCS). METHODS: All children with NCS (n=23) or CLD (n=35) attending the Pediatric Gastroenterology Clinic between November 2003 and July 2005 were screened for AAT deficiency using phenotyping through isoelectric focusing of plasma. RESULTS: Of the 58 children studied, 57 had normal PiMM phenotype. One child with CLD had the M1E type of normal variant. None of the patients had the abnormal phenotype PiZZ. CONCLUSION: AAT deficiency is infrequent among children with CLD and NCS in our region.