Giant splenic artery mycotic aneurysm presenting with massive hematemesis.

We report a 40-year-old man with rheumatic heart disease who presented with abdominal pain for three weeks and hematemesis for 24 hours. CT scan showed a large splenic artery aneurysm without evidence of pancreatitis. Mycotic aneurysm due to infective endocarditis was considered and confirmed by echocardiogram, which showed aortic and mitral valve regurgitation and vegetations. He was managed successfully with coil embolization of the aneurysm and antibiotics.     

EGPred: prediction of eukaryotic genes using ab initio methods after combining with sequence similarity approaches

EGPred is a Web-based server that combines ab initio methods and similarity searches to predict genes, particularly exon regions, with high accuracy. The EGPred program proceeds in the following steps: (1) an initial BLASTX search of genomic sequence against the RefSeq database is used to identify protein hits with an E-value <1; (2) a second BLASTX search of genomic sequence against the hits from the previous run with relaxed parameters (E-values <10) helps to retrieve all probable coding exon regions; (3) a BLASTN search of genomic sequence against the intron database is then used to detect probable intron regions; (4) the probable intron and exon regions are compared to filter/remove wrong exons; (5) the NNSPLICE program is then used to reassign splicing signal site positions in the remaining probable coding exons; and (6) finally ab initio predictions are combined with exons derived from the fifth step based on the relative strength of start/stop and splice signal sites as obtained from ab initio and similarity search. The combination method increases the exon level performance of five different ab initio programs by 4%-10% when evaluated on the HMR195 data set. Similar improvement is observed when ab initio programs are evaluated on the Burset/Guigo data set. Finally, EGPred is demonstrated on an approximately 95-Mbp fragment of human chromosome 13. The list of predicted genes from this analysis are available in the supplementary material. The EGPred program is computationally intensive due to multiple BLAST runs during each analysis. The EGPred server is available at http://www.imtech.res.in/raghava/egpred/.     

Frequency of TPMT alleles in Indian patients with acute lymphatic leukemia and effect on the dose of 6-mercaptopurine

Functional polymorphisms in the thiopurine methyl transferase (TPMT) gene have been associated with varying levels of enzyme activity and the occurrence of toxicity related to thiopurines. A total of 98 patients (66 pediatric and 32 adults) with precursor B acute lymphoblastic leukemia (Pre-B ALL) were evaluated for TPMT gene polymorphisms. The inability to tolerate 6-mercaptopurine (6-MP) at conventional doses was considered as a surrogate marker of hematologic toxicity. The allele frequency of TPMT*2, *3A, *3B and *3C in the study population was 0.5, 0, 0 and 2.6%, respectively, similar to the frequency observed in other Asian populations. Five patients were heterozygous for TPMT*3C variant allele, and one of these patient’s was compound heterozygous with TPMT*2 variant as the other allele. The impact of TPMT polymorphisms on the toxicity and treatment outcome was assessed in 66 pediatric patients only, as there was no variant TPMT detected in the adult patients. Three of the 5 patients (60%) heterozygous for TPMT*2 or TPMT*3C polymorphisms and 12/61 patients (20%) with wild type TPMT genotype had more than 10% of reduction of 6-MP dose (P = 0.07). The presence of TPMT polymorphisms did not seem to completely explain the variation in 6-MP toxicity in this small group of patients. Other novel variants in TPMT or variations in the genes involved in transport and biotransformation of 6-MP need to be evaluated in the Indian population.     

Role of minimal residual disease monitoring in acute promyelocytic leukemia treated with arsenic trioxide in frontline therapy

Data on minimal residual disease (MRD) monitoring in acute promyelocytic leukemia (APL) are available only in the context of conventional all-trans retinoic acid plus chemotherapy regimens. It is recognized that the kinetics of leukemia clearance is different with the use of arsenic trioxide (ATO) in the treatment of APL. We undertook a prospective peripheral blood RT-PCR-based MRD monitoring study on patients with APL treated with a single agent ATO regimen. A total of 151 patients were enrolled in this study. A positive RT-PCR reading at the end of induction therapy was significantly associated on a multivariate analysis with an increased risk of relapse (relative risk = 4.9; P = .034). None of the good risk patients who were RT-PCR negative at the end of induction relapsed. The majority of the relapses (91%) happened within 3 years of completion of treatment. After achievement of molecular remission, the current MRD monitoring strategy was able to predict relapse in 60% of cases with an overall sensitivity and specificity of 60% and 93.2%, respectively. High-risk group patients and those that remain RT-PCR positive at the end of induction are likely to benefit from serial MRD monitoring by RT-PCR for a period of 3 years from completion of therapy.     

A novel 26 bp deletion [HBB: c.20_45del26bp] in exon 1 of the β-globin gene causing β-thalassemia major

Molecular characterization of β-thalassemia (β-thal) is essential in prevention and in understanding the biology of the disease. Deletion mutations are relatively uncommon in β-thal. In this report, we describe a novel 26 bp deletion from codon 6 to codon 14 in the β-globin in a consanguineous family from Tamil Nadu, India. This novel mutation causes a shift in the normal reading frame of the β-globin coding sequence, and consequently, a premature chain termination of translation due to the creation of a stop codon at the position of codon 21. The identification of this novel deletional mutation adds to the repertoire of β-thal mutations in India.     

Obstructive sleep apnea and diabetic neuropathy: a novel association in patients with type 2 diabetes

Rationale: Diabetic peripheral neuropathy is common and causes significant morbidity. Obstructive sleep apnea (OSA) is also common in patients with type 2 diabetes. Because OSA is associated with inflammation and oxidative stress, we hypothesized that OSA is associated with peripheral neuropathy in type 2 diabetes. Objectives: To assess the relationship between OSA and peripheral neuropathy in patients with type 2 diabetes. Methods: A cross-sectional study of adults with type 2 diabetes recruited randomly from the diabetes clinic of two UK hospitals. Measurements and Main Results: Peripheral neuropathy was diagnosed using the Michigan Neuropathy Screening Instrument. OSA (apnea-hypopnea index ≥ 5 events/h) was assessed using home-based, multichannel respiratory monitoring. Serum nitrotyrosine was measured by ELISA, lipid peroxide by spectrophotometer, and microvascular function by laser speckle contrast imaging. Two hundred thirty-four patients (mean [SD] age, 57 [12] yr) were analyzed. OSA prevalence was 65% (median apnea-hypopnea index, 7.2; range, 0-93), 40% of which were moderate to severe. Neuropathy prevalence was higher in patients with OSA than those without (60% vs. 27%, P < 0.001). After adjustment for possible confounders, OSA remained independently associated with diabetic neuropathy (odds ratio, 2.82; 95% confidence interval, 1.44-5.52; P = 0.0034). Nitrotyrosine and lipid peroxide levels (n = 102, 74 with OSA) were higher in OSA and correlated with hypoxemia severity. Cutaneous microvascular function (n = 71, 47 with OSA) was impaired in OSA. Conclusions: We describe a novel independent association between diabetic peripheral neuropathy and OSA. We identified increased nitrosative/oxidative stress and impaired microvascular regulation as potential mechanisms. Prospective and interventional studies are needed to assess the impact of OSA and its treatment on peripheral neuropathy development and progression in patients with type 2 diabetes.