CYBA and GSTP1 variants associate with oxidative stress under hypobaric hypoxia as observed in high-altitude pulmonary oedema

HAPE (high-altitude pulmonary oedema) is characterized by pulmonary hypertension, vasoconstriction and an imbalance in oxygen-sensing redox switches. Excess ROS (reactive oxygen species) contribute to endothelial damage under hypobaric hypoxia, hence the oxidative-stress-related genes CYBA (cytochrome b-245 α polypeptide) and GSTP1 (glutathione transferase Pi 1) are potential candidate genes for HAPE. In the present study, we investigated the polymorphisms -930A/G and H72Y (C/T) of CYBA and I105V (A/G) and A114V (C/T) of GSTP1, individually and in combination, in 150 HAPE-p (HAPE patients), 180 HAPE-r (HAPE-resistant lowland natives) and 180 HLs (healthy highland natives). 8-Iso-PGF2α (8-iso-prostaglandin F2α) levels were determined in plasma and were correlated with individual alleles, genotype, haplotype and gene-gene interactions. The relative expression of CYBA and GSTP1 were determined in peripheral blood leucocytes. The genotype distribution of -930A/G, H72Y (C/T) and I105V (A/G) differed significantly in HAPE-p compared with HAPE-r and HLs (P≤0.01). The haplotypes G-C of -930A/G and H72Y (C/T) in CYBA and G-C and G-T of I105V (A/G) and A114V (C/T) in GSTP1 were over-represented in HAPE-p; in contrast, haplotypes A-T of -930A/G and H72Y (C/T) in CYBA and A-C of I105V (A/G) and A114V (C/T) in GSTP1 were over-represented in HAPE-r and HLs. 8-Iso-PGF2α levels were significantly higher in HAPE-p and in HLs than in HAPE-r (P=2.2×10(-16) and 1.2×10(-14) respectively) and the expression of CYBA and GSTP1 varied differentially (P<0.05). Regression analysis showed that the risk alleles G, C, G and T of -930A/G, H72Y (C/T), I105V (A/G) and A114V (C/T) were associated with increased 8-iso-PGF2α levels (P<0.05). Interaction between the two genes revealed over-representation of most of the risk-allele-associated genotype combinations in HAPE-p and protective-allele-associated genotype combinations in HLs. In conclusion, the risk alleles of CYBA and GSTP1, their haplotypes and gene-gene interactions are associated with imbalanced oxidative stress and, thereby, with high-altitude adaptation and mal-adaptation.     

Leflunomide: an unlikely trigger and mechanistically a beneficial drug for alopecia areata

Clinical Rheumatology -     

A cost effective endovascular approach for management of post-catheterization profunda femoris artery pseudoaneurysm using thrombin

Post-catheterization PSA is one of the most commonly encountered vascular complications of cardiac and peripheral angiographic procedures. We report the case of patient who developed deep-seated profunda femoris artery pseudoaneurysm (PSA) following cardiac catheterization. Despite, repeated ultrasound guided compressions the PSA failed to close and instead produced local site pressure ulcers. The secondary infection followed which precluded use of percutaneous thrombin injection. The PSA was finally closed via a total endovascular technique combining intravascular thrombin injection and coil embolization, thus obviating the need for expensive measures like cover stents or invasive surgical repairs.     

Long-term contraception by steroid-releasing implants. II. A preliminary report on long-term contraception by a single silastic implant containing norethindrone acetate (ENTA) in women.

A preliminary report on the long-term contraceptive effectiveness and acceptability of a single subdermal silastic implant containing norethindrone acetate (ENTA) is presented. The 4 types of implants used varied in length, wall thickness, and amount of ENTA; implant A contained 20-25 mg ENTA, implant B contained 30-35 mg ENTA, implant C contained 45-50 mg ENTA as was longer than all the other implants, and implant D contained 40 mg ENTA and had a greater wall thickness than all the other implants. 213 women volunteers received a single implant and were followed for a total of 909 cycles. 2 of 13 women receiving implant A, 2 of 39 women receiving implant B, 3 of 76 women receiving implant C, and none of the 85 women receiving implant D became pregnant. Implant D had the longest expected life-span (10 months). Menstrual irregularities were fewest with implants A (23%) and D (20%), and greatest with implant C (42%). there were no complaints of nausea, insomnia, tender breasts, or loss of libido. 4 patients with implant B and 6 patients with implant C had the capsules removed for medical reasons. More detailed studies of implant D are in progress.     

Diabetic retinal neurodegeneration as a form of diabetic retinopathy

Purpose

To review the evidence supporting diabetic retinal neurodegeneration (DRN) as a form of diabetic retinopathy.

Method

Review of literature.

Results

DRN is recognized to be a part of retinopathy in patients with diabetes mellitus (DM), in addition to the well-established diabetic retinal vasculopathy (DRV). DRN has been noted in the early stages of DM, before the onset of clinically evident diabetic retinopathy. The occurrence of DRN has been confirmed in animal models of DM, histopathological examination of donor’s eyes from diabetic individuals and assessment of neural structure and function in humans. DRN involves alterations in retinal ganglion cells, photoreceptors, amacrine cells and bipolar cells, and is thought to be driven by glutamate, oxidative stress and dysregulation of neuroprotective factors in the retina. Potential therapeutic options for DRN are under evaluation.

Conclusions

Literature is divided on the temporal relation between DRN and DRV, with evidence of both precedence and simultaneous occurrence. The relationship between DRN and multi-system neuropathy in DM is yet to be evaluated critically.

     

Experience with generic pegylated L-asparaginase in children with acute lymphoblastic leukemia and monitoring of serum asparaginase activity

Abstract

Background: Pegylated asparaginase (P-Asp) though integral to acute lymphoblastic leukemia (ALL) therapy is often not accessible to patients in developing countries. We share our clinical experience with generic P-Asp along with monitoring of asparaginase activity. Methods: In this prospective observational study, patients ≤18?years of age with ALL were assigned to receive either generic P-Asp or native asparaginase (N-Asp) in a non-randomized manner. Treatment protocol was based on ALL BFM-95 backbone. The dose of P-Asp was 1500?IU/m² by intravenous route during induction (Ia) and re-induction (IIa) phase of therapy. Results: N-Asp or P-Asp was administered to 52 and 54 of the 106 eligible patients respectively. Demographic and disease characteristics were comparable in both arms. The mean trough levels for N-Asp and P-Asp were 156.87?±?22.35?IU/L and 216.03?±?73.40?IU/L, respectively (p value <0.001) and all patients achieved therapeutic levels during Ia. Incidence of asparaginase-attributable toxicity was similar in the two arms in both phases of treatment, although hospitalization due to noninfectious causes was more common in P-Asp arm during Ia (13% versus 0%, p value, 0.01). Clinical hypersensitivity and silent inactivation were not observed during Ia while these occurred in 13% and 5% of patients in the N-Asp arm and P-Asp arms of IIa, respectively. The 2-year event free survival for P-Asp and N-Asp groups was 84% and 80.7%, respectively (p value 0.85). Conclusion: Generic P-Asp was observed to be efficacious and well tolerated in our patients and adequate therapeutic levels were sustained for 2 weeks.     

Indomethacin therapy in the treatment of polyhydramnios due to placental chorioangioma.

A 26-year-old primigravida presented with acute polyhydramnios at 30 weeks gestation. Ultrasonography revealed a large placental chorioangioma with severe hydramnios. No anomalies were detected in the fetus. Preterm labor started with respiratory distress and indomethacin, 25 mg was given every 6 hours. The patient showed a good response with improvement of the hydramnios and respiratory symptoms. A normal infant with no neonatal complications was delivered 3 weeks later.