Thioredoxin reductase may be essential for the normal growth of hyperbaric oxygen-treated human lens epithelial cells

We have shown previously with in vivo and in vitro animal models that the lens epithelium, in contrast to the nucleus, is remarkably resistant to hyperoxia. The main purpose of this study was to investigate the mRNA response of cultured human lens epithelial cells (LECs) to challenge by a high level of hyperbaric oxygen. Cells were treated for 3 hr with 50 atm of 99% O2, and then cultured normally for various times up to 11 days. Although the cells appeared normal immediately after the O2-treatment, they failed to grow and suffered 50% cell loss, as well as significant mitochondrial damage, during normal post-culture. Growth of the cells resumed after 3 days and by day 11, the number of O2-treated cells was the same as the controls. Remarkably, the 3 hr O2-treatment produced no immediate effects on either the cellular level of GSH, or on the activities of a number of antioxidant enzymes including glyceraldehyde-3-phosphate dehydrogenase, which is generally regarded as being highly sensitive to oxidation. In contrast, the activity of thioredoxin reductase (TrxR) was severely affected by the O2, decreasing by 51% after the 3 hr exposure. O2-induced death of the cells appeared to be caused by loss of ATP since a 31% decrease in ATP level occurred immediately after the O2-treatment, in spite of a 46% increase in lactate production. Analysis with real-time PCR showed a maximum 3-6-fold increase in mRNA levels 9 hr after the 3 hr O2-exposure for the enzymes heme oxygenase-1 (HO-1), MnSOD and TrxR1 (the cytoplasmic form of TrxR). These results were confirmed with the use of one-step RT-PCR and Northern blotting. Initial upregulation of message for HO-1 occurred a few hours before any upregulation of MnSOD could be detected, suggesting that release of free iron from the degradation of heme by HO-1 may have played a role in the upregulation of the dismutase. No significant changes in mRNA levels were observed for the antioxidant enzymes catalase, CuZnSOD, glutathione reductase and glutathione peroxidase, or for the antioxidant protein thioredoxin. Recovery of TrxR activity over a 4-day period appeared to parallel the return of the cells to a normal rate of growth. The results indicate that damaging effects of hyperoxia on cultured LECs occur primarily in the mitochondria, rather than in the cytoplasm. Cells avoid O2-induced cell death, and return to a normal rate of proliferation by upregulating mRNA levels for HO-1, MnSOD and TrxR1. It appears that full activity of TrxR1, an enzyme required for the production of deoxyribonucletides for DNA synthesis, is essential for the normal growth of O2-challenged LECs.     

Pheochromocytoma associated with pregnancy

Pheochromocytoma associated with pregnancy is rare with potentially lethal consequences. Antepartum diagnosis improves the maternal and perinatal outcome. The issue of mode of delivery is unresolved. Its definitive treatment is surgical resection preceded by medical management. Surgical resection may be done during caesarean section as is reported in the present case.     

Glomerular and tubular function in glycogen storage disease

Urinary protein and calcium excretion were assessed in 77 patients with the hepatic glycogen storage diseases (GSD): 30 with GSD-I (median age 12.4 years, range 3.2–32.9 years), 25 with GSD-III (median age 10.5 years, range 4.2–31.3 years) and 22 with GSD-IX (median age 11.8 years, range 1.2–35.4 years). Inulin (C _inulin) and para-aminohippuric acid (C _PAH) clearances were also measured in 33 of these patients. Those with GSD-I had significantly greater albumin (F=15.07,P<0.001), retinolbinding protein (RBP) (F=14.66,P<0.001),N-acetyl--d glucosaminidase (NAG) (F=9.41,P<0.001) and calcium (F=7.41,P=0.001) excretion than those with GSD-III and GSD-IX. GSD-I patients (n=18) also had significantly higherC _inulin (F=5.57,P=0.009), butC _PAH did not differ (F=0.77, NS). Renal function was normal in GSD-III and GSD-IX patients. In GSD-I,C _inulin (r=–0.51,P=0.03) and NAG excretion (r=–0.40,P=0.03) were inversely correlated with age, whereas albumin excretion was positively correlated with age (r=+0.41,P=0.03). RBP and calcium excretion were generally high throughout all age groups. Hyperfiltration in GSD-I is associated with renal tubular proteinuria that occurs before the onset of significant albuminuria. Deficiency of glucose-6-phosphatase within the proximal renal tubule may primarily cause tubular dysfunction, glomerular hyperfiltration being a secondary phenomenon.     

Urinary monocyte chemoattractant protein-1 correlates with disease activity in lupus nephritis

Monocyte chemoattractant protein-1 (MCP-1) has a pathogenic role in murine lupus nephritis (LN). We recruited 25 pediatric and adolescent systemic lupus erythematosus (SLE) patients from our lupus clinic [13 (52%) patients with LN and 12 (48%) lupus non-nephritis patients] and evaluated their urinary and plasma MCP-1 levels compared to adult and childhood controls. The median age and SLE disease duration of patients were 14.4 and 5.5 years, respectively. LN patients had a higher median renal (p?=?0.01) British Isles Lupus Assessment Group (BILAG) index, with a tendency for higher total BILAG scores (p?=?0.2). There were significantly increased urinary MCP-1 levels in the LN patients compared to healthy controls (p?<?0.001) whose values were significantly higher than lupus non-nephritis children (p<?0.004). Urinary MCP-1 levels correlated well with total BILAG scores (r?=?0.82, p?=?0.04). There were no differences in plasma MCP-1 levels between SLE patient groups and pediatric controls, although the levels in the childhood controls were elevated compared to those of the adult controls (p?<?0.04). These results provide evidence of increased urinary—but not plasma—MCP-1 levels in children with LN, which correlates well with SLE disease activity as measured by the BILAG index.     

Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo-controlled, dose-escalation study

CONTEXT: In previous 1-yr trials, treatment with pramlintide (120 microg), an analog of the beta-cell hormone amylin, induced sustained reductions in A1C and body weight in insulin-using subjects with type 2 diabetes. OBJECTIVE: To assess the potential of pramlintide as an antiobesity agent, we assessed the weight effect, safety, and tolerability of pramlintide in non-insulin-treated obese subjects with and without type 2 diabetes at doses greater than previously studied. DESIGN/SETTING: We performed a randomized, double-blind, placebo-controlled, multicenter study. PATIENTS: A total of 204 obese subjects [80/20% female/male, age 48 +/- 10 yr, and body mass index 37.8 +/- 5.6 kg/m(2) (mean +/- SD)] participated in the study. INTERVENTION: For 16 wk, without concomitant lifestyle intervention, subjects self-administered pramlintide (nonforced dose escalation < or = 240 microg) or placebo via sc injection three times a day before meals. MAIN OUTCOME MEASURES: Weight, waist circumference, tolerability, and safety were the main outcome measures. RESULTS: Pramlintide was generally well tolerated, with 88% of subjects able to escalate to the maximum dose of 240 microg. Withdrawal rates were similar between placebo (25%) and pramlintide-treated subjects (29%). Subjects completing 16 wk of pramlintide treatment experienced placebo-corrected reductions in body weight of 3.7 +/- 0.5% (3.6 +/- 0.6 kg; P < 0.001) and waist circumference (3.6 +/- 1.1 cm; P < 0.01). Approximately 31% of pramlintide-treated subjects achieved > or =5% weight loss (vs. 2% placebo; P < 0.001). More pramlintide than placebo-treated subjects reported improvements in appetite control (72% vs. 31%), weight control (63% vs. 24%), and overall well-being (52% vs. 17%). No unexpected safety signals were observed. The most common adverse event reported was mild, transient nausea. Pramlintide-treated subjects not reporting nausea experienced weight loss similar to those who did (3.6 +/- 0.5% and 3.9 +/- 0.5%, respectively). CONCLUSION: These results support continued evaluation of pramlintide as a potential treatment for obesity.     

A bimodal association of vitamin D levels and vascular disease in children on dialysis

In addition to its classical role in calcium-phosphate homeostasis, vitamin D has anti-inflammatory effects that may influence vascular disease. This study examined the impact of vitamin D levels on the vascular phenotype in 61 children who had been on dialysis for >or=3 mo and in 40 age-matched control subjects. All dialysis patients were prescribed daily oral 1-alpha hydroxyvitamin D(3). 92% of patients were deficient in 25-hydroxyvitamin D [25(OH)D]. 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels were low in 36% and high in 11% of patients. There was a weak correlation between 1 alpha-hydroxyvitamin D(3) dosage and 1,25(OH)(2)D levels. Both carotid intima-media thickness and calcification scores showed a U-shaped distribution across 1,25(OH)(2)D levels: patients with both low and high 1,25(OH)(2)D had significantly greater carotid intima-media thickness (P < 0.0001) and calcification (P = 0.0002) than those with normal levels. Low 1,25(OH)(2)D levels were associated with higher high-sensitivity C-reactive protein (P < 0.0001). Calcification was most frequently observed in patients with the lowest 1,25(OH)(2)D and the highest high-sensitivity C-reactive protein. In contrast, 25(OH)D levels did not correlate with any vascular measure. In conclusion, both low and high 1,25(OH)(2)D levels are associated with adverse morphologic changes in large arteries, and this may be mediated through the effects of 1,25(OH)(2)D on calcium-phosphate homeostasis and inflammation. For optimization of strategies to protect the vasculature of dialysis patients, careful monitoring of 1,25(OH)(2)D levels may be required.     

Geriatric hemodialysis rehabilitation care

The 2 objectives of this review are to provide background information about functional status in older dialysis patients and to discuss the utility of geriatric dialysis rehabilitation. We performed a literature search using PubMed and MedLine. All relevant texts were reviewed for information on functional status and disability in the renal population and in the general population. Data pertaining to geriatric rehabilitation and geriatric dialysis rehabilitation were also reviewed. We show how disability and functional limitations are more prevalent in populations with advanced stages of chronic kidney disease (CKD) compared with those with only mild stages of CKD. We describe data showing that dedicated geriatric dialysis rehabilitation units, using interdisciplinary care models, result in more than 70% of patients meeting their rehabilitation goals and being successfully discharged home. Nephrologists increasingly will be faced with problems arising from functional decline. We conclude by offering suggestions for future changes that may help to stem the rising tide of dialysis disability.     

Pregnancy with dilated and peripartum cardiomyopathy: maternal and fetal outcome

Background

A retrospective review of the records of all the patients of dilated cardiomyopathy (DCM) with pregnancy at PGIMER, Chandigarh, India, in order to find out maternal and fetal outcome.

Materials and methods

We did a retrospective analysis of records of diagnosed cases of DCM from 1994 to 2010. There were records of 38 patients who had DCM with pregnancy. Detailed history was followed by systemic examination, routine investigations and echocardiography. Multidisciplinary care was given to these women by obstetrician, cardiologist, anesthetist and neonatologist. Pharmacotherapy consisted to diuretics, alpha and beta blockers and heparin or low-dose aspirin for thrombo prophylaxis. Elective induction of labor was advised after 37 weeks of gestation subject to favorability of cervix.

Results

Out of 1,472 patients of heart disease during study period, 38 women had DCM. Out of these, 8 (21 %) had idiopathic cardiomyopathy, two had DCM due to thyrotoxicosis and 28 (73.6 %) patients had peripartum cardiomyopathy. Mean gestational age at the time of presentation was 35 weeks. Majority of the patients (19/38) presented with complaints of exertional dyspnoea. Mean LVEF at the time of diagnosis was 32.28 %. There were six (15.8 %) maternal deaths and all of them had global hypokinesia on echocardiography and presented in NYHA class IV. Fetal outcome too depended upon maternal cardiac status. There were eight stillbirths and all the patients who had IUFD belonged to class IV. Twelve patients (40 %) had preterm delivery. Mean birth weight of babies was 2 kg.