Tissue specific expression of sialic acid metabolic pathway: role in GNE myopathy

Journal of Muscle Research and Cell Motility - GNE myopathy is an adult-onset degenerative muscle disease that leads to extreme disability in patients. Biallelic mutations in the rate-limiting...     

Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury

Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia/reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia/reperfusion injury.     

First Hour Initiation of Breastfeeding and Exclusive Breastfeeding at Six Weeks: Prevalence and Predictors in a Tertiary Care Setting

Objective

To assess the prevalence of first hour breastfeeding initiation and exclusive breastfeeding at 6 wk and identify its barriers in healthy term babies born in a tertiary hospital setting.

Methods

A prospective observational cohort study was carried out in consecutively selected 400 mothers who delivered (normal, instrumental or cesarean) term healthy babies in a tertiary care hospital setting. All mother-infant dyads were enroled within 48 h of delivery.

Results

Breastfeeding was initiated within first hour in 255 out of 400, i.e., 64 % of babies. Cesarean delivery and male gender were strongest risk factors for delayed initiation of breastfeeding [OR (95 % CI)?=?1.99 (1.14–3.48) and 34.17 (17.10–70.40) respectively]. Among the babies followed up till 6–8 wk, 83 % were exclusively breastfed. Breast milk substitutes were given in 172/400 (43 %) babies on day one, which emerged as an independent predictor of failure to continue exclusive breastfeeding at 6 wk (OR 2.96; 95 % CI 1.09–8.06). Odds of exclusive breastfeeding were two times higher in babies breastfed within first hour (n?=?255/400, 64 %) when compared to babies initiated breastfeeds beyond first hour (n?=?145/400, 36 %) (OR 2.01;05 % CI 1.12–3.61).

Conclusions

Cesarean section and male gender emerged as significant risk factors for delayed initiation (beyond first hour) of breastfeeding in the index study cohort. In addition, use of breast milk substitute emerged as the only predictor for failure to continue exclusive breastfeeding at six weeks in a tertiary care hospital.     

Screening high-risk cancer patients for VTE: A prospective observational study

Background

The utility of screening for venous thromboembolism (VTE) in cancer patients is unknown. We evaluated this in a prospective cohort study of cancer patients initiating a new chemotherapy regimen and deemed high-risk (score ≥ 3) based on a validated Risk Score.

Methods

Patients were evaluated with baseline and Q4 (± 1) week serial ultrasonography for up to 16 weeks; additionally, computed tomography scans for restaging were also evaluated for VTE.

Results

The study population comprised 35 patients. Pancreatic and gastro-esophageal cancers were the most common diagnoses. Of these, 8 (23%) developed a VTE. This included 5 patients with DVT alone (14%), 1 patient with PE alone (3%) and 2 (6%) with both. Ultrasound examinations identified asymptomatic DVT in 9.3% of patients at baseline; 0% at weeks 4 and 8 and 5.6% at week 12. Restaging CT scans identified asymptomatic PE in one patient at week 6 and in one patient at week 9 with subsequent DVT at week 10.

Conclusions

Screening for asymptomatic VTE has not been previously used as a clinical strategy in ambulatory cancer patients. We report that one-tenth of patients at baseline had occult DVT and in this high-risk population, screening at baseline may be of value.     

Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver

A 30-d course of oral administration of a semipurified extract of the root of Withania somnifera consisting predominantly of withanolides and withanosides reversed behavioral deficits, plaque pathology, accumulation of β-amyloid peptides (Aβ) and oligomers in the brains of middle-aged and old APP/PS1 Alzheimer's disease transgenic mice. It was similarly effective in reversing behavioral deficits and plaque load in APPSwInd mice (line J20). The temporal sequence involved an increase in plasma Aβ and a decrease in brain Aβ monomer after 7 d, indicating increased transport of Aβ from the brain to the periphery. Enhanced expression of low-density lipoprotein receptor-related protein (LRP) in brain microvessels and the Aβ-degrading protease neprilysin (NEP) occurred 14-21 d after a substantial decrease in brain Aβ levels. However, significant increase in liver LRP and NEP occurred much earlier, at 7 d, and were accompanied by a rise in plasma sLRP, a peripheral sink for brain Aβ. In WT mice, the extract induced liver, but not brain, LRP and NEP and decreased plasma and brain Aβ, indicating that increase in liver LRP and sLRP occurring independent of Aβ concentration could result in clearance of Aβ. Selective down-regulation of liver LRP, but not NEP, abrogated the therapeutic effects of the extract. The remarkable therapeutic effect of W. somnifera mediated through up-regulation of liver LRP indicates that targeting the periphery offers a unique mechanism for Aβ clearance and reverses the behavioral deficits and pathology seen in Alzheimer's disease models.     

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.     

Sudden unexpected death in epilepsy in lamotrigine randomized‐controlled trials

Purpose: Nonrandomized studies of the relationship of antiepileptic drugs (AEDs) with sudden unexpected death in epilepsy (SUDEP) may be susceptible to confounding by tonic–clonic seizure frequency, polypharmacy, and other potential risk factors for SUDEP. We evaluated the risk of SUDEP with lamotrigine (LTG) compared to active comparators and placebo in randomized controlled clinical trials conducted by GlaxoSmithKline (GSK) between 1984 and 2009. Methods: Among 7,774 subjects in 42 randomized clinical trials, there were 39 all‐cause deaths. Ten deaths occurred >2 weeks after discontinuation of study medication and were excluded. Narrative summaries of deaths were independently reviewed by three clinical experts (TT, LH, DF), who were blinded to randomized treatment arm. The risk of definite or probable SUDEP was compared between treatment arms for each trial type (placebo‐controlled, active‐comparator, crossover), using exact statistical methods. Key Findings: Of 29 on‐treatment deaths, eight were definite/probable SUDEP, four were possible SUDEP, and 17 were non‐SUDEP. The overall, unadjusted rate of definite/probable SUDEP for LTG was 2.2 events per 1,000‐patient years (95% confidence interval [95% CI] 0.70–5.4). The odds ratios (OR) for on‐treatment, definite/probable SUDEP in LTG arms relative to comparator arms, adjusted for length of exposure and trial, were the following: placebo‐controlled, OR 0.22 (95% CI 0.00–3.14; p = 0.26); active‐comparator, OR 2.18 (95% CI 0.17–117; p = 0.89); and placebo‐controlled cross‐over, OR 1.08 (95% CI 0.00–42.2; p = 1.0). Significance: There was no statistically significant difference in rate of SUDEP between LTG and comparator groups. However, the CIs were wide and a clinically important effect cannot be excluded.