Design of modified U1i molecules against HIV-1 RNA

Several gene therapeutic approaches have been proposed to add to current antiretroviral therapy against HIV-1. U1 interference (U1i) is a promising new gene therapy tool that targets mRNAs with modified U1 snRNAs. For efficient inhibition, the 3'-terminal exon of pre-mRNAs must be recognized by the modified U1 snRNA. Subsequent interaction between the U1-associated 70K protein and poly(A) polymerase leads to inhibition of polyadenylation and consequently degradation of the pre-mRNA. We designed 14 new U1i inhibitors against HIV-1 mRNA regions that are 100% complementary to at least 70% of HIV-1 sequences listed in the HIV database. All U1i inhibitors were tested transiently in HIV-1 production assays as well as luciferase reporter experiments and three candidates were examined further in stably lentivirus-transduced T cell lines. We identified U1i-J that targets the region encoding the NF-κB binding sites as the most effective inhibitor that substantially reduced viral protein expression. The potency of J is determined in part by the presence of a duplicated target within the HIV-1 mRNA. The stably transduced SupT1 T cells were challenged with HIV-1 but no antiviral effect was detected. U1i inhibitors can be potent suppressors of HIV-1 production in transient assays but further optimization of this antiviral approach is needed.     

Propofol pharmacokinetics in young healthy Indian subjects

Objectives:

To analyze population pharmacokinetics of Propofol in Indian patients after single bolus dose of Propofol using WINNONLIN program.

Materials and Methods:

Population pharmacokinetics of Propofol was investigated in Indian subjects in 26 elective surgical patients (14 males and 12 females) following single bolus dose of 2 mg/kg propofol. A total of 364 samples were estimated by High Performance Liquid Chromatography and pharmacokinetic parameters were derived using WINNONLIN (5.2). The effect of demographic characters of the study population on pharmacokinetic parameters was investigated.

Results:

Three-compartment model was used to describe the pharmacokinetic data of Propofol in Indian subjects. Initial volume of distribution (V1) clearance (Cl) and steady state volume of distribution (Vd_ss) was 13.5 ± 3.3 l, 1.08 ± 0.42 l/min, and 77.69 ± 48.0 l, respectively. Body weight best described the volume of central compartment (V1) as well as elimination clearance (P<0.01).

Conclusion:

Pharmacokinetics of Propofol in young healthy Indian subjects show lower volume of distribution and clearance as compared with most of the western data. Body weight best describes the V1, Vd_ss, and Clearance in this group.KEY WORDS: Anesthetics, propofol, pharmacokinetics, volume of distribution     

Synthesis, spectroscopic, thermal and antimicrobial studies of Co(II), Ni(II), Cu(II) and Zn(II) complexes with Schiff base derived from 4-amino-3-mercapto-6-methyl-5-oxo-1,2,4-triazine

Coordination complexes of Co(II), Ni(II), Cu(II) and Zn(II) with Schiff base derived from syringaldehyde and 4-amino-3-mercapto-6-methyl-5-oxo-1,2,4-triazine have been synthesized. These complexes have been characterized by elemental analysis, magnetic moment, spectroscopic (IR, Electronic, ¹H NMR, ESR) and thermogravimetric analysis. Magnetic and spectral data suggest octahedral geometry for Co(II), Ni(II) and Zn(II) complexes and square planar for Cu(II) complexes. The presence of coordinated water in metal complexes was confirmed by thermal and IR data. The Schiff base and its metal complexes have been screened for antibacterial (Pseudomonas aeruginosa, Bacillus subtilis, Escherichia coli, Staphylococcus aureus) and antifungal activities (Aspergillus niger, A. flavus). A comparison is made between activities of complexes with Schiff base and with the standard antibiotics.     

The nicotinic α7 receptor agonist GTS-21 improves cognitive performance in ketamine impaired rhesus monkeys

The cognitive deficits associated with schizophrenia are recognized as a core component of the disorder, yet there remain no available therapeutics to treat these symptoms of the disease. As a result, there is a need for establishing predictive preclinical models to identify the therapeutic potential of novel compounds. In the present study, rhesus monkeys were trained in the object retrieval-detour task, which is dependent on the prefrontal cortex, a brain region implicated in the cognitive deficits associated with schizophrenia. The NMDA receptor antagonist ketamine significantly impaired performance without affecting measures of motor or visuospatial abilities. Pre-treatment with the nicotinic α7 agonist GTS-21 (0.03?mg/kg) significantly attenuated the ketamine-induced impairment, consistent with reports from clinical trials suggesting that nicotinic α7 receptor agonism has pro-cognitive potential in clinical populations. In contrast, pretreatment with the acetylcholinesterase inhibitor donepezil failed to reverse the ketamine-induced impairment, consistent with studies showing a lack of pro-cognitive effects in patients with schizophrenia. These data suggest that the ketamine-impaired object retrieval-detour task could provide a model with improved predictive validity for drug development, and confirm the need for additional efforts in back-translation. This article is part of a Special Issue entitled 'Cognitive Enhancers'.     

Comparative assessment of platelet GpIIb/IIIa receptor occupancy ratio with Eptifibatide/Tirofiban in patients presenting with ACS and undergoing PCI

BackgroundThe level of platelet inhibition by a Glycoprotein IIb/IIIa (Gp_IIb/IIIa) antagonist therapy necessary to minimize thrombotic complications in patients undergoing percutaneous coronary intervention (PCI) is a subject of debate. The degree of platelet inhibition obtained 10 min after start of Gp_IIb/IIIa antagonist therapy predicts adverse events after PCI. The aim of this study was to look at platelet inhibition and to compare platelet Gp_IIb/IIIa receptors occupancy ratio (GpRO) with Eptifibatide and Tirofiban using various dose regimens and correlate with 30-day clinical outcomes in patients presenting with high-risk acute coronary syndromes (ACS) and undergoing PCI.MethodsThe patients were divided into four sub groups: (1) Eptifibatide two intracoronary bolus (180 μg/kg) alone (E^B); or (2) two intravenous bolus (180 μg/kg) followed by infusion at 2 μg/kg/min for 24 h (E^B + Inf); and (3) Tirofiban standard bolus dose (0.4 μg/kg) over 30 min followed by infusion at 0.1 μg/kg/min (T^Std); or (4) at ADVANCE dose bolus (25 μg/kg) over 3 min, followed by infusion at 0.1 μg/kg/min (T^Adv). Number of Gp_IIb/IIIa receptors was assessed by flow cytometry at baseline and 10 min after the bolus and percentage of free receptors was determined to calculate the GpRO. Patients were followed for 30 days for any major adverse cardiac events (MACE).Results200 consecutive patients (including 74% with ST-elevation ACS) were enrolled. GpRO in groups E^B (n = 48) and E^B + Inf (n = 44) were 62.7% ± 27.2% and 61.4% ± 6.1% respectively while in the groups T^Std (n = 96) and T^Adv (n = 12) groups were 35.1% ± 17.74% and 68.8% ± 27.3% respectively. The GpRO was similar in E^B, E^B + Inf and T^Adv groups and was significantly higher than T^Std group (p < 0.0001). The 30-day MACE rates in E^B (4.2%), E^B + Inf (4.5%) and T^Adv (4.2%) were significantly lower than T^Std group (12.5%) (p < 0.01).ConclusionsStandard dose Tirofiban results in significantly lower rates of Gp_IIb/IIIa receptor occupancy ratio and this correlated with higher incidence of 30-day MACE in high-risk ACS patients undergoing PCI.     

Appendicitis in obese children

During the past two decades, the incidence of childhood obesity has increased at alarming rates throughout the world. Obesity is associated with a variety of physiological changes that may impair a patient’s response to surgery. With the rising rates of childhood obesity, pediatric surgeons must appreciate differences in the management and outcomes of these patients. Difficult physical examination, elevated inflammatory blood markers, and negative influence of obesity on the detection rate of the appendix on ultrasound have been reported causing diagnostic challenging of appendicitis in obese children. Moreover, obesity is associated with longer hospital stay and higher morbidity and minimal invasive techniques’ superior outcomes over open technique in children undergoing appendectomy.     

Survival Analysis of Down Syndrome Cohort in a Tertiary Health Care Center in India

Objective

To identify the major causes of death in Down Syndrome (DS), the ages at which mortality rates are the highest and recognize factors associated with it.

Methods

The prospective cohort-based study was carried out in a tertiary health care center. Children with DS (n?=?543) counseled at the Center of Medical Genetics, Sir Ganga Ram Hospital from 2005 through 2009 were followed up in year 2010. Survival curves and Cox’s proportional hazards regression analysis were used to determine the effect of different variables on survival.

Results

Total mortality was 13 %, of which 80.3 % was in children less than 2 y of age. Presence of congenital heart disease (CHD) increased the risk of mortality by 5.7 folds (p?=?0.001). A definitive survival benefit after cardiac intervention was noted, although it differed with the type of CHD. Sex, maternal age at time of birth and karyotypes did not show a significant correlation with survival.

Conclusions

The higher DS infant mortality observed in the present study could be attributed to financial constraints of the families and misconceptions amongst health professionals. It is recommended that a nation-wide DS registry be created to study the morbidity and mortality in Down syndrome from birth. The findings of this study will help clinicians in making management decisions and enable better counseling.     

Hirschsprung’s disease associated with Down syndrome: a meta-analysis of incidence, functional outcomes and mortality

Purpose

Down syndrome (DS) is the most frequent chromosomal abnormality associated with Hirschsprung’s disease (HD). It has often been suggested that this association results in poorer outcomes with regard to postoperative complications, continence and mortality. On the other hand, the results after surgical treatment of HD in patients with DS are reportedly similar to those in cases with HD alone. The objective of this study was to determine the incidence of DS in cohorts with HD, and to compare pre-/postoperative complications, functional outcome and mortality between cohorts with and without coexisting DS.

Methods

A systematic literature-based search for relevant cohorts was conducted using multiple online databases. The number of DS cases in HD cohorts was recorded and data on pre-/postoperative complications, functional outcome and mortality were extracted. Pooled odds ratios with 95 % confidence intervals were calculated using meta-analysis methodology.

Results

Sixty-one articles met defined inclusion criteria, comprising data from 16,497 patients with HD. The overall incidence of DS among them was 7.32 %. Vice versa, the incidence of HD in 29,418 patients with DS was 2.62 %. There were no significant differences regarding the male-to-female ratio between cohorts with and without coexisting DS (4:1 vs. 3:1 respectively; P = 0.5376). The rate of additional comorbidities was significantly higher in HD associated with DS (P < 0.0001). Recto-sigmoid HD was in both cohorts the most common type of HD (P = 0.8231). Long-segment HD was significantly more frequent in HD with coexisting DS (P = 0.0267), while total colonic aganglionosis occurred significantly more often in HD without DS (P = 0.0003). There were no significant differences in preoperative constipation/obstruction (P = 0.5967), but the rate of preoperative enterocolitis was significantly higher in HD associated with DS (P = 0.0486). Postoperative complications such as recurrent enterocolitis (P = 0.0112) and soiling (P = 0.0002) were significantly more frequent in HD with coexisting DS. Although not statistically significant, fecal incontinence (P = 0.1014) and persistent constipation (P = 0.1670) occurred more often after surgical treatment of HD with DS. The mortality rate was significantly higher in HD associated with DS (P < 0.0001).

Conclusions

The association of HD with DS is well-recognized with an incidence of 7.32 %. A large number of patients with DS continue to have persistent bowel dysfunction after surgical treatment of HD. Our data provide strong evidence that the coexistence of HD and DS is associated with higher rates of pre-/postoperative enterocolitis, poorer functional outcomes and increased mortality.