A short-term study of the safety pharmacokinetics and efficacy of ritonavir, an inhibitor of HIV-1 protease

Background: Reverse-transcriptase inhibitors have only moderate clinical efficacy against the human immunodeficiency virus type 1 (HIV-1). Ritonavir is an inhibitor of HIV-1 protease with potent in vitro anti-HIV properties and good oral bioavailability. Methods: We evaluated the antiviral activity and safety of ritonavir in a double-blind, randomized, placebo-controlled phase 1 and 2 study of 84 HIV-positive patients with 50 or more CD4+ lymphocytes per cubic millimeter. The patients were randomly assigned to one of four regimens of ritonavir therapy, or to placebo for four weeks and then (by random assignment) to one of the ritonavir regimens. Results: During the first 4 weeks, increases in CD4+ lymphocyte counts and reductions in the log number of copies of HIV-1 RNA per milliliter of plasma were similar among the four dosage groups, but in the three lower-dosage groups there was a return to base-line levels by 16 weeks. After 32 weeks, in the seven patients in the highest-dosage group (600 mg of ritonavir every 12 hours), the median increase from base line in the CD4+ lymphocyte count was 230 cells per cubic millimeter, and the mean decrease in the plasma concentration of HIV-1 RNA (as measured by a branched-chain DNA assay) was 0.81 log (95 percent confidence interval, 0.40 to 1.22). In a subgroup of 17 patients in the two higher-dosage groups, RNA was also measured with an assay based on the polymerase chain reaction, and after eight weeks of treatment there was a mean maximal decrease in viral RNA of 1.94 log (95 percent confidence interval, 1.37 to 2.51). Adverse events included nausea, circumoral paresthesia, elevated hepatic aminotransferase levels, and elevated triglyceride levels. Ten withdrawals from the study were judged to be related to ritonavir treatment. Conclusions: In this short-term study, ritonavir was well tolerated and had potent activity against HIV-1, but its clinical benefits remain to be established

A cluster randomised trial of a telephone-based intervention for parents to increase fruit and vegetable consumption in their 3- to 5-year-old children: study protocol

Background: Inadequate fruit and vegetable consumption in childhood increases the risk of developing chronic disease. Despite this, a substantial proportion of children in developed nations, including Australia, do not consume sufficient quantities of fruits and vegetables. Parents are influential in the development of dietary habits of young children but often lack the necessary knowledge and skills to promote healthy eating in their children. The aim of this study is to assess the efficacy of a telephone-based intervention for parents to increase the fruit and vegetable consumption of their 3- to 5-year-old children. Methods/Design: The study, conducted in the Hunter region of New South Wales, Australia, employs a cluster randomised controlled trial design. Two hundred parents from 15 randomly selected preschools will be randomised to receive the intervention, which consists of print resources and four weekly 30-minute telephone support calls delivered by trained telephone interviewers. The calls will assist parents to increase the availability and accessibility of fruit and vegetables in the home, create supportive family eating routines and role-model fruit and vegetable consumption. A further two hundred parents will be randomly allocated to the control group and will receive printed nutrition information only. The primary outcome of the trial will be the change in the child's consumption of fruit and vegetables as measured by the fruit and vegetable subscale of the Children's Dietary Questionnaire. Pre-intervention and post-intervention parent surveys will be administered over the telephone. Baseline surveys will occur one to two weeks prior to intervention delivery, with follow-up data collection calls occurring two, six, 12 and 18 months following baseline data collection. Discussion: If effective, this telephone-based intervention may represent a promising public health strategy to increase fruit and vegetable consumption in childhood and reduce the risk of subsequent chronic disease. Trial registration: Australian Clinical Trials Registry ACTRN12609000820202

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of hiv-1 protease

Reverse-transcriptase inhibitors have only moderate clinical efficacy against the human immunodeficiency virus type 1 (HIV-1). Ritonavir is an inhibitor of HIV-1 protease with potent in vitro anti-HIV properties and good oral bioavailability. We evaluated the antiviral activity and safety of ritonavir in a double-blind, randomized, placebo-controlled phase 1 and 2 study of 84 HIV-positive patients with 50 or more CD4+ lymphocytes per cubic millimeter. The patients were randomly assigned to one of four regimens of ritonavir therapy, or to placebo for four weeks and then (by random assignment) to one of the ritonavir regimens. During the first 4 weeks, increases in CD4+ lymphocyte counts and reductions in the log number of copies of HIV-1 RNA per milliliter of plasma were similar among the four dosage groups, but in the three lower-dosage groups there was a return to base-line levels by 16 weeks. After 32 weeks, in the seven patients in the highest-dosage group (600 mg of ritonavir every 12 hours), the median increase from base line in the CD4+ lymphocyte count was 230 cells per cubic millimeter, and the mean decrease in the plasma concentration of HIV-1 RNA (as measured by a branched-chain DNA assay) was 0.81 log (95 percent confidence interval, 0.40 to 1.22). In a subgroup of 17 patients in the two higher-dosage groups, RNA was also measured with an assay based on the polymerase chain reaction, and after eight weeks of treatment there was a mean maximal decrease in viral RNA of 1.94 log (95 percent confidence interval, 1.37 to 2.51). Adverse events included nausea, circumoral paresthesia, elevated hepatic aminotransferase levels, and elevated triglyceride levels. Ten withdrawals from the study were judged to be related to ritonavir treatment. In this short-term study, ritonavir was well tolerated and had potent activity against HIV-1, but its clinical benefits remain to be established

A short-term study of the safety pharmacokinetics and efficacy of ritonavir, an inhibitor of HIV-1 protease

Background: Reverse-transcriptase inhibitors have only moderate clinical efficacy against the human immunodeficiency virus type 1 (HIV-1). Ritonavir is an inhibitor of HIV-1 protease with potent in vitro anti-HIV properties and good oral bioavailability. Methods: We evaluated the antiviral activity and safety of ritonavir in a double-blind, randomized, placebo-controlled phase 1 and 2 study of 84 HIV-positive patients with 50 or more CD4+ lymphocytes per cubic millimeter. The patients were randomly assigned to one of four regimens of ritonavir therapy, or to placebo for four weeks and then (by random assignment) to one of the ritonavir regimens. Results: During the first 4 weeks, increases in CD4+ lymphocyte counts and reductions in the log number of copies of HIV-1 RNA per milliliter of plasma were similar among the four dosage groups, but in the three lower-dosage groups there was a return to base-line levels by 16 weeks. After 32 weeks, in the seven patients in the highest-dosage group (600 mg of ritonavir every 12 hours), the median increase from base line in the CD4+ lymphocyte count was 230 cells per cubic millimeter, and the mean decrease in the plasma concentration of HIV-1 RNA (as measured by a branched-chain DNA assay) was 0.81 log (95 percent confidence interval, 0.40 to 1.22). In a subgroup of 17 patients in the two higher-dosage groups, RNA was also measured with an assay based on the polymerase chain reaction, and after eight weeks of treatment there was a mean maximal decrease in viral RNA of 1.94 log (95 percent confidence interval, 1.37 to 2.51). Adverse events included nausea, circumoral paresthesia, elevated hepatic aminotransferase levels, and elevated triglyceride levels. Ten withdrawals from the study were judged to be related to ritonavir treatment. Conclusions: In this short-term study, ritonavir was well tolerated and had potent activity against HIV-1, but its clinical benefits remain to be established

Rapid Induction of Hypothalamic Iodothyronine Deiodinase Expression by Photoperiod and Melatonin in Juvenile Siberian Hamsters (Phodopus sungorus)

Production of T(3) in the mediobasal hypothalamus is critical for regulation of seasonal reproductive physiology. Type 2 iodothyronine deiodinase (DIO2) and DIO3 enzymes catalyze the prohormone T(4) into biologically-active T(3) and biologically-inactive rT(3), respectively. In several seasonally-breeding vertebrates, DIO2 and DIO3 expression is implicated in photoperiod signal transduction in adulthood. These experiments tested the hypothesis that juvenile Siberian hamsters, which are highly responsive to photoperiod at weaning (postnatal day [PND]18), exhibit rapid and sustained changes in hypothalamic dio3 mRNA expression during photoperiod-induced and photoperiod-inhibited puberty. Hypothalamic dio2 and dio3 expression was measured via quantitative PCR in hamsters born and reared in a long-day photoperiod (15L:9D) and weaned on PND18 into short-day photoperiods (9L:15D). In SD males, hypothalamic dio3 mRNA was elevated 2.5-fold within 3 days (PND21) and continued to increase (>20-fold) through PND32; changes in dio3 mRNA preceded inhibition of gonadotropin (FSH) secretion and gonadal regression in SD. Females exhibited comparable dio3 responses to SD. In LD males, dio3 remained low and invariant from PND18–PND32. In contrast, dio2 mRNA rose conspicuously on PND21, independent of photoperiod, returning to basal levels thereafter. In LD, a single afternoon melatonin (MEL) injection on PND18 or PND20 was sufficient to increase hypothalamic dio3 mRNA, and dio3 increased in proportion to the number of successive days of MEL treatment. SD photoperiods and MEL exert rapid, sustained, and additive effects on hypothalamic dio3 mRNA, which may play a central role in inhibiting maturation of the peripubertal hypothalamo-pituitary-gonadal axis