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

Efficacy of chronic morphine in a rat model of cancer-induced bone pain: Behavior and in dorsal horn pathophysiology

Morphine is one of the main analgesics in cancer-induced bone pain (CIBP). To investigate the efficacy of morphine in CIBP and alteration in dorsal horn pathophysiology, systemic morphine was administered (3 mg/kg) bi-daily between days 11 and 15 after MRMT-1 carcinoma cell injections (compared with a single injection (3 mg/kg) of morphine on day 15, and acute spinal morphine (0.1, 1, 10 μg/50 μL). The chronic systemic morphine schedule significantly attenuated pain behavior (von Frey 15 g; P < .01) to a greater extent than acute systemic morphine (von Frey 15 g; P < .05). In vivo electrophysiology (day 15 chronic systemic morphine) showed an attenuation of hyperexcitable wide dynamic range (WDR) neurons, but the abnormal raised WDR to nociceptive specific neuronal ratio remained. Acute spinal morphine attenuated electrical and natural WDR neuronal response in shams at a lower dose (1 μg) compared with cancer (10 μg). Chronic morphine is more effective at attenuating pain-related behaviors than single doses, although the dorsal horn retains a pathophysiologic characterization.Peer reviewe

A pronociceptive role for the 5-HT2 receptor on spinal nociceptive transmission: An in vivo electrophysiological study in the rat

Serotonin (5-HT) plays a major yet complex role in modulating spinal nociceptive transmission as a consequence of the number of 5-HT receptor subtypes. These include the 5-HT2 receptor, which is further sub classified into 5-HT2A, B and C. Studies have described both a pro- and antinociceptive action following 5-HT2A-receptor activation; therefore, to shed light on the directional nature of spinal 5-HT2A receptor activity, we investigated the effects of spinal administration of the 5-HT2A receptor antagonist, ketanserin, on the evoked responses of dorsal horn neurones to electrical, mechanical and thermal stimulation. We also assessed the effects of systemic administration of ritanserin, a 5-HT2A/2C receptor antagonist and spinal application of (±)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride (DOI) (3.6 and 17.8 μg/50 μl), a 5-HT2A/2C agonist, on the same evoked neuronal responses. Ketanserin (1, 10 and 100 μg/50 μl) produced a dose related inhibition of the evoked responses to noxious mechanical punctate and thermal stimuli only. Ritanserin (2 mg/kg) replicated the inhibitory effects seen with ketanserin on the natural evoked neuronal responses and also potently inhibited the C-fibre, post discharge, input and wind-up evoked responses. DOI increased the mechanical and thermal evoked responses, an effect reversed by ketanserin. Thus, our findings show that spinal ketanserin (1–100 μg/50 μl) and systemic ritanserin (2 mg/kg), at these doses, have similar antinociceptive effects, whereas the agonist, DOI, produced excitatory effects, on spinal neuronal activity. Our data, therefore, supports a pronociceptive role for 5-HT2 receptors, most likely through modulation of 5-HT2A receptor activity, on spinal nociceptive transmission under normal conditions

Gestational diabetes: opportunities for improving maternal and child health

Gestational diabetes, the most common medical disorder in pregnancy, is defined as glucose intolerance resulting in hyperglycaemia that begins or is first diagnosed in pregnancy. Gestational diabetes is associated with increased pregnancy complications and long-term metabolic risks for the woman and the offspring. However, the current diagnostic and management strategies recommended by national and international guidelines are mainly focused on short-term risks during pregnancy and delivery, except the Carpenter-Coustan criteria, which were based on the risk of future incidence of type 2 diabetes post-gestational diabetes. In this Personal View, first, we summarise the evidence for long-term risk in women with gestational diabetes and their offspring. Second, we suggest that a shift is needed in the thinking about gestational diabetes; moving from the perception of a short-term condition that confers increased risks of large babies to a potentially modifiable long-term condition that contributes to the growing burden of childhood obesity and cardiometabolic disorders in women and the future generation. Third, we propose how the current clinical practice might be improved. Finally, we outline and justify priorities for future research.No specific funding. CLM receives support from the Diabetes UK Harry Keen Intermediate Clinical Fellowship (17/0005712) and the EFSD-Novo Nordisk Foundation Future Leader’s Award (NNF19SA058974); PS’s time was in part supported by a project grant from the Medical Research Council (MRC), UK (MR/R020981/1)