Referrals from primary care with foreskin symptoms: Room for improvement.

AIMS: Referrals to secondary care for boys with foreskin symptoms require face-to-face review, resulting in time out of school / work and costs to the family. This study aimed to review outcomes of referrals to ascertain if there was scope to reduce referrals. METHODS: New patients referred to a UK regional paediatric surgery clinic during 2019 were identified and screened retrospectively. Medical records for boys over one year of age referred due to foreskin symptoms were reviewed. RESULTS: Of 2598 referrals, 1939 (75%) were boys & 1094 were > 1 yr; 398 (21%) were referred with foreskin symptoms at median age 7.2 yrs (IQR 4-10). 307 (77%) were diagnosed with physiological phimosis, 67 (18%) with pathological phimosis, 9 (2%) with balanitis (the remainder had 'smegma' retention cysts, preputial adhesions, tight frenulum or anatomical abnormalities). 211 (53%) were discharged at the initial appointment, this was significantly more likely for younger boys, and those with physiological phimosis (p<0.001). 62 (16%) were prescribed topical steroids (more likely in older boys, p<0.001). 70 (18%) were offered surgery: circumcisions (n = 51), preputioplasties (n = 13), other (n = 4). The circumcision rate was therefore 12%. Age at referral was positively correlated with GP trial of steroid (older more likely), diagnosis (physiological phimosis more likely if younger) and outcome (topical steroids or surgery more likely if older): Spearman's rank correlation p<0.001. CONCLUSIONS: Over 75% of boys referred had a normal foreskin, over half were discharged at their first review. Improved knowledge amongst parents and primary care providers could reduce referrals and save money and resources. LEVEL OF EVIDENCE: Level IV - Case series with no comparison group.

Review: The Role of Wnt/ß-Catenin Signalling in Neural Crest Development in Zebrafish.

The neural crest (NC) is a multipotent cell population in vertebrate embryos with extraordinary migratory capacity. The NC is crucial for vertebrate development and forms a myriad of cell derivatives throughout the body, including pigment cells, neuronal cells of the peripheral nervous system, cardiomyocytes and skeletogenic cells in craniofacial tissue. NC induction occurs at the end of gastrulation when the multipotent population of NC progenitors emerges in the ectodermal germ layer in the neural plate border region. In the process of NC fate specification, fate-specific markers are expressed in multipotent progenitors, which subsequently adopt a specific fate. Thus, NC cells delaminate from the neural plate border and migrate extensively throughout the embryo until they differentiate into various cell derivatives. Multiple signalling pathways regulate the processes of NC induction and specification. This review explores the ongoing role of the Wnt/ß-catenin signalling pathway during NC development, focusing on research undertaken in the Teleost model organism, zebrafish (Danio rerio). We discuss the function of the Wnt/ß-catenin signalling pathway in inducing the NC within the neural plate border and the specification of melanocytes from the NC. The current understanding of NC development suggests a continual role of Wnt/ß-catenin signalling in activating and maintaining the gene regulatory network during NC induction and pigment cell specification. We relate this to emerging models and hypotheses on NC fate restriction. Finally, we highlight the ongoing challenges facing NC research, current gaps in knowledge, and this field's potential future directions.

Adaptation of the carbamoyl-phosphate synthetase enzyme in an extremophile fish.

Tetrapods and fish have adapted distinct carbamoyl-phosphate synthase (CPS) enzymes to initiate the ornithine urea cycle during the detoxification of nitrogenous wastes. We report evidence that in the ureotelic subgenus of extremophile fish Oreochromis Alcolapia, CPS III has undergone convergent evolution and adapted its substrate affinity to ammonia, which is typical of terrestrial vertebrate CPS I. Unusually, unlike in other vertebrates, the expression of CPS III in Alcolapia is localized to the skeletal muscle and is activated in the myogenic lineage during early embryonic development with expression remaining in mature fish. We propose that adaptation in Alcolapia included both convergent evolution of CPS function to that of terrestrial vertebrates, as well as changes in development mechanisms redirecting CPS III gene expression to the skeletal muscle.

Exploring the Expression of Cardiac Regulators in a Vertebrate Extremophile: The Cichlid Fish Oreochromis (Alcolapia) alcalica.

Although it is widely accepted that the cellular and molecular mechanisms of vertebrate cardiac development are evolutionarily conserved, this is on the basis of data from only a few model organisms suited to laboratory studies. Here, we investigate gene expression during cardiac development in the extremophile, non-model fish species, Oreochromis (Alcolapia) alcalica. We first characterise the early development of O. alcalica and observe extensive vascularisation across the yolk prior to hatching. We further investigate heart development by identifying and cloning O. alcalica orthologues of conserved cardiac transcription factors gata4, tbx5, and mef2c for analysis by in situ hybridisation. Expression of these three key cardiac developmental regulators also reveals other aspects of O. alcalica development, as these genes are expressed in developing blood, limb, eyes, and muscle, as well as the heart. Our data support the notion that O. alcalica is a direct-developing vertebrate that shares the highly conserved molecular regulation of the vertebrate body plan. However, the expression of gata4 in O. alcalica reveals interesting differences in the development of the circulatory system distinct from that of the well-studied zebrafish. Understanding the development of O. alcalica embryos is an important step towards providing a model for future research into the adaptation to extreme conditions; this is particularly relevant given that anthropogenic-driven climate change will likely result in more freshwater organisms being exposed to less favourable conditions.

Medicinal Chemistry - XXth International Symposium.

The XXth International Symposium on Medicinal Chemistry (EFMC-ISMC 2008) was organized by the Austrian Chemical Society on behalf of the European Federation for Medicinal Chemistry (EFMC). Approximately 1400 scientists from 58 nations congregated over the course of the event to discuss the latest advances in the fields of neurodegenerative diseases, antipsychotics, pain, diabetes, COPD and asthma, immunology, antivirals and oncology. The agenda included plenary and award lectures, oral sessions, and over 600 poster presentations.

Zinc and copper: pharmacological probes and endogenous modulators of neuronal excitability.

As well as being key structural components of many proteins, increasing evidence suggests that zinc and copper ions function as signaling molecules in the nervous system and are released from the synaptic terminals of certain neurons. In this review, we consider the actions of these two ions on proteins that regulate neuronal excitability. In addition to the established actions of zinc, and to a lesser degree copper, on excitatory and inhibitory ligand-gated ion channels, we show that both ions have a number of actions on selected members of the voltage-gated-like ion channel superfamily. For example, zinc is a much more effective blocker of one subtype of tetrodotoxin (TTX)-insensitive sodium (Na+) channel (NaV1.5) than other Na+ channels, whereas a certain T-type calcium (Ca2+) channel subunit (CaV3.2) is particularly sensitive to zinc. For potassium (K+) channels, zinc can have profound effects on the gating of certain KV channels whereas zinc and copper have distinct actions on closely related members of the 2 pore domain potassium channel (K2P) channel family. In addition to direct actions on these proteins, zinc is able to permeate a number of membrane proteins such as (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors, Ca2+ channels and some transient receptor potential (trp) channels. There are a number of important physiological and pathophysiological consequences of these many actions of zinc and copper on membrane proteins, in terms of regulation of neuronal excitability and neurotoxicity. Furthermore, the concentration of free zinc and copper either in the synaptic cleft or neuronal cytoplasm may contribute to the etiology of certain disease states such as Alzheimer's disease (AD) and epilepsy.

LCZ696 : a new paradigm for the treatment of heart failure?

INTRODUCTION: Heart failure (HF) represents a significant healthcare issue because of its ever-increasing prevalence, poor prognosis and complex pathophysiology. Currently, blockade of the renin-angiotensin-aldosterone system (RAAS) is the cornerstone of treatment; however, the combination of RAAS blockade with inhibition of neprilysin (NEP), an enzyme that degrades natriuretic peptides, has recently emerged as a potentially superior treatment strategy. AREAS COVERED: Following the results of the recent Phase III Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure clinical trial in patients with chronic HF with reduced ejection fraction (HF-REF), this review focuses on LCZ696 , a first-in-class angiotensin receptor NEP inhibitor. This drug consists of a supramolecular complex containing the angiotensin receptor inhibitor valsartan in combination with the NEP inhibitor prodrug, AHU377. Following oral administration, the LCZ696 complex dissociates and the NEP inhibitor component is metabolized to the active form (LBQ657). Aspects of the trial that might be relevant to clinical practice are also discussed. EXPERT OPINION: Speculation that LCZ696 will pass the scrutiny of regulatory agencies for HF-REF appears to be justified, and it is likely to become a core therapeutic component in the near future. Replication of the eligibility criteria and titration protocol used in the PARADIGM-HF trial would be valuable in clinical practice and may minimize the risk of adverse events. Although long-term data remain to be generated, the promising results regarding hypertension are likely to expedite acceptance of the drug for HF-REF.

Safety and effectiveness of a fixed-dose combination of olmesartan, amlodipine, and hydrochlorothiazide in clinical practice.

BACKGROUND: Clinical trials indicate that the use of fixed-dose combinations (FDCs) is associated with a higher level of treatment adherence and prolonged blood pressure (BP) control. The aim of this study was to document the safety and effectiveness of the FDC olmesartan/amlodipine/hydrochlorothiazide in patients with essential hypertension in clinical practice. METHODS: This multicenter, prospective, 24-week, noninterventional study enrolled 5,831 patients from primary care offices in Germany and Austria. Inclusion criteria were a diagnosis of essential hypertension and newly initiated treatment with the FDC. RESULTS: The mean age of patients was 63.5 years, almost 50% of patients had a time since diagnosis of essential hypertension of over 5 years, and approximately 70% of patients had at least one cardiovascular risk factor, including 29.4% of patients with diabetes mellitus. Following approximately 24 weeks of treatment, the mean reduction in systolic/diastolic BP was 29.0/14.0 mmHg, a BP response was observed by 94.2% of patients, and a target BP of <140/90 mmHg was attained in 67.5% of patients. At least one adverse drug reaction (ADR) was experienced by 1.2% of patients, with the most common being peripheral edema. Subanalyses demonstrated that the following factors did not have a significant influence on the ADR rate: age (<65 years versus ≥65 years), diabetes mellitus (no/yes), cardiovascular risk (low/high), and concomitant medication (no/yes). CONCLUSION: This study demonstrates that in clinical practice, treatment with the three-drug combination as an FDC tablet resulted in a very high proportion of patients with a BP response and control, accompanied by a very low rate of ADRs.

U300, a novel long-acting insulin formulation.

INTRODUCTION: Insulin glargine (100 U/ml; U100) was the first long-acting basal insulin analog to be introduced into clinical practice and it remains the most widely used. Although U100 is an effective and safe treatment, research is ongoing to optimize the time-action profile. The focus of this review is insulin glargine [rDNA origin] injection 300 U/ml (U300), a novel formulation that contains a higher concentration of insulin than U100. AREAS COVERED: The clinical efficacy and safety of U300 in patients with type 1 and type 2 diabetes mellitus are discussed, with an emphasis on recently released data from the Phase III EDITION clinical trials. EXPERT OPINION: The higher concentration of insulin in U300 results in a distinct pharmacokinetic and pharmacodynamic profile. U300 has a longer duration of action than U100 and plasma insulin exposure is less variable. Both insulin formulations exhibit a similar efficacy and safety profile, but importantly, U300 is associated with less body weight gain and a lower incidence of hypoglycaemic events.

G(alpha)q-mediated regulation of TASK3 two-pore domain potassium channels: the role of protein kinase C.

The TASK subfamily of two pore domain potassium channels (K2P) gives rise to leak potassium currents, which contribute to the resting membrane potential of many neurons and regulate their excitability. K2P channels are highly regulated by phosphorylation and by G protein-mediated pathways. In this study, we show that protein kinase C (PKC) inhibits recombinant TASK3 channels. Inhibition by PKC is blocked by the PKC inhibitors bisindolylmaleimide 1 hydrochloride (BIM) and 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole (Gö6976). Gene-silencing experiments with a validated small interfering RNA sequence against PKCalpha ablates the effect of PKC. PKC acts directly on hTASK3 channels to phosphorylate an identified amino acid in the C terminus region (Thr341), thereby reducing channel current. PKC also inhibits mTASK3 channels despite their having a quite different C-terminal structure to hTASK3 channels. Activation of M(3) muscarinic receptors inhibits both hTASK3 channels expressed in tsA-201 cells and standing outward potassium current (IK(SO)) in mouse cerebellar granule neurons through the activation of the G protein Galpha(q), because both effects are abolished by the selective Galpha(q) antagonist YM-254890 (J Biol Chem 279:47438-47445, 2004). This inhibition is not directly transduced through activation of PKC because inhibition persists in mutated PKC-insensitive hTASK3 channels. Instead, inhibition seems to occur through a direct action of Galpha(q) on the channel. Nevertheless, preactivation of PKC blocks muscarinic inhibition of both TASK3 channels and IK(SO). Our results suggest that activation of PKC (via phospholipase C) has a role in opposing inhibition after M(3) receptor activation rather than transducing it and may act as a negative regulator of G protein modulation to prevent prolonged current inhibition.