Systematic review of effectiveness of bisphosphonates in treatment of low bone mineral density and fragility fractures in juvenile idiopathic arthritis.

AIMS: To evaluate the currently available evidence for the effectiveness of bisphosphonates in children with low bone mineral density (BMD) and fragility fractures associated with juvenile idiopathic arthritis (JIA), and the safety of bisphosphonates in JIA and other conditions. METHODS: Literature databases were searched using a structured search strategy. The effectiveness review included any studies of children with JIA treated with bisphosphonates. The safety review also included studies of osteogenesis imperfecta. Quantitative data analysis was not undertaken because of the heterogeneity of the studies; findings were summarised using tables and narrative synthesis. RESULTS: Ninety four studies were identified. Sixteen studies (78 JIA children) were included in the effectiveness review: one randomised controlled trial, three controlled cohort studies, 11 case series, and one case report. At baseline, children had low BMD below the expected values for age and sex matched children. In all studies, treatment with bisphosphonates increased BMD compared with baseline: the mean percentage increase in spine BMD ranged from 4.5% to 19.1%. Overall, studies were heterogeneous and of variable quality. A total of 59 papers were included in the safety review; treatment durations were up to three years. The most common side effect was a flu-like reaction with intravenous treatment. This occurred during the first infusion and was transient; the symptoms were managed with paracetamol and did not occur during subsequent cycles. CONCLUSIONS: Bisphosphonates are a promising treatment for low BMD and fragility fractures in children with JIA. However, the quality of the current evidence is variable and better studies are needed to more clearly assess their role.     

Effects of two synthetic parathyroid hormone-related protein fragments on maternofetal transfer of calcium and magnesium and release of cyclic AMP by the in-situ perfused rat placenta.

Two human parathyroid hormone-related protein (hPTHrP) fragments were tested for effects on maternofetal transfer of 45Ca and Mg across the in-situ perfused rat placenta at 21 days of gestation (term = 23 days). The fetal placental circulation was perfused with a Mg-free Krebs-Ringer solution and the unidirectional maternofetal clearance (Kmf) of 45Ca and Mg compared with that of 51Cr-EDTA, the latter being employed as a paracellular diffusional marker. Placental perfusion with hPTHrP(1-34) (100 ng/ml) or hPTHrP(75-86)amide (50 ng/ml) did not significantly alter the Kmf of 45Ca or that of Mg. In separate rats, however, hPTHrP(1-34) but not hPTHrP(75-86)amide stimulated marked placental cyclic AMP (cAMP) release, the peak response of 63 +/- 7 pmol/min occurring 10 min after the beginning of the peptide perfusion. A lower dose of hPTHrP(1-34) (4 ng/ml) produced a similar peak release of cAMP, as did [Nle8,21, Tyr34]-rPTH(1-34)amide (4 ng/ml) and the adenylate cyclase agonist forskolin (17 mumol/l). Forskolin also rapidly increased the Kmf of 45Ca but not that of Mg or 51Cr-EDTA. The present study indicates that hPTHrP does not acutely affect maternofetal transfer of Ca or Mg across the perfused rat placenta. The data also question the role played by cAMP in the stimulatory actions of forskolin on placental Ca transport.     

Association between the DRD2 A1 allele and opium addiction in the Iranian population.

Dysfunction of the central dopaminergic neurotransmission has been suggested to play an important role in the etiology of certain neuropsychiatric disorders such as drug abuse. It has been shown that the dopamine D2 receptor (DRD2) gene dysfunction is associated with multi-drug addiction. Addiction to opium is the most common form of drug abuse in Iran. We studied the allelic association between DRD2 Taq I A polymorphism in 100 opium-dependent Iranian patients and 130 unrelated controls. A 310 bp (base pair) region surrounding Taq I site at the DRD2 locus was amplified by polymerase chain reaction (PCR) and the PCR product was incubated with Taq I restriction enzyme. The A1 allele remained intact while the A2 allele was cut. Significant association was observed between A1 allele and addiction in the patients group (P < 0.0001). Moreover, the frequency of A1A1 genotype was significantly higher in opium users than controls (P < 0.0001). Our result indicates that DRD2 might be involved in the pathophysiology of opium addiction.     

Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies

Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.3 years of age) across 19 countries were reviewed. Overall mortality was 54.7% (13.4% in utero or stillborn), with a 50.4% probability of death before the age of 6 months (critical period). Contrary to previous publications, we found that bisphosphonate treatment had no survival benefit based on a start-time matched analysis and inconclusive results when initiated within 2 weeks of birth. Despite a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 deficiencies, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively), mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157). Higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared with that of ABCC6 (11.8%; p = 0.0001). Eleven affected individuals presenting with rickets and without a GACI diagnosis, termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1 variants. Approximately 70% of these patients demonstrated evidence of ectopic calcification or complications similar to those seen in individuals with GACI, which shows that ARHR2 is not a distinct condition from GACI but represents part of the spectrum of ENPP1 deficiency. Overall, this study identified an early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets almost exclusive to ENPP1 deficiency, and a spectrum of heterogenous calcification and multiple organ complications with both ENPP1 and ABCC6 variants, which suggests an overlapping pathology. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.     

Quantitative determination of trimethylamine in urine by solid-phase microextraction and gas chromatography-mass spectrometry

Trimethylaminuria (fish odour syndrome) is diagnosed from an increase in urinary excretion of trimethylamine with decreased trimethylamine oxide. We report a new quantitative stable isotope dilution gas chromatography-mass spectrometry procedure for the analysis of these metabolites using solid-phase microextraction (SPME). Both polydimethylsiloxane and mixed Carboxen-polydimethylsiloxane SPME fibres were found to be suitable for the headspace extraction of TMA. This new sampling technique could have wide application for the analysis of volatile and semi-volatile compounds by metabolic screening laboratories.     

Cortical bone geometry in asthmatic children.

At the mid-radius, pre-pubertal asthmatic children had smaller periosteal and endosteal circumferences and thicker cortical shells compared to controls, when assessed by peripheral quantitative computed tomography. Asthmatics had diminished periosteal expansion for muscle size, suggesting that asthma, its treatment, or its effects on physical activity had resulted in impaired adaptation of bone to muscle loading. Alterations in cortical bone geometry might explain the increased fracture risk in asthmatic children.     

Mechanical and Durability Evaluation of Metakaolin as Cement Replacement Material in Concrete

Due to the increasing prices of cement and its harmful effect on the environment, the use of cement has become highly unsustainable in concrete. There is a considerable need for promoting the use of cement replacement materials. This study investigates the effect of variable percentages of metakaolin (MK) on the mechanical and durability performance of concrete. Kaolin clay (KC) was used in the current research to prepare the MK by the calcination process; it was ground in a ball mill to its maximum achievable fineness value of 2550 m²/Kg. Four replacement levels of MK, i.e., 5%, 10%, 15%, and 20% by weight of cement, in addition to control samples, at a constant water-to-cement (w/c) ratio of 0.55 were used. For evaluating the mechanical and durability performance, 27 cubes (6 in. × 6 in. × 6 in.) and 6 cylinders (3.875 in. diameter, 2 in. height) were cast for each mix. These samples were tested for compressive strength under standard conditions and in an acidic environment, in addition to being subjected to water permeability, sorptivity, and water absorption tests. Chemical analysis revealed that MK could be used as pozzolana as per the American Society for Testing and Materials (ASTM C 618:2003). The results demonstrated an increased compressive strength of concrete owing to an increased percentage of MK in the mix with aging. In particular, the concrete having 20% MK after curing under standard conditions exhibited 33.43% higher compressive strength at 90 days as compared to similarly aged control concrete. However, with increasing MK, the workability of concrete decreased drastically. After being subjected to an acid attack (immersing concrete cubes in 2% sulfuric acid solution), the samples exhibited a significant decrease in compressive strength at 90 days in comparison to those without acid attack at the same age. The density of acid attack increased with increasing MK with a maximum corresponding to 5% MK concrete. The current findings suggest that the local MK has the potential to produce good-quality concrete in a normal environment.     

Senior triaging of ENT emergency clinic referrals alleviates pressures on the outpatient department

IntroductionThe ear, nose and throat (ENT) emergency clinic is managed by foundation year (FY) doctors from taking referrals to discharging patients, under the supervision of a registrar. FYs learn essential skills and knowledge on how to manage common ENT problems. The clinic is often overloaded because of a high patient demand, and this limits the opportunities for teaching. We hypothesised that the clinic bookings would be better managed if referrals from general practitioners (GPs) were triaged by registrars.MethodsTelephone referrals from GPs for the ENT emergency clinic were directed to the on-call ENT registrar, between 8am and 1pm from Monday to Friday, and to the FY outside of this period. Consecutive referrals to the emergency clinic were analysed in a baseline audit and a post-intervention cycle.ResultsA total of 646 and 611 patients were given clinic appointments in the first and second cycles, respectively. Clinic session overbookings decreased from 85% to 46.3%. Appointments for referrals that were deemed inappropriate had reduced from 22% to 12.1%.Discussion and ConclusionInvolvement of a registrar in taking referrals for the ENT emergency clinic was associated with a reduction in clinic overbookings. It is feasible and productive to involve a senior decision maker in the operational management of the emergency clinic, while preserving the delivery of this service by FYs for its training value.     

Inhibitory potential of nitrogen,oxygen and sulfur containing heterocyclic scaffolds against acetylcholinesterase and butyrylcholinesterase

Heterocycles are the key structures in organic chemistry owing to their immense applications in the biological, chemical, and pharmaceutical fields. Heterocyclic compounds perform various noteworthy functions in nature, medication, innovation etc. Most frequently, pure nitrogen heterocycles or various positional combinations of nitrogen, oxygen, and sulfur atoms in five or six-membered rings can be found. Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes is a popular strategy for the management of numerous mental diseases. In this context, cholinesterase inhibitors are utilized to relieve the symptoms of neurological illnesses like dementia and Alzheimer''s disease (AD). The present review focuses on various heterocyclic scaffolds and their role in designing and developing new potential AChE and BChE inhibitors to treat AD. Moreover, a detailed structure–activity relationship (SAR) has been established for the future discovery of novel drugs for the treatment of AD. Most of the heterocyclic motifs have been used in the design of new potent cholinesterase inhibitors. In this regard, this review is an endeavor to summarize the biological and chemical studies over the past decade (2010–2022) describing the pursuit of new N, O and S containing heterocycles which can offer a rich supply of promising AChE and BChE inhibitory activities.

The present review focuses on various heterocyclic scaffolds and their role in designing and developing new potential AChE and BChE inhibitors to treat AD.     

Shifting balance from neurodegeneration to regeneration of the brain： a novel therapeutic approach to Alzheimer＇s disease and related neurodegenerative conditions

<正>Neurodegeneration is one of the biggest public health problems in modern society.Age-associated neurodegeneration,which is accelerated several-fold in Alzheimer’s disease(AD)alone,is not only an enormous social and economic burden to the affected individuals and their families,but is also a great scientific challenge.