Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis.

BACKGROUND: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis. METHODS: This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK. RESULTS: Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5-10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing. CONCLUSIONS: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.

The genomic landscape of familial glioma.

Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3, and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.

Inorganic liquid photovoltaic cell: tetravalent molybdenum in water.

An inorganic liquid photovoltaic cell is described. The cell is based on the reaction 2Mo(4+) <--> Mo(5+) + Mo(3+), with pentavalent molybdenum formed in the illuminated half-cell and trivalent molybdenum formed in the dark half-cell. In the photochemical reaction pentavalent molybdenum precipitates. Consequently, the cell has the capability of storing energy.

Australian private midwives with hospital visiting rights in Queensland: Structures and processes impacting clinical outcomes.

BACKGROUND: Reporting the outcomes for women and newborns accessing private midwives with visiting rights in Australia is important, especially since this data cannot currently be disaggregated from routinely collected perinatal data. AIM: 1) Evaluate the outcomes of women and newborns cared for by midwives with visiting access at one Queensland facility and 2) explore private midwives views about the structures and processes contributing to clinical outcomes. METHODS: Mixed methods. An audit of the 'all risk' 529 women receiving private midwifery care. Data were compared with national core maternity variables using Chi square statistics. Telephone interviews were conducted with six private midwives and data analysed using thematic analysis. FINDINGS: Compared to national data, women with a private midwife were significantly more likely to be having a first baby (49.5% vs 43.6% p=0.007), to commence labour spontaneously (84.7% vs 52.7%, p<0.001), experience a spontaneous vaginal birth (79% vs 54%, p<0.001) and not require pharmacological pain relief (52.9% vs 23.1%, p<0.001). The caesarean section rate was significantly lower than the national rate (13% vs 32.8%, p<0.001). In addition fewer babies required admission to the Newborn Care Unit (5.1% vs 16%, p<0.001). Midwives were proud of their achievements. Continuity of care was considered fundamental to achieving quality outcomes. Midwives valued the governance processes embedded around the model. CONCLUSIONS: Private midwives with access to the public system is safe. Ensuring national data collection accurately captures outcomes relative to model of care in both the public and private sector should be prioritised.

An Interstitial 4q Deletion with a Mosaic Complementary Ring Chromosome in a Child with Dysmorphism, Linear Skin Pigmentation, and Hepatomegaly.

Interstitial deletions of 4q are rarely reported, vary in size, and have limited genotype-phenotype correlations. Here, genome-wide array CGH analysis identified a 21.6 Mb region of copy number loss at 4q12-q21.1 in a patient diagnosed with dysmorphism, linear skin pigmentation, and hepatomegaly. An additional small ring chromosome was detected in 5/30 cells examined via G-banding. Confirmation of the origin of the ring chromosome was obtained by FISH analysis which identified that the ring chromosome contained material from the deleted region of chromosome 4 and was therefore complementary to the 21.6 Mb deletion. Further microarray studies in the proband using a different microarray platform showed no evidence of mosaicism. This case highlights the importance of an integrated approach to cytogenetic analysis and demonstrates the value of G-banding for detecting mosaicism, as current microarray platforms are unable to detect low level mosaics.

Crystalline solids.

Many drugs exist in the crystalline solid state due to reasons of stability and ease of handling during the various stages of drug development. Crystalline solids can exist in the form of polymorphs, solvates or hydrates. Phase transitions such as polymorph interconversion, desolvation of solvate, formation of hydrate and conversion of crystalline to amorphous form may occur during various pharmaceutical processes, which may alter the dissolution rate and transport characteristics of the drug. Hence it is desirable to choose the most suitable and stable form of the drug in the initial stages of drug development. The current focus of research in the solid-state area is to understand the origins of polymorphism at the molecular level, and to predict and prepare the most stable polymorph of a drug. The recent advances in computational tools allow the prediction of possible polymorphs of the drug from its molecular structure. Sensitive analytical methods are being developed to understand the nature of polymorphism and to characterize the various crystalline forms of a drug in its dosage form. The aim of this review is to emphasize the recent advances made in the area of prediction and characterization of polymorphs and solvates, to address the current challenges faced by pharmaceutical scientists and to anticipate future developments.

Biological stress responses in high and low trait anxious students.

In an investigation of biological indicators of stress in normal humans, undergraduate psychology students were differentiated on trait anxiety and assessed under baseline, preexam (stress), and postexam conditions. Assessment at each condition involved drawing 20 ml of blood, followed by self-reporting for selected questionnaires. Self-reports included state anxiety, general psychological symptomatology, dysfunctional attitudes, academic confidence, sleep patterns, and intake of drugs, including alcohol and caffeine. Blood was analyzed for whole blood serotonin content, plasma MHPG, and platelet imipramine binding. Baseline differences between high and low trait anxious students on biological measures were significant only for whole blood serotonin content. Variation across situational conditions was significant for whole blood serotonin, with an increase under the stressful condition for both anxiety groups. Thus, serotonin is highlighted as an important factor in the human response to stress, whereas expected differences in MHPG were not observed. The serotonergic response to stress was not explained by changes in psychological or physical state variables. Changes in serotonin content were positively correlated with changes in platelet imipramine binding.

The CAMDEX: a standardized instrument for the diagnosis of mental disorder in the elderly: a replication with a US sample.

The Cambridge Mental Disorders of the Elderly Examination (CAMDEX) was developed by Roth, et al (1986) to assist in the early diagnosis and measurement of dementia in the elderly. In this study the CAMDEX was administered to a mixed group of independently diagnosed elderly psychiatric patients and control subjects in the United States. The CAMDEX was found to have a high interrater reliability with a mixed group of clinicians of varying backgrounds. The diagnostic scales and the cognitive section of the CAMDEX demonstrated considerable promise in distinguishing between independently diagnosed populations of depressed, demented, and normal subjects. The results suggest comparability between samples of subjects in England and the US, and that the CAMDEX is a promising instrument for use in both research and clinical settings.

Erythrocyte membrane structure in bipolar affective disorder: a non-replication.

Fifteen bipolar patients were compared with sixteen controls in an attempt to replicate the findings of Pettegrew et al. in 1982 of decreased fluidity in the hydrocarbon core of the erythrocyte membrane. No significant differences were seen between groups. The present control group shows very similar membrane characteristics to the original control series; however, the bipolar patient group is not similar. Possible explanations are discussed.

Blunted ACTH and cortisol response to afternoon tryptophan infusion in euthymic bipolar patients.

The serotonin precursor tryptophan was used to test neuroendocrine responses in remitted bipolar patients and controls. Tryptophan was administered in the afternoon when spontaneous cortisol secretion is lower than in the morning. Following pilot studies at various doses, 50 mg/kg L-tryptophan was given i.v. over 20 min to 11 patients and 14 controls. Controls demonstrated cortisol release, whereas the response curve for patients was indistinguishable from placebo. Differences between groups were significant at 15, 30, and 45 min. Changes in adrenocorticotropic hormone were consistent with those in cortisol. Prolactin and growth hormone levels increased in both patients and controls following tryptophan. Higher doses caused gastrointestinal upset in some subjects.

Foundations of chemical microscopy. 1. Solid-state characterization of 5-nitrobarbituric acid (dilituric acid) and its complexes with group IA and group IIA cations.

5-Nitrobarbituric acid (dilituric acid) has been used as a chemical microscopic reagent for the qualitative identification of alkali metal (Group IA) and alkaline earth (Group IIA) cations. This methodology was based on the characterization of observed crystal morphologies, since a unique crystal habit could be associated with each adduct product. To understand the scientific foundations which permitted chemical microscopy to function as a useful analytical technique, the products formed between dilituric acid and the Group IA and IIA cations were characterized using polarizing optical microscopy, powder X-ray diffraction, thermal analysis and solid-state nuclear magnetic resonance. It was found that the origins of the different crystal morphologies associated with each of the adduct arose from the ability of the systems to form various hydrate species, which could also contain structural variations due to cation/diliturate packing patterns.

Applications of chiroptical spectroscopy for the characterization of pharmaceutical compounds.

Many pharmaceutical compounds contain one or more centers of dissymmetry, thus presenting a unique series of regulatory and compendial requirements. Although most often characterized using chiral chromatography, these molecules can be effectively studied using the various techniques of chiroptical spectroscopy. Techniques which have been found to be very useful for such work include polarimetry, optical rotatory dispersion, circular dichroism, and circularly polarized luminescence. The principles underlying each effect will be briefly outlined, and the application of each illustrated through the inclusion of appropriate examples.

Foundations of chemical microscopy, 2 derivatives of primary phenylalkylamines with 5-nitrobarbituric acid.

5-Nitrobarbituric acid (dilituric acid) was extensively used with great success as a chemical microscopic reagent for the qualitative identification of primary phenylalkylamines. This methodology was based on the characterization of observed crystal morphologies, since a unique crystal habit could be associated with each adduct product. To understand the scientific foundations which permitted chemical microscopy to function as a useful analytical technique, the products formed between dilituric acid and a series of primary phenylalkylamines were characterized using polarizing optical microscopy, powder X-ray diffraction, thermal analysis, and solid-state nuclear magnetic resonance. It was deduced that the origins of the different crystal morphologies associated with each of the crystalline adducts arose from the ability of the systems to form differing structural types and/or hydrates upon crystallization. The degree of hydration in the crystalline phenylalkylamine adducts appeared to increase as additional carbon atoms were added between the aromatic ring and the terminal amine group of the aliphatic sidechain.

Stability of revex, nalmefene hydrochloride injection, in injectable solutions.

The short-term stability of Revex, nalmefene hydrochloride injection, was determined in a number of diluents commonly employed for intravenous use. An HPLC method was used to follow the potency of the diluted solutions, and was fully validated for its intended concentration range prior to its use. Dilutions of Revex were prepared separately in 0.9% sodium chloride injection, 0.45% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.45% sodium chloride injection, lactated Ringer's injection, 5% dextrose and lactated Ringer's injection and 5% sodium hydrogencarbonate injection. Each admixture was stored at 4 degrees C, room temperature (21 degrees C) and 40 degrees C, with samples being tested after storage at each temperature for 0, 24, 48 and 72 h. Defining stability as the retention of at least 95% of the initial drug concentration at the end of the storage period, it was concluded that the diluted solutions of Revex were uniformly stable for up to 72 h in all of the injectable solutions maintained at either 4, 21 or 40 degrees C.

The determination of palladium in fosinopril sodium (monopril) by ICP-MS.

A rapid, sensitive ICP-MS method was developed to determine palladium in fosinopril sodium. The assay could not be carried out in a purely aqueous solvent owing to the instability of the palladium species in this media. It was found that the most appropriate vehicle for solubilization of this material was a solution of 25% (v/v) 2-butoxyethanol and water. A minimum quantifiable limit of 0.1 microns g-1 for Pd in the sample (corresponding to 1 ng Pd mL-1 in the analyte solution) was obtained.

Solid-state NMR and IR for the analysis of pharmaceutical solids: polymorphs of fosinopril sodium.

The two polymorphic modifications of fosinopril sodium have been characterized as to their differences in melting behaviour, powder X-ray diffraction patterns, Fourier transform infrared spectra (FTIR), and solid-state 31P- and 13C-NMR spectra. The polymorphs were found to be enantiotropically related based upon melting point, heat of fusion, and solution mediated transformation data. Analysis of the solid-state FTIR and 13C-NMR data indicated that the environment of the acetal side chain of fosinopril sodium differed in two polymorphs, and that there might be cis-trans isomerization about the C6-N peptide bond. These conformational differences are postulated as the origin of the observed polymorphism.

Cross-cultural studies in Alzheimer's disease.

The search for risk factors for Alzheimer's disease would be greatly enhanced by identification of populations with significantly different prevalence rates, particularly if these populations consisted of ethnic groups now living in different environments and cultures. Evidence is presented that two such groups are worthy of further study: subjects of African origin living in Africa and in the West and Native Americans living on and off reserves.

The diagnosis of dementia associated with alcoholism: a preliminary report of a new approach.

The historical, clinical, neurological and neuropsychological features of 13 subjects with independently diagnosed dementia associated with alcoholism (AlcD) were compared to 13 subjects with probable Alzheimer's disease (AD), matched for age and severity of dementia. Neurological abnormalities were present in all the subjects with AlcD even though the diagnosis of Wernicke-Korsakoff was recorded in only one of these subjects. Only one subject with probable AD demonstrated any neurological abnormality. There was no difference between the AD and AlcD subjects in either the total scores of the Mini-Mental State Examination (MMSE) or in any of the subscores. The presence of neurological signs does appear to be a useful method to assist in the diagnosis of AlcD.

Liposomal formulation of mirfentanil hydrochloride.

Mirfentanil hydrochloride, a novel CNS analgesic with a short duration of action, was successfully encapsulated in liposomes having a variety of compositions. The lipid composition of the formulation was varied to optimize the stabilization of liposomes and the encapsulation of solutes. Retention of mirfentanil hydrochloride was evaluated by storing loaded liposomes at several temperatures, and also after the physical stressing of formulations. High efficiency of drug encapsulation was observed in liposomes prepared using dipalmitoyl-L-alpha-phosphatidylcholine (DPPC) and the ternary mixture of dimyristoyl-L-alpha-phosphatidylcholine, cholesterol, and dicetyl phosphate (DMPC/CHOL/DCP), both with and without the further incorporation of monosialoganglioside (GM1). Only 35% of encapsulated drug was lost when the formulations containing GM1 were incubated with human plasma over a 24 hour period, suggesting that liposomal formulations containing GM1 could be used to control drug release in vivo.

Stability of Revex, nalmefene hydrochloride injection.

The stability of Revex, nalmefene hydrochloride injection, has been studied at several temperatures for periods up to 36 months. The data were obtained using a HPLC method for the potency determination, and for the level of the sole degradation product (2,2'-bisnalmefene). These methods were found to be characterized by excellent precision, linearity, and accuracy over the analyte concentration ranges established. The stability data were found to be interpretable using first-order kinetics, and essentially comparable rate constants were calculated for both the potency loss and the formation of 2,2'-bisnalmefene. Applying the Arrhenius equation to these data, a rate constant of 0.00441 month-1 was deduced for the reactions taking place at 25 degrees C. This low value is consistent with the excellent stability exhibited by the product, and amply justifies its shelf life.