Interleukin (IL) 31 induces in cynomolgus monkeys a rapid and intense itch response that can be inhibited by an IL-31 neutralizing antibody.

BACKGROUND: Overexpression or administration of interleukin 31 (IL-31) has been shown to induce a profound itch response in mice and dogs. The chronic pruritus observed in mouse IL-31 transgenic mice results in the development of skin lesions and alopecia through excoriation from excessive scratching, a condition similar to that observed in patients with atopic dermatitis (AD). OBJECTIVE: To test whether IL-31 induces pruritus in non-human primates and, if so, whether treatment with an anti-IL-31 neutralizing monoclonal antibody (mAb) can block the response. METHODS: A series of studies was conducted in cynomolgus monkeys to evaluate the itch response to recombinant cynomolgus IL-31 (cIL-31) administration. Three routes of cIL-31 administration (intravenous, intradermal, and subcutaneous) were evaluated. Subcutaneous treatment with a humanized anti-human IL-31 mAb cross-reactive to cIL-31 was subsequently tested for its ability to block the response to intradermal cIL-31 administration. RESULTS: Each route of cIL-31 delivery elicited a scratching response immediately after cIL-31 administration and lasted at least 3 h. Treatment with the IL-31 mAb inhibited the cIL-31-mediated scratching response in a dose-dependent manner. CONCLUSION: These results demonstrate that an IL-31 mAb can inhibit IL-31-mediated pruritus in vivo, and could be an effective therapy for pruritic skin conditions like AD where IL-31 upregulation may play a role.

The Haw River syndrome: dentatorubropallidoluysian atrophy (DRPLA) in an African-American family.

Haw River Syndrome (HRS) is a dominant neurodegenerative disease that has affected five generations of an African-American family in rural North Carolina. The disorder represents a unique spectrum of multiple system degenerations resembling Huntington's disease, spinocerebellar atrophy and dentatorubropallidoluysian atrophy (DRPLA), a neurodegenerative disease that has been primarily reported in Japan. Recently, DRPLA has been shown to be due to an expanded trinucleotide repeat located on chromosome 12pter-p12. We have genotyped this family and found HRS to be tightly linked to the DRPLA region. Further examination demonstrates that, despite their distinct cultural origins and clinical and pathological differences, HRS is caused by the same expanded CTG-B37 repeat as DRPLA.

Multiple model triangulation to identify factors associated with lameness in British sheep flocks.

Identification of factors associated with an outcome can be challenging when the number of explanatory variables is large in relation to the number of observations. Multiple model triangulation, where results from several model types are combined, improves the likelihood of identifying true predictor variables. The aim of this study was to use triangulation to identify covariates likely to be truly associated with the prevalence of lameness in sheep flocks in Great Britain. Data were collected using a questionnaire sent to 3200 sheep farmers in Great Britain in 2018. The useable response rate was 14.1 %. The geometric mean prevalence of lameness was 1.4 % (95 % CI 1.2-1.7) for ewes, and 0.6 % (95 % CI 0.5-0.9) for lambs, however, approximately 60 % flocks had >2% prevalence of lameness in ewes. Four model types were investigated, two generalised linear models (negative binomial and quasi-Poisson) built using stepwise selection, and two elastic net models (Poisson and Gaussian distributions) refined with selection stability estimation. Triangulated covariates were those selected in three or all four models - 10 for ewes and 12 for lambs. Higher prevalence of lameness in ewes was associated with 5-100% feet bleeding during routine foot trimming compared with not foot trimming, footbathing the flock to treat severe footrot (SFR) and always using formalin in footbaths, both compared with not footbathing, using FootVax™ for <1 year compared with not using FootVax™, and never quarantining new or returning sheep to the farm for >3 weeks compared with always. Lower prevalence of lameness in ewes was associated with vaccinating with FootVax™ for >5 years compared with not vaccinating, peat soil compared with no peat soil, and having no lame ewes to treat. Higher prevalence of lameness in lambs was associated with 5-100% feet bleeding during routine foot trimming, always foot trimming ewes with SFR, not knowingly selecting replacement ewes from ewes that were never lame compared with always, replacement sheep purchased and homebred compared with only homebred, treating lambs >3 days after recognition of lameness compared with 0-3 days and footbathing the flock to treat interdigital dermatitis compared with not footbathing at all. Lower prevalence of lameness in lambs was associated with peat soil, flocks in Scotland versus England, an altitude of >230-500 m compared with ≤230 m, never using antibiotic injection to treat lambs with SFR compared with always, and having no lame lambs to treat. We conclude triangulation identified reliable management practices for farmers to implement to minimise lameness in sheep.

A review of novel biological tools used in screening for the early detection of lung cancer.

Lung cancer is the most common cancer worldwide and causes more deaths per year than any other cancer. It has a very poor 5-year survival rate of 8-16%, partly because of comorbidity preventing curative treatments but mainly because of the disease presenting with symptoms only when it is at an advanced and incurable stage. When lung cancer is detected earlier and is amenable to radical treatments such as potentially curative surgery and radical radiotherapy, 5-year survival rates are much higher (up to 67%). Therefore reliable detection of lung cancer at this earlier (usually asymptomatic) stage of disease should be an important way to improve outcomes. This review discusses the principles of screening with respect to lung cancer, concentrating mainly on the biological modalities used to detect it. The lack of impact achieved by early studies using sputum cytology (in conjunction with chest radiographs) is described, and then newer technology used to measure other biomarkers in sputum, serum, exhaled breath and bronchial mucosa to diagnose (early) lung cancer is detailed. Many techniques show promise, but debate continues about which population to screen and what is the most (cost) effective modality to use. Moreover, no single biomarker or combination of biomarkers in screening has yet been shown to reduce lung cancer mortality in large prospective randomised studies.

Sleep-disordered breathing and cardiovascular disease.

Sleep-disordered breathing (SDB) describes a group of disorders characterised by abnormalities in the frequency and/or depth of breathing while asleep. The most common type is the obstructive sleep apnoea/hypopnoea syndrome (OSAHS); it affects 2-4% of the adult population and is an independent risk factor for hypertension. Another type is central sleep apnoea (CSA), which includes Cheyne-Stokes respiration; it is most commonly seen in patients with congestive heart failure and other critical illnesses including cerebrovascular accidents. There is accumulating evidence that both these types of SDB are associated with cardiac failure, arrhythmias and coronary artery disease. Treatment of OSAHS with continuous positive airway pressure (CPAP) has lowered blood pressure, reduced the frequency and severity of some arrhythmias, and improved markers of endovascular inflammation. CPAP has had a mild positive effect on left ventricular function in chronic heart failure by treating co-existent SDB, but it has not improved mortality, possibly because it does not fully treat associated CSA. Clinicians need to be aware of the increasing associations of SDB, especially OSAHS, with cardiovascular dysfunction, as treatment of co-existent SDB will not only improve sleepiness, quality of life, and driving risk, but there is growing evidence that it may also improve cardiovascular risk itself, even in non-sleepy subjects.

Autonomic nervous system control of the cardiovascular and respiratory systems in asthma.

Patients with asthma have exaggerated bronchoconstriction of their airways in response to certain indirect (e.g. cold air, allergens, dust, exercise) or direct (e.g. inhaled methacholine) stimuli. This 'hyper-reactivity' usually co-exists with airway inflammation, although the pathophysiological mechanisms underlying these changes are not fully understood. It is likely that this hyper-reactivity is associated with abnormal autonomic nervous system (ANS) control. In particular, the parasympathetic (vagal) component of the ANS appears to be implicated in the pathogenesis of asthma. In addition, several studies have suggested the existence of differential alteration in ANS function following exercise in asthmatics compared with non-asthmatic individuals. Several early studies suggested that the altered autonomic control of airway calibre in asthma might be reflected by a parallel change in heart rate. Cardiac vagal reactivity does indeed appear to be increased in asthma, as demonstrated by the cardiac response to various autonomic functions tests. However, other studies have reported a lack of association between bronchial and cardiac vagal tone, and this is in accord with the concept of system-independent ANS control. This review provides a discussion of cardiovascular-autonomic changes associated with either the pathophysiology of asthma per se or with asthma pharmacotherapy treatment. Previous investigations are summarised suggesting an apparent association between altered autonomic-cardiovascular control and bronchial asthma. The full extent of autonomic dysfunction, and its clinical implications, has yet to be fully determined and should be the subject of future investigation.

Cannibalistic sexual phagocytosis in Dictyostelium discoideum is modulated by adenosine via an A2-like receptor.

A unique aspect of phagocytosis during the sexual cycle of Dictyostelium discoideum is the ability of the zygote giant cell (ZGC) to attract and engulf hundreds of amoebae of the same species. The work presented here is one of two initial attempts to understand the signal transduction pathways that are involved during this event. Our data indicate that the uptake of amoebae by the ZGCs is negatively modulated by 5'-AMP and adenosine (ADO). The hierarchical inhibition of phagocytosis by the ADO analogues, N-ethylcarboxyadiadenosine and phenyl isopropyl adenosine, argue that the phagocytosis of amoebae by ZGCs is mediated by an ADO receptor, which is similar to the purinogenic class of receptor, A2. As with the A2 receptor, stimulation of cells by ADO binding causes an up-regulation of cAMP synthesis thereby increasing the intracellular levels of cAMP. During the phagocytic phase of sexual development, 5'-AMP and ADO undergo marked and successive increases in amounts supporting their natural role in modulating phagocytosis. This negative modulation of phagocytosis by ADO is similar to that found in mammalian macrophages and may represent an evolutionary precursor to that regulatory process. Furthermore, the slowing of phagocytosis has important implications to sexual development of D. discoideum.

Signal transduction during cannibalistic sexual phagocytosis: calcium is not the trigger but GTP-binding protein function is essential.

After fertilization, the zygote giant cell of Dictyostelium discoideum chemoattracts and subsequently engulfs hundreds of amoebae of the same species and strains from which it was derived. A pharmacological approach indicates that, while it may have some role, calcium is not the trigger for this cannibalistic phagocytic process. Of several agents that perturb intracellular calcium levels [A23187, LaCl, 8-diethylamino-octyl-3,4,5-trimethoxylbenzoate (TMB-8), and chlorotetracycline], only A23187 had an effect in reducing amoebal ingestion. In keeping with this, agents which interfered with downstream effectors of calcium function did not alter sexual phagocytosis. Calmidazolium and trifluoperazine, which inhibit calmodulin function, were ineffective, as were a protein kinase C inhibitor (staurosporine) and activator (phorbol 12-myristate 13-acetate). On the other hand, the nucleotide analogues GTP gamma S and GDP beta S both inhibited sexual phagocytosis indicating a role for GTP-binding protein activity at some stage in the process. Sub-fractionation of cells from non-phagocytic and phagocytic stage cell cultures followed by immunolocalization after SDS-PAGE and western blotting revealed a number of GTP-binding proteins in both the cell membrane and intracellular membrane fractions that might function during the events of sexual phagocytosis.

Periodic vestibulocerebellar ataxia, an autosomal dominant ataxia with defective smooth pursuit, is genetically distinct from other autosomal dominant ataxias.

BACKGROUND: Periodic vestibulocerebellar ataxia is an autosomal dominant disorder characterized by defective smooth pursuit, gaze-evoked nystagmus, ataxia, and vertigo. The age of onset ranges from the third to the sixth decade. To date, all patients have originated from North Carolina, suggesting a single common founder. OBJECTIVE: To clarify the classification of periodic vestibulocerebellar ataxia by determining whether it is allelic to other autosomal dominant cerebellar ataxias for which genes have been either localized or identified. METHODS: Blood was collected and DNA isolated from 66 subjects (19 affected individuals) in two multigenerational families. The microsatellite markers used in the analysis either flanked or were tightly linked to the disease gene regions. Two-point and multipoint linkage analyses were performed to define the limits of exclusion. RESULTS: Periodic vestibulocerebellar ataxia was excluded from loci linked to spinocerebellar ataxia type 1 (chromosome 6p), type 2 (chromosome 12q) type 3/Machado/Joseph disease (chromosome 14q), type 4 (chromosome 16q), and type 5 (11cent) as well as to episodic ataxia with myokymia (chromosome 12p), episodic ataxia with nystagmus (chromosome 19p), acetazolamide-responsive hereditary paroxysmal cerebellar ataxia (chromosome 19p), and dentatorubral-pallidoluysian atrophy/Haw River syndrome (chromosome 12p). CONCLUSION: Periodic vestibulocerebellar ataxia is genetically distinct from those autosomal dominant ataxias for which chromosomal localization has been established.

Recurrence of Wegener's granulomatosis 13 years after renal transplantation.

Wegener's granulomatosis (WG) can cause renal failure, requiring long-term renal replacement therapy. Renal transplantation in patients with WG is successful, but the risk for recurrence of the disease necessitates continued vigilance. We report a patient that originally presented with acute renal failure secondary to a pauci-immune focal necrotizing crescentic glomerulonephritis. Subsequent nasal involvement and serologic tests for antineutrophil cytoplasmic antibodies suggested a diagnosis of WG.

Chromosomal abnormalities in a psychiatric population.

Over a 3.5 year period of time, 345 patients hospitalized for psychiatric problems were evaluated cytogenetically. The patient population included 76% males and 94% children with a mean age of 12 years. The criteria for testing was an undiagnosed etiology for mental retardation and/or autism. Cytogenetic studies identified 11, or 3%, with abnormal karyotypes, including 4 fragile X positive individuals (2 males, 2 females), and 8 with chromosomal aneuploidy, rearrangements, or deletions. While individuals with chromosomal abnormalities do not demonstrate specific behavioral, psychiatric, or developmental problems relative to other psychiatric patients, our results demonstrate the need for an increased awareness to order chromosomal analysis and fragile X testing in those individuals who have combinations of behavioral/psychiatric, learning, communication, or cognitive disturbance.

Urogenital infection by Mycobacterium bovis relapsing after 50 years.

A 64-year-old man was referred to chest clinic after presenting initially with painless haematuria. Bladder biopsies showed granulomatous inflammation and subsequent urine cultures grew Mycobacterium bovis. He had been treated empirically for genito-urinary tuberculosis twice previously and on both occasions his haematuria ceased. Although the early hospital notes have been destroyed we believe this represents a very late and recurrent relapse of cystitis due to M. bovis.

Multi-system Infection with Nocardia farcinica-therapy with linezolid and minocycline.

We describe a case of disseminated infection with a multiple-resistant strain of Nocardia farcinica, probably resulting from direct inoculation during a road traffic accident. Initial presentation was with pulmonary symptoms, with subsequent development of cutaneous, renal, soft tissue and cerebral involvement. Precise microbiological diagnosis was delayed. Once sensitivity test results were available, the patient was stabilised on linezolid and minocycline. Premature withdrawal of therapy at one month resulted in recrudescence of infection, requiring re-institution of treatment. Linezolid was discontinued after a total of 4 months, because of evidence of myelosuppression and visual impairment, which subsequently improved. Monotherapy with minocycline was continued for a total of 12 months. The patient now remains well.

Impairment magnification during dynamic trunk motions.

STUDY DESIGN: An examination of a group of patients with low back disorder and a group of healthy (asymptomatic) individuals asked to produce trunk motions under sincere and insincere experimental conditions. Trunk motion components were examined to determine which combination of motion components could best distinguish between sincere and insincere efforts. OBJECTIVE: To determine whether examination of trunk motion components could be used to identify impairment magnification during unresisted repeated bending tasks. SUMMARY OF BACKGROUND DATA: Trunk motion measures can be used to assess and "benchmark" the status of the low back. However, these measures typically are clinically useful only if the individual is producing an effort that does not magnify the impairment during the functional evaluation. This study addressed the issue of impairment magnification during the production of free dynamic trunk motion. METHODS: The trunk motion characteristics of 100 healthy individuals and 100 patients with chronic low back disorders were documented. All participants were asked to produce the trunk motions in two different types of conditions. In the one experimental condition, they were asked to produce sincere trunk motions. In the other experimental condition they were asked to pretend either that they were experiencing low back pain (the asymptomatic group) or that their pain was worse than it actually was (group with low back pain). RESULTS: A combination of trunk motion measures was able to distinguish well between the conditions. Sensitivity and specificity for the asymptomatic group were 92%, whereas they were 75% for the group with low back pain. Overall, sensitivity and specificity were 81.5% for all the participants combined. CONCLUSIONS: These results indicate that motion measures can be used to help assess impairment magnification during functional trunk motion testing. These measures can provide a means by which to scrutinize the quality of quantitative measures indicating the extent of a low back disorder. These objective motion measures also can be used to complement other subjective observational methods for the assessment of impairment.

Detection of Lewis antigen structural change by FTIR spectroscopy.

Mucins are a family of extensively glycosylated, high molecular weight glycoproteins. Secretion of mucins with altered terminal carbohydrate moieties alters the rheological and viscoelastic properties of mucus and observed glycosylation changes in respiratory diseases may vary with disease status. Structural modifications to the Lewis x antigen with sialic acid (sialyl-Lewis x) and sulphate (sulfo-Lewis x) in particular are associated with respiratory diseases and deemed potential biomarkers for disease diagnosis, severity and progression. The major aim of this study was to evaluate the ability of Fourier transform infrared spectroscopy (FTIR) to detect, via infrared (IR) spectra, the structural changes between the Lewis x antigen and sialylated and sulphated derivatives. Although FTIR only provides information on vibrations of chemical groups, we show that by comparing mono- and oligosaccharide specific IR spectra it is possible to determine the contribution of key sugar moieties to the altered Lewis x spectral pattern.

Temporal changes in glucose and insulin homeostasis after biliopancreatic diversion and laparoscopic adjustable gastric banding.

BACKGROUND: Obesity surgery is associated with improvement in type 2 diabetes mellitus. Our aim was to examine the effects of biliopancreatic diversion (BPD) and laparoscopic adjustable gastric banding (LAGB) on the body mass index, fasting insulin level, glucose level, and insulin resistance in morbidly obese subjects with type 2 diabetes mellitus. The setting was the Department of Surgery, Morriston Hospital (Swansea, Wales, United Kingdom). METHODS: A total of 13 morbidly obese patients (7 BPD, 6 LAGB) underwent serial measurements of fasting glucose and insulin at baseline, immediately after surgery (days 1-7), and 1, 6, and 12 months postoperatively. The homeostasis model of assessment-insulin resistance was calculated. RESULTS: In the BPD group, the glucose levels had normalized by day 3 (5.6 ± 1 mmol/L) and the difference was statistically significant at 6 and 12 months postoperatively (5 ± .7 and 4.4 ± .5 mmol/L, respectively). The insulin levels had improved from day 1, and the difference was statistically significant at days 2, 5, 6, and 7 (19 ± 9, 14.2 ± 7, 15.2 ± 8, and 17.4 ± 8 mU/L, respectively). All diabetes medications were stopped on the fourth postoperative day. In the LAGB group, no statistically significant changes were seen in the glucose levels. Statistically significant changes in insulin were seen on days 1 and 2 (19 ± 13 and 13 ± 6.5 mU/L, respectively). The homeostatic model of assessment-insulin resistance had improved in both groups (BPD, 1.6 ± 1.2, P < .01; and LAGB, 4.3 ± 1.4, P < .05). CONCLUSION: BPD causes immediate remission of type 2 diabetes mellitus. Leptin might play an important role in the early improvement of insulin resistance in fasting states after BPD. In the LAGB group, glucose homeostasis improved, but the patients still required diabetes medications, although the dosages were reduced.

Smoking habits and attitudes toward tobacco bans among United Kingdom hospital staff and students.

SETTING: A group of United Kingdom (UK) hospitals. OBJECTIVE: To estimate the current smoking habits of health care professionals (HCPs) in a country with active tobacco control measures, and to record their attitudes to national and hospital tobacco bans. DESIGN: A cross-sectional survey of 500 HCPs. RESULTS: HCPs reported a lower rate of current smoking (7%) than the general population (24%). Doctors (2.6%) and medical students (3.8%) were less likely to be current smokers than both nurses (8.7%) and allied health professionals (10.9%, P < 0.001). The vast majority felt national legislation had been effective (88%) and well complied with (82%). Around a third of respondents believed the ban had led to a reduction in admissions for acute coronary syndrome. Almost all respondents were in favour of restrictions on smoking in health care premises. A higher proportion of UK doctors (69%) than nurses (52%) favoured a complete ban (odds ratio 2.01, 95% confidence interval 1.14-3.56). CONCLUSION: Self-reported smoking patterns in UK health professionals are lower than previously and compared to other industrialised and developing countries. Support for bans is very high, but differences remain in behaviour and especially attitudes to local bans according to professional status, although this gap is also narrowing.

Influence of long-term oxygen therapy on cardiac acceleration and deceleration capacity in hypoxic patients with chronic obstructive pulmonary disease.

BACKGROUND: There is increasing interest in cardiovascular co-morbidities of chronic obstructive pulmonary disease (COPD). Heart rate turbulence (HRT) and phase-rectified signal averaging (PRSA) techniques quantify the heart's acceleration/deceleration capacities. We postulated that these methods can help assess the integrity of cardiac control in hypoxic COPD. METHODS: Eight hypoxic stable COPD patients, nine healthy age-matched older adults and eight healthy young adults underwent ECG monitoring for 24 h. Patients with COPD were also monitored following 4 weeks of standardized oxygen therapy. HRT measures [turbulence onset (TO), turbulence slope (TS)] and PRSA-derived acceleration/deceleration (AC, DC) indices were quantified within 6-h blocks to assess circadian variation. RESULTS: There were between-group differences for variables TS, DC and AC (P<0·0005, η(2) = 0·54-0·65), attributable solely to differences between healthy young and COPD subjects. Only HR (P<0·0005) and DC index (P = 0·008) showed circadian variation. A significant interaction 'trend' effect for HR (F(9,87) = 2·52, P = 0·015, η(2) = 0·21) reflected the strong influence of COPD on HR circadian variation (afternoon and night values being different to those in healthy subjects). CONCLUSIONS: As expected, heart rate dynamics were substantially diminished in older (healthy and COPD) groups compared with healthy young controls. Patients with COPD showed similar heart rate dynamics compared with age-matched controls, both before and after hypoxia correction. However, there was a suggestion of diminished DC in COPD compared with age-matched controls (P = 0·059) that was absent following oxygen therapy. TS, DC and AC indices were altered by similar degrees in older subjects, apparently indicating equivalent tonic dysfunction of sympathetic/parasympathetic systems with ageing.

Influence of smoking abstinence and nicotine replacement therapy on heart rate and QT time-series.

SUMMARY: Many smokers attempt to quit without using nicotine replacement therapy (NRT) or pharmacotherapy, i.e. 'cold-turkey'. The cardiac implications of this are important but are incompletely understood. Previous studies have associated smoking cessation with improvements in heart rate (HR) and its variability, but its influence on QT time-series is unclear. Furthermore, the relative influence on these parameters of acute nicotine withdrawal and of NRT has not been adequately compared. Additional insight might come from analysing the dynamic (e.g. fractal) properties of electrocardiographic data during different levels of nicotine exposure. We examined the influence of smoking cessation, during cold-turkey and subsequent NRT, on HR and QT time-series during 30 days of smoking abstinence. Seven smokers and sixteen healthy non-smokers received ECG monitoring at baseline (Day 0). Smokers subsequently refrained from smoking without using NRT for 24 h, and then received NRT for 29 days. ECG monitoring was repeated at Days 1, 7, 30. Following smoking cessation we observed that: HR and rate-corrected QT were both reduced, heart rate variability (HRV) increased (improved), and QT variability index (QTVI) showed signs of improvement (trend only). Improvements in HR and QT were maintained throughout NRT use, whilst improvements in HRV and QTVI were sustained for at least the early stages of NRT. The dynamic (multifractal) properties of HR and QT were similar for smokers and non-smokers, and were unchanged by smoking abstinence or NRT. Our results provide tentative evidence that electrocardiographic improvements during a cold-turkey smoking quit attempt (acute nicotine withdrawal) are maintained during NRT pharmacotherapy.