IntroductionChronic non-productive coughing is a major complication of pulmonary disease and can also occur in many individuals without identifiable underlying pathology. The common clinical link in ...patients with cough is an enhanced sensitivity of the respiratory system to stimuli that subsequently evoke excessive coughing. The aetiology of this ‘cough hypersensitivity syndrome’ is unclear but believed to involve hypersensitivity of the sensory neural pathways that innervate the airways and lungs.MethodsIn the present study, we used functional brain imaging to compare central neural responses to airway stimulation using inhaled capsaicin in healthy people and patients with cough hypersensitivity.ResultsHypersensitivity in response to inhaled capsaicin coincided with elevated neural activity in the midbrain in a region encompassing the nucleus cuneiformis (left: p<0.001; right: p<0.001) and periaqueductal gray (p=0.008) in comparison to normal sensitivity in controls. The enhanced activity noted in the midbrain is similar to that occurring in patients with chronic pain, thus providing empirical evidence to support the notion that cough and pain share neurobiological similarities. Furthermore, patients with cough hypersensitivity displayed difficulty controlling their cough, which manifested as a failure to suppress cough during capsaicin challenge (ie, reduced cough frequency) in controls compared with patients with cough hypersensitivity (p=0.046). Cough suppression was associated with reduced activity in a forebrain network that included the dorsomedial prefrontal and anterior mid-cingulate cortices. Additionally, cough frequency was correlated with activity in the right inferior frontal gyrus (R2=0.6, p<0.001) and right anterior insula (R2=0.6, p<0.001), regions previously implicated in voluntary cough suppression.ConclusionsThese findings provide insight into the central neurobiology of cough hypersensitivity and suggest that both central amplification of cough sensory inputs and reduced capacity to suppress cough motor behaviours define patients with problematic cough.
Heterozygous (carrier) status for an autosomal recessive condition is traditionally considered to lack significance for an individual's health, but this assumption has been challenged by a growing ...body of evidence. Carriers of several autosomal recessive disorders and some X-linked diseases are potentially at risk for the pathology manifest in homozygotes. This minireview provides an overview of the literature regarding health risks to carriers of two common autosomal recessive conditions on the Recommended Uniform Screening Panel: sickle cell disease sickle cell trait (SCT) and cystic fibrosis (CF). We also consider and comment on bioethical and policy implications for newborn blood screening (NBS). Health risks for heterozygotes, while relatively low for individuals, are often influenced by intrinsic (e.g., other genomic variants or co-morbidities) and extrinsic (environmental) factors, which present opportunities for personalized genomic medicine and risk counseling. They create a special challenge, however, for developing screening/follow-up policies and for genetic counseling, particularly after identification and reporting of heterozygote status through NBS. Although more research is needed, this minireview of the SCT and CF literature to date leads us to propose that blanket terms such as “healthy heterozygotes” or “unaffected carriers” should be superseded in communications about NBS results, in favor of a more nuanced paradigm of setting expectations for health outcomes with “genotype-to-risk.” In the molecular era of NBS, it remains clear that public health needs to become better prepared for the full range of applied genetics.
•Mendelian recessive conditions have traditionally been thought to spare the carriers.•A growing body of evidence challenges the prevailing dogma of healthy heterozygotes.•Research shows that people with sickle cell trait and CF carriers have disease risks.•Mothers of boys with X-linked adrenoleukodystrophy also have a high risk for disease.•Policies and practices in newborn screening need to adapt to deal with carrier risks.
Aims
This review provides an up‐to‐date curated source of information on alcohol, tobacco and illicit drug use and their associated mortality and burden of disease. Limitations in the data are also ...discussed, including how these can be addressed in the future.
Methods
Online data sources were identified through expert review. Data were obtained mainly from the World Health Organization, United Nations Office on Drugs and Crime and Institute for Health Metrics and Evaluation.
Results
In 2015, the estimated prevalence among the adult population was 18.4% for heavy episodic alcohol use (in the past 30 days); 15.2% for daily tobacco smoking; and 3.8, 0.77, 0.37 and 0.35% for past‐year cannabis, amphetamine, opioid and cocaine use, respectively. European regions had the highest prevalence of heavy episodic alcohol use and daily tobacco use. The age‐standardized prevalence of alcohol dependence was 843.2 per 100 000 people; for cannabis, opioids, amphetamines and cocaine dependence it was 259.3, 220.4, 86.0 and 52.5 per 100 000 people, respectively. High‐income North America region had among the highest rates of cannabis, opioid and cocaine dependence. Attributable disability‐adjusted life‐years (DALYs) were highest for tobacco smoking (170.9 million DALYs), followed by alcohol (85.0 million) and illicit drugs (27.8 million). Substance‐attributable mortality rates were highest for tobacco smoking (110.7 deaths per 100 000 people), followed by alcohol and illicit drugs (33.0 and 6.9 deaths per 100 000 people, respectively). Attributable age‐standardized mortality rates and DALYs for alcohol and illicit drugs were highest in eastern Europe; attributable age‐standardized tobacco mortality rates and DALYs were highest in Oceania.
Conclusions
In 2015 alcohol use and tobacco smoking use between them cost the human population more than a quarter of a billion disability‐adjusted life years, with illicit drugs costing further tens of millions. Europeans suffered proportionately more, but in absolute terms the mortality rate was greatest in low‐ and middle‐income countries with large populations and where the quality of data was more limited. Better standardized and rigorous methods for data collection, collation and reporting are needed to assess more accurately the geographical and temporal trends in substance use and its disease burden.
Reports from individual centres suggest a preponderance of females with chronic cough. Females also have heightened cough reflex sensitivity. Here we have reviewed the age and sex of unselected ...referrals to 11 cough clinics. To investigate the cause of any observed sex dimorphism, functional magnetic resonance imaging of putative cough centres was analysed in normal volunteers. The demographic profile of consecutive patients presenting with chronic cough was evaluated. Cough challenge with capsaicin was undertaken in normal volunteers to construct a concentration-response curve. Subsequent functional magnetic resonance imaging during repeated inhalation of sub-tussive concentrations of capsaicin observed areas of activation within the brain and differences in the sexes identified. Of the 10,032 patients presenting with chronic cough, two-thirds (6591) were female (mean age 55 years). The patient profile was largely uniform across centres. The most common age for presentation was 60-69 years. The maximum tolerable dose of inhaled capsaicin was lower in females; however, a significantly greater activation of the somatosensory cortex was observed. Patients presenting with chronic cough from diverse racial and geographic backgrounds have a strikingly homogeneous demographic profile, suggesting a distinct clinical entity. The preponderance of females may be explained by sex-related differences in the central processing of cough sensation.
A 48 year old female presented with right-sided weakness. Acute imaging showed multifocal vessel irreg- ularities and acute infarcts in the left parietal lobe, left internal capsule and pons. She was ...aggressively treated with anti-thrombotic therapy and glucocorticoids, for clinical concern of vasculitis.Despite maximal secondary prevention, she had further bi-hemispheric, multi-territorial strokes on days 11, 14, 15, 20 and 21 of admission. There was significant haemorrhagic transformation on Day 23.She died on Day 25, due to secondary hydrocephalus causing trans-tentorial herniation. Post-mortem examination showed:1: Severe, multifocal Cystic Medial Degeneration of the intracranial, extracerebral vasculature with dis- sections and secondary atherosclerosis.2: Cystic medical necrosis of the aorta.Cystic Medial Degeneration is a necrotic vasculopathy of large arteries (generally the aorta) with poorly understood pathogenesis. It causes degeneration of collagen and elastin within the arterial wall, predis- posing to ischaemia, haemorrhage and aneurysm formation. It associates with connective tissue disorders. CMD has been scarcely described intracranially. It shares some histological features with segmental arterial mediolysis, which has itself been described as being mostly fatal when cerebral vasculature isaffected.We highlight this case to clinicians encountering patients with unexplained stroke syndromes. There unfor- tunately does not appear to be an effective treatment.
•Averaging less than 20 consecutive TMS-evoked MEPs gives highly variable results.•More than 25 paired-pulse stimuli are required for highly reliable SICI estimates.•After 30 successive pulses, ICF ...measures stabilize with low inter-session reliability.
Transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) are frequently used to assess corticospinal and intercortical activities. Trial to trial variance of the potentials is commonly observed, and averages of multiple MEPs are usually reported. Multiple trials have resources implications and are not compatible with some experimental protocols. This study investigated the minimum number of MEPs required to reliably assess corticospinal excitability (CSE), short interval intracortical inhibition (SICI) and intercortical facilitation (ICF), within and between sessions. Fifteen healthy volunteers received 35 single-pulse TMS for CSE assessments and 35 paired-pulse TMS for SICI and ICF measurements. Intra- and intersession reliability were examined using intra-class correlation coefficient tests, and stability of the measures was assessed using a general equation estimation analysis. Coefficients of variation were used to probe the effects of inter-individual variability on reliability results. All analyses were carried out on cumulative averages. The optimal number of trials to ensure “excellent” intra and inter-session reliability with low inter-individual variability and the highest level of stability was found to be 20 for CSE and 26 for SICI assessments. Although 30 consecutive trials produced highly reliable ICF measures within a session, inter-session reliability was not significant across 35 trials. These findings have significant implications for improving time efficiency of TMS experiments without compromising intra- or intersession reliability.
Introduction: Synthetic cannabinoids are an emerging clinical and public health concern. The current study aimed to determine: (1) The characteristics and circumstances of death of all recorded cases ...of synthetic cannabinoid-related sudden or unnatural death in Australia, (2) The toxicology of cases and (3) Their major organ pathology.
Methods: Retrospective study of all cases in Australia in which synthetic cannabinoid use was a mechanism contributory to death (n = 55) retrieved from the National Coronial Information System (2000-2017). Information was collected on cause of death, demographics, drug use history, circumstances of death, toxicology and major organ pathology.
Results: The mean age was 37.2 years and 91.1% were male. Causes of death comprised of accidental toxicity (38.2%), accidental toxicity/cardiovascular disease (9.1%), natural disease (20.0%), suicide (10.9%) and traumatic accident (10.9%). The most common clinical presentation proximal to death was sudden collapse (25.5%). Cardiovascular disease was prominent: severe atherosclerosis (20.0%), myocardial replacement fibrosis (18.0%), cardiomegaly (12.0%). The most frequent synthetic cannabinoids were the indazolecarboxemides (61.8%), most commonly AB-CHMINACA (38.2%). The most frequent other substances were alcohol (34.5%) and Δ
9
-THC (23.6%).
Conclusions: AB-CHMINACA was the most commonly seen synthetic cannabinoid. There was a high representation of relatively older decedents and of older males in particular. While acute toxicity was the most common cause of death, cardiovascular disease was prominent.
Purpose of Review
Abdominal pain occurs frequently in children; chronic abdominal pain affects about 15% of children. There is always an initial concern for serious organic medical conditions; these ...can be eliminated with careful history and physical examination, especially looking for “red flags.” These children are often subjected to numerous invasive and noninvasive tests; excessive testing should be avoided. There is no evidence extensive testing improves patient outcome or satisfaction. Recent guidelines recommend celiac serology and fecal calprotectin/lactoferrin as the optimal screening tests. Anxiety is often a co-morbidity; the continued testing and lack of explanation exacerbate the symptoms and cause more dysfunction.
Recent Findings
Ongoing research suggests chronic abdominal pain is a complex interaction of genetics, environmental factors including diet, changes in the microbiome, previous life events, and stresses. The gut-brain axis is now more accurately described as the microbiome-gut-brain axis. Many disturbances have been reported but it remains unclear which are causative versus reactive. Therapeutic interventions have targeted one or more of the components but rarely in a coordinated manner. A positive diagnosis and explanation of pathophysiology are crucial first steps. A holistic approach that focuses on restoration of functioning and well-being is the best approach. A non-pharmacologic approach is the favored initial therapy; many children improve with counseling and assurance that there are no serious organic disorders. A trusting relationship with child and family is an integral part of the treatment plan.
Summary
Pediatric chronic abdominal pain is commonly encountered in practice. Serious conditions can be eliminated by determining whether any of the so-called red flags are present and judicious testing. High quality evidence is lacking for many proposed treatments. Data interpretation is confounded by a high placebo response rate, even when the placebo is unblinded. The current best evidence is for non-pharmacologic treatments including cognitive behavioral therapy and hypnosis. Neuromodulation is a new, promising intervention.
Mitochondrial dysfunction commonly presents with ocular findings as a part of a systemic disorder. These ophthalmic manifestations can be the first sign of a mitochondrial abnormality, which ...highlights the key role of a comprehensive ophthalmic assessment. On the other hand, a number of visually disabling genetic and acquired eye diseases with no curative treatment show abnormal mitochondrial function. Recent advances in mitochondrial research have improved our understanding of previously unexplained ocular disorders utilising better diagnostic approaches. Further studies on mitochondrial dysfunction and novel modalities of treatment will help to improve outcomes of these conditions. In this review article we discuss the clinical picture of common mitochondrial-related eye diseases, diagnostic approaches and possible treatment options including a very recent interesting report about gene therapy, with a particular focus on glaucoma.
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