Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome

Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) represent the two ends of a clinical spectrum of disease caused by deficiency of mevalonate kinase (MVK), the first committed enzyme of cholesterol biosynthesis. At least 30 patients with MVA and 180 patients with HIDS have been reported worldwide. MVA is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises. The febrile episodes are commonly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal symptoms, arthralgia and skin rashes. Life expectancy is often compromised. In HIDS, only febrile attacks are present, but a subgroup of patients may also develop neurological abnormalities of varying degree such as mental retardation, ataxia, ocular symptoms and epilepsy. A reduced activity of MVK and pathogenic mutations in the MVK gene have been demonstrated as the common genetic basis in both disorders. In MVA, the diagnosis is established by detection of highly elevated levels of mevalonic acid excreted in urine. Increased levels of immunoglobulin D (IgD) and, in most patients of immunoglobulin A (IgA), in combination with enhanced excretion of mevalonic acid provide strong evidence for HIDS. The diagnosis is confirmed by low activity of mevalonate kinase or by demonstration of disease-causing mutations. Genetic counseling should be offered to families at risk. There is no established successful treatment for MVA. Simvastatin, an inhibitor of HMG-CoA reductase, and anakinra have been shown to have beneficial effect in HIDS

Improving the development, monitoring and reporting of stroke rehabilitation research: consensus-based core recommendations from the Stroke Recovery and Rehabilitation Roundtable (SRRR)

Recent reviews have demonstrated that the quality of stroke rehabilitation research has continued to improve over the last four decades but despite this progress there are still many barriers in moving the field forward. Rigorous development, monitoring and complete reporting of interventions in stroke trials are essential in providing rehabilitation evidence that is robust, meaningful and implementable. An international partnership of stroke rehabilitation experts committed to develop consensus-based core recommendations with a remit of addressing the issues identified as limiting stroke rehabilitation research in the areas of developing, monitoring and reporting stroke rehabilitation interventions. Work exploring each of the three areas took place via multiple teleconferences and a two-day meeting in Philadelphia in May 2016. A total of 15 recommendations were made. To validate the need for the recommendations the group reviewed all stroke rehabilitation trials published in 2015 (n=182 papers). Our review highlighted that the majority of publications did not clearly describe how interventions were developed or monitored during the trial. In particular, under-reporting of the theoretical rationale for the intervention and the components of the intervention calls into question many interventions that have been evaluated for efficacy. More trials were found to have addressed the reporting of interventions recommendations than those related to development or monitoring. Nonetheless the majority of reporting recommendations were still not adequately described. To progress the field of stroke rehabilitation research and to ensure stroke patients receive optimal evidence based clinical care we urge the research community to endorse and adopt our recommendations

Inhaled tobramycin solution-associated recurrent eosinophilia and severe persistent bronchospasm in a patient with cystic fibrosis: a case report

BACKGROUND: Delivery of tobramycin by inhalation to the lungs of patients with cystic fibrosis (CF) who are infected with Pseudomonas aeruginosa has been proven to be effective and safe. The aerosol administration allows high concentrations of tobramycin to be delivered to the site of infection with limited systemic absorption. In rare patients, systemic absorption of inhaled tobramycin may be significant enough to produce toxic effects, such as renal and vestibular toxicities. CASE PRESENTATION: We report a patient with CF who developed recurrent eosinophilia and severe persistent bronchospasm following repeated administration of preservative-free tobramycin by inhalation, beginning at 16 months of age. Also, he developed similar signs and symptoms when he was administered tobramycin intravenously on one occasion at 5 1/2 years. The patient had a history of environmental allergies. Temporal sequence of his signs and symptoms after each administration of tobramycin (similar to re-challenge testing), and his improvement after discontinuation of the drug strongly suggest an adverse drug reaction. CONCLUSION: Hypersensitivity reaction should be considered in patients who develop recurrent eosinophilia and deterioration of pulmonary function following the use of tobramycin by inhalation or by intravenous administration

Compromized geranylgeranylation of RhoA and Rac1 in mevalonate kinase deficiency

Mevalonate kinase deficiency (MKD) is an autoinflammatory disorder caused by mutations in the MVK gene resulting in decreased activity of the enzyme mevalonate kinase (MK). Although MK is required for biosynthesis of all isoprenoids, in MKD, in particular, the timely synthesis of geranylgeranyl pyrophosphate appears to be compromised. Because small guanosine triphosphatases (GTPases) depend on geranylgeranylation for their proper signaling function, we studied the effect of MK deficiency on geranylgeranylation and activation of the two small GTPases, RhoA and Rac1. We demonstrate that both geranylgeranylation and activation of the two GTPases are more easily disturbed in MKD cells than in control cells when the flux though the isoprenoid biosynthesis pathway is suppressed by low concentrations of simvastatin. The limited capacity of geranylgeranylation in MKD cells readily leads to markedly increased levels of nonisoprenylated and activated GTPases, which will affect proper signaling by these GTPases

IκBβ acts to inhibit and activate gene expression during the inflammatory response

The activation of pro-inflammatory gene programs by nuclear factor-κB (NF-κB) is primarily regulated through cytoplasmic sequestration of NF-κB by the inhibitor of κB (IκB) family of proteins1. IκBβ, a major isoform of IκB, can sequester NF-κB in the cytoplasm2, although its biological role remains unclear. Although cells lacking IκBβ have been reported3, 4, in vivo studies have been limited and suggested redundancy between IκBα and IκBβ5. Like IκBα, IκBβ is also inducibly degraded; however, upon stimulation by lipopolysaccharide (LPS), it is degraded slowly and re-synthesized as a hypophosphorylated form that can be detected in the nucleus6, 7, 8, 9, 10, 11. The crystal structure of IκBβ bound to p65 suggested this complex might bind DNA12. In vitro, hypophosphorylated IκBβ can bind DNA with p65 and c-Rel, and the DNA-bound NF-κB:IκBβ complexes are resistant to IκBα, suggesting hypophosphorylated, nuclear IκBβ may prolong the expression of certain genes9, 10, 11. Here we report that in vivo IκBβ serves both to inhibit and facilitate the inflammatory response. IκBβ degradation releases NF-κB dimers which upregulate pro-inflammatory target genes such as tumour necrosis factor-α (TNF-α). Surprisingly, absence of IκBβ results in a dramatic reduction of TNF-α in response to LPS even though activation of NF-κB is normal. The inhibition of TNF-α messenger RNA (mRNA) expression correlates with the absence of nuclear, hypophosphorylated-IκBβ bound to p65:c-Rel heterodimers at a specific κB site on the TNF-α promoter. Therefore IκBβ acts through p65:c-Rel dimers to maintain prolonged expression of TNF-α. As a result, IκBβ^(−/−) mice are resistant to LPS-induced septic shock and collagen-induced arthritis. Blocking IκBβ might be a promising new strategy for selectively inhibiting the chronic phase of TNF-α production during the inflammatory response

Incidence rates of progressive childhood encephalopathy in Oslo, Norway: a population based study

<p>Abstract</p> <p>Background</p> <p>Progressive encephalopathy (PE) in children is a heterogeneous group of diseases mainly composed of metabolic diseases, but it consists also of neurodegenerative disorders where neither metabolic nor other causes are found. We wanted to estimate the incidence rate and aetiology of PE, as well as the age of onset of the disease.</p> <p>Methods</p> <p>We included PE cases born between 1985 and 2003, living in Oslo, and registered the number presenting annually between 1985 and 2004. Person-years at risk between 0 and 15 years were based on the number of live births during the observation period which was divided into four 5-year intervals. We calculated incidence rates according to age at onset which was classified as neonatal (0–4 weeks), infantile (1–12 months), late infantile (1–5 years), and juvenile (6–12 years).</p> <p>Results</p> <p>We found 84 PE cases representing 28 diagnoses among 1,305,997 person years, giving an incidence rate of 6.43 per 100,000 person years. The age-specific incidence rates per 100,000 were: 79.89 (<1 year), 8.64 (1–2 years), 1.90 (2–5 years), and 0.65 (>5 years). 66% (55/84) of the cases were metabolic, 32% (27/54) were neurodegenerative, and 2% (2/84) had HIV encephalopathy. 71% (60/84) of the cases presented at < 1 year, 24% (20/84) were late infantile presentations, and 5% (4/84) were juvenile presentations. Neonatal onset was more common in the metabolic (46%) (25/55) compared to the neurodegenerative group (7%) (2/27). 20% (17/84) of all cases were classified as unspecified neurodegenerative disease.</p> <p>Conclusion</p> <p>The overall incidence rate of PE was 6.43 per 100,000 person years. There was a strong reduction in incidence rates with increasing age. Two-thirds of the cases were metabolic, of which almost half presented in the neonatal period.</p

Disparities and risks of sexually transmissible infections among men who have sex with men in China: a meta-analysis and data synthesis.

BACKGROUND: Sexually transmitted infections (STIs), including Hepatitis B and C virus, are emerging public health risks in China, especially among men who have sex with men (MSM). This study aims to assess the magnitude and risks of STIs among Chinese MSM. METHODS: Chinese and English peer-reviewed articles were searched in five electronic databases from January 2000 to February 2013. Pooled prevalence estimates for each STI infection were calculated using meta-analysis. Infection risks of STIs in MSM, HIV-positive MSM and male sex workers (MSW) were obtained. This review followed the PRISMA guidelines and was registered in PROSPERO. RESULTS: Eighty-eight articles (11 in English and 77 in Chinese) investigating 35,203 MSM in 28 provinces were included in this review. The prevalence levels of STIs among MSM were 6.3% (95% CI: 3.5-11.0%) for chlamydia, 1.5% (0.7-2.9%) for genital wart, 1.9% (1.3-2.7%) for gonorrhoea, 8.9% (7.8-10.2%) for hepatitis B (HBV), 1.2% (1.0-1.6%) for hepatitis C (HCV), 66.3% (57.4-74.1%) for human papillomavirus (HPV), 10.6% (6.2-17.6%) for herpes simplex virus (HSV-2) and 4.3% (3.2-5.8%) for Ureaplasma urealyticum. HIV-positive MSM have consistently higher odds of all these infections than the broader MSM population. As a subgroup of MSM, MSW were 2.5 (1.4-4.7), 5.7 (2.7-12.3), and 2.2 (1.4-3.7) times more likely to be infected with chlamydia, gonorrhoea and HCV than the broader MSM population, respectively. CONCLUSION: Prevalence levels of STIs among MSW were significantly higher than the broader MSM population. Co-infection of HIV and STIs were prevalent among Chinese MSM. Integration of HIV and STIs healthcare and surveillance systems is essential in providing effective HIV/STIs preventive measures and treatments. TRIAL REGISTRATION: PROSPERO NO: CRD42013003721

Understanding the theoretical underpinning of the exercise component in a fall prevention programme for older adults with mild dementia: a realist review protocol

Background Older adults with mild dementia are at an increased risk of falls. Preventing those at risk from falling requires complex interventions involving patient-tailored strength- and balance-challenging exercises, home hazard assessment, visual impairment correction, medical assessment and multifactorial combinations. Evidence for these interventions in older adults with mild cognitive problems is sparse and not as conclusive as the evidence for the general community-dwelling older population. The objectives of this realist review are (i) to identify the underlying programme theory of strength and balance exercise interventions targeted at those individuals that have been identified as falling and who have a mild dementia and (ii) to explore how and why that intervention reduces falls in that population, particularly in the context of a community setting. This protocol will explain the rationale for using a realist review approach and outline the method. Methods A realist review is a methodology that extends the scope of a traditional narrative or systematic evidence review. Increasingly used in the evaluation of complex interventions, a realist enquiry can look at the wider context of the intervention, seeking more to explain than judge if the intervention is effective by investigating why, what the underlying mechanism is and the necessary conditions for success. In this review, key rough programme theories were articulated and defined through discussion with a stakeholder group. The six rough programme theories outlined within this protocol will be tested against the literature found using the described comprehensive search strategy. The process of data extraction, appraisal and synthesis is outlined and will lead to the production of an explanatory programme theory. Discussion As far as the authors are aware, this is the first realist literature review within fall prevention research and adds to the growing use of this methodology within healthcare. This synthesis of evidence will provide a valuable addition to the evidence base surrounding the exercise component of a fall intervention programme for older adults with mild dementia and will ultimately provide clinically relevant recommendations for improving the care of people with dementia

Prospective Newborn Screening for SCID in Germany: A First Analysis by the Pediatric Immunology Working Group (API)

Background: T-cell receptor excision circle (TREC)-based newborn screening (NBS) for severe combined immunodeficiencies (SCID) was introduced in Germany in August 2019. / Methods: Children with abnormal TREC-NBS were referred to a newly established network of Combined Immunodeficiency (CID) Clinics and Centers. The Working Group for Pediatric Immunology (API) and German Society for Newborn Screening (DGNS) performed 6-monthly surveys to assess the TREC-NBS process after 2.5 years. / Results: Among 1.9 million screened newborns, 88 patients with congenital T-cell lymphocytopenia were identified (25 SCID, 17 leaky SCID/Omenn syndrome (OS)/idiopathic T-cell lymphocytopenia, and 46 syndromic disorders). A genetic diagnosis was established in 88%. Twenty-six patients underwent hematopoietic stem cell transplantation (HSCT), 23/26 within 4 months of life. Of these, 25/26 (96%) were alive at last follow-up. Two patients presented with in utero onset OS and died after birth. Five patients with syndromic disorders underwent thymus transplantation. Eight syndromic patients deceased, all from non-immunological complications. TREC-NBS missed one patient, who later presented clinically, and one tracking failure occurred after an inconclusive screening result. / Conclusion: The German TREC-NBS represents the largest European SCID screening at this point. The incidence of SCID/leaky SCID/OS in Germany is approximately 1:54,000, very similar to previous observations from North American and European regions and countries where TREC-NBS was implemented. The newly founded API-CID network facilitates tracking and treatment of identified patients. Short-term HSCT outcome was excellent, but NBS and transplant registries will remain essential to evaluate the long-term outcome and to compare results across the rising numbers of TREC-NBS programs across Europe

The history of attention deficit hyperactivity disorder

The contemporary concept of attention deficit hyperactivity disorder (ADHD) as defined in the DSM-IV-TR (American Psychiatric Association 2000) is relatively new. Excessive hyperactive, inattentive, and impulsive children have been described in the literature since the nineteenth century. Some of the early depictions and etiological theories of hyperactivity were similar to current descriptions of ADHD. Detailed studies of the behavior of hyperactive children and increasing knowledge of brain function have changed the concepts of the fundamental behavioral and neuropathological deficits underlying the disorder. This article presents an overview of the conceptual history of modern-day ADHD