Alpha Lipoic Acid for Symptomatic Peripheral Neuropathy in Patients with Diabetes: A Meta-Analysis of Randomized Controlled Trials

Objective. We performed a systematic review of the literature to evaluate the effects of alpha lipoic acid for symptomatic peripheral neuropathy in patients with diabetes mellitus. Research design and methods. The databases MEDLINE and EMBASE were searched using the key words “lipoic acid”, “thioctic acid”, “diabet∗”, and the MeSH-terms “thioctic acid” and “diabetes mellitus”. Randomised controlled trials using the TSS score as the outcome measure were selected and assessed for their methodological quality. Study selection and quality assessment were performed independently by three observers. Results. Overall, the pooled standardized mean difference estimated from all trials revealed a reduction in TSS scores of −2.26 (CI: −3.12 to −1.41; P = 0.00001) in favour of alpha lipoic acid administration. Subgroup analyses of oral administration (−1.78 CI: −2.45 to −1.10; P = 0.00001) and intravenous administration (−2.81 CI: −4.16 to −1.46; P = 0.0001) confirmed the robustness of the overall result. Conclusions. When given intravenously at a dosage of 600 mg/day over a period of 3 weeks, alpha lipoic acid leads to a significant and clinically relevant reduction in neuropathic pain (grade of recommendation A). It is unclear if the significant improvements seen after 3–5 weeks of oral administration at a dosage of >600 mg/day are clinically relevant

What methods are used to promote patient and family involvement in healthcare regulation? A multiple case study across four countries

Background In the regulation of healthcare, the subject of patient and family involvement figures increasingly prominently on the agenda. However, the literature on involving patients and families in regulation is still in its infancy. A systematic analysis of how patient and family involvement in regulation is accomplished across different health systems is lacking. We provide such an overview by mapping and classifying methods of patient and family involvement in regulatory practice in four countries; Norway, England, the Netherlands, and Australia. We thus provide a knowledge base that enables discussions about possible types of involvement, and advantages and difficulties of involvement encountered in practice. Methods The research design was a multiple case study of patient and family involvement in regulation in four countries. The authors collected 1) academic literature if available and 2) documents of regulators that describe user involvement. Based on the data collected, the authors from each country completed a pre-agreed template to describe the involvement methods. The following information was extracted and included where available: 1) Method of involvement, 2) Type of regulatory activity, 3) Purpose of involvement, 4) Who is involved and 5) Lessons learnt. Results Our mapping of involvement strategies showed a range of methods being used in regulation, which we classified into four categories: individual proactive, individual reactive, collective proactive, and collective reactive methods. Reported advantages included: increased quality of regulation, increased legitimacy, perceived justice for those affected, and empowerment. Difficulties were also reported concerning: how to incorporate the input of users in decisions, the fact that not all users want to be involved, time and costs required, organizational procedures standing in the way of involvement, and dealing with emotions. Conclusions Our mapping of user involvement strategies establishes a broad variety of ways to involve patients and families. The four categories can serve as inspiration to regulators in healthcare. The paper shows that stimulating involvement in regulation is a challenging and complex task. The fact that regulators are experimenting with different methods can be viewed positively in this regard

Axial heterogeneity and filtered-load dependence of proximal bicarbonate reabsorption

A theoretical model was developed to examine the role of physical and chemical factors in the control of bicarbonate reabsorption in the renal proximal tubule. Included in the model were axial and radial variations in the concentrations of HCO3-, CO2 and related chemical species in the tubule lumen and epithelial cells. Relations between these concentrations and the solute fluxes across the brush border and basolateral membranes were also included, as were reaction rate and equilibrium expressions to describe the various buffering processes in the lumen and cells. The two most critical membrane parameters, the rate constant for H+ secretion at the brush border and the effective permeability of HCO3- at the basolateral membrane, were evaluated by comparing model predictions with available free-flow micropuncture data in the rat. It was found that the experimental observations could be explained only by decreasing one or both of these membrane parameters with axial position, suggesting a progressive decrease in HCO3- reabsorptive capacity along the tubule. For single nephron filtered loads of HCO3- up to about 1,400 pmol/min, absolute bicarbonate reabsorption was predicted to increase nearly in proportion to filtered load, whereas it was calculated to be relatively constant at higher filtered loads, irrespective of how filtered load was assumed to be varied. These predictions are in excellent agreement with most of the available micropuncture data in rats, as is the prediction that HCO3- reabsorption should change in parallel with CO2 partial pressure in the filtrate, at a given filtered load of HCO3–. Certain discrepancies between the model predictions and experimental observations are evident at very high filtered loads, and the implications of these are discussed in terms of possible adaptive responses of the tubule

De novo variants disturbing the transactivation capacity of POU3F3 cause a characteristic neurodevelopmental disorder

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder

Oral Long-Term Complications of Allogeneic Haematopoietic Stem Cell Transplantation

INTRODUCTION: Kinesin superfamily (KIF) genes encode motor proteins that have fundamental roles in brain functioning, development, survival and plasticity by regulating the transport of cargo along microtubules within axons, dendrites and synapses. Mouse knockout studies support these important functions in the nervous system. The role of KIF genes in intellectual disability (ID) has so far received limited attention, although previous studies have suggested that many ID genes impinge on synaptic function. METHODS: By applying next-generation sequencing (NGS) in ID patients, we identified likely pathogenic mutations in KIF4A and KIF5C. To further confirm the pathogenicity of these mutations, we performed functional studies at the level of synaptic function in primary rat hippocampal neurons. RESULTS AND CONCLUSIONS: Four males from a single family with a disruptive mutation in the X-linked KIF4A (c.1489-8_1490delins10; p.?- exon skipping) showed mild to moderate ID and epilepsy. A female patient with a de novo missense mutation in KIF5C (c.11465A>C; p.(Glu237Lys)) presented with severe ID, epilepsy, microcephaly and cortical malformation. Knock-down of Kif4a in rat primary hippocampal neurons altered the balance between excitatory and inhibitory synaptic transmission, whereas the mutation in Kif5c affected its protein function at excitatory synapses. Our results suggest that mutations in KIF4A and KIF5C cause ID by tipping the balance between excitatory and inhibitory synaptic excitability

A Double-Blind, Randomized, Placebo-Controlled Clinical Trial on Benfotiamine Treatment in Patients With Diabetic Nephropathy

OBJECTIVE - To investigate the effect of benfotiamine on urinary albumin excretion (UAE) and the tubular damage marker kidney injury molecule-1 (KIM-1) in patients with type 2 diabetes and nephropathy. RESEARCH DESIGN AND METHODS - Patients with type 2 diabetes and UAE equivalent to 15-300 mg/24 h, despite ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs), were randomly assigned to 12 weeks of benfotiamine (900 mg/day) (n = 39) or placebo (n = 43). RESULTS - Compared with placebo, benfotiamine treatment resulted in significant improvement of thiamine status (P <0.001). Benfotiamine treatment did not significantly decrease 24-h UAE or 24-h KIM-1 excretion. CONCLUSIONS - In patients with type 2 diabetes and nephropathy, high-dose benfotiamine treatment for 12 weeks in addition to ACE-Is or ARBs did not reduce UAE or KIM-1 excretion, despite improvement of thiamine status

Active participation of patients with type 2 diabetes in consultations with their primary care practice nurses - what helps and what hinders:a qualitative study

Background:Patients with type 2 diabetes mellitus (T2DM) receiving primary care regularly visit their practicenurses (PNs). By actively participating during medical consultations, patients can better manage their disease,improving clinical outcomes and their quality of life. However, many patients with T2DM do not activelyparticipate during medical consultations. To understand the factors affecting engagement of patients withT2DM, this study aimed to identify factors that help or hinder them from actively participating inconsultations with their primary care PNs.Methods:Two semi-structured focus groups and 12 semi-structured individual interviews were conductedwith patients with T2DM (n= 20) who were undergoing treatment byprimary care PNs. All interviews weretranscribed verbatim and analyzed using a two-step approach derived from the context-mapping framework.Results:Four factors were found to help encourage patients to actively participate in their consultation:developing trusting relationships with their PNs,having enough time in the appointment, deliberatelypreparing for consultations, and allowing for the presence of a spouse. Conversely, four factors were found tohinder patients from participating during consultations: lacking the need or motivation to participate,readjusting to a new PN, forgetting to ask questions, and ineffectively expressing their thoughts.Conclusion:Patients lacked the skills necessary to adequately prepare for a consultation and achieve anactive role. In addition, patients’keen involvement appeared to benefit from a trusting relationship with theirPNs. When active participation is impeded by barriers such as a lack of patient’s skills, facilitators should beintroduced at an early stage

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

PURPOSE: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. METHODS: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. RESULTS: We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). CONCLUSION: The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Clinical Applicability of Transient Elastography for Estimating Liver Stiffness in Patients with Type 2 Diabetes Mellitus

Background: Type 2 diabetes mellitus (T2DM) is a risk factor for the development of non-alcoholic fatty liver disease, which can lead to liver fibrosis and ultimately to cirrhosis. Transient elastography (TE), by using the FibroScan, and is a non-invasive ultrasonography method to measure liver elasticity. TE has been related with the degree of liver fibrosis. Objective: To investigate the applicability of TE in daily clinical practice among T2DM patients. Method: In a non-academic teaching hospital, T2DM patients without a history of liver disease the degree of liver stiffness was measured using TE. Successful measurements were defined as 10 validated measurements per patient and an interquartile range (IQR) to median ratio of ≤30%. Results: In 90 of 126 patients (71%) valid measurements were be obtained. Among the patients with invalid measurements, 33 had &lt; 10 valid measurements and 3 had a IQR to median ratio of &lt;30%. The percentage of invalid measurements was 12% in patients with a BMI &lt;30 kg/m2 and 39% in patients with a BMI ≥30 kg/m2. Among the 90 patients with valid liver stiffness measurements, the median liver stiffness was 6.7 [4.6-8.5] kPa with a IQR of measurements of 1.1 [0.6-1.8] kPa and IQR to median ratio of 17 (13-23)%. Conclusion: The success rate of TE measurements using the FibroScan in patients with T2DM was 71%, with a lower success rate in patients with a BMI ≥ 30 kg/m2. This diagnostic modality needs further investigation being introduced as a marker of fibrosis in daily diabetes practice

Epigenetic Regulation of Learning and Memory by Drosophila EHMT/G9a

Behavioral phenotyping and genome-wide profiling of the histone modifier EHMT in Drosophila reveals a mechanism through which an epigenetic writer may control cognition