Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment.

In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.

Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data.

BACKGROUND: The cobalamin E (cblE) (MTRR, methionine synthase reductase) and cobalamin G (cblG) (MTR, methionine synthase) defects are rare inborn errors of cobalamin metabolism leading to impairment of the remethylation of homocysteine to methionine. METHODS: Information on clinical and laboratory data at initial full assessment and during the course of the disease, treatment, outcome and quality of life was obtained in a survey-based, retrospective study from physicians caring for patients with the CblE or CblG defect. In addition, data on enzyme studies in cultured skin fibroblasts and mutations in the MTRR and MTR gene were analysed. RESULTS: In 11 cblE and 13 cblG patients, failure to thrive, feeding problems, delayed milestones, muscular hypotonia, cognitive impairment and macrocytic anaemia were the most frequent symptoms. Delay in diagnosis depended on age at first symptom and clinical pattern at presentation and correlated significantly with impaired communication abilities at follow-up. Eighteen/22 patients presented with brain atrophy or white matter disease. Biochemical response to treatment with variable combinations of betaine, cobalamin, folate was significant. The overall course was considered improving (n = 8) or stable (n = 15) in 96% of patients, however the average number of CNS symptoms per patient increased significantly over time and 16 of 23 patients were classified as developmentally delayed or severely handicapped. In vitro enzyme analysis data showed no correlation with outcome. Predominantly private mutations were detected and no genotype- phenotype correlations evident. CONCLUSIONS: The majority of patients with the cblE and cblG defect show limited clinical response to treatment and have neurocognitive impairment.

Development and pilot testing of an integrated, web-based self-management program for irritable bowel syndrome (IBS).

BACKGROUND: Although essential, many medical practices are unable to adequately support irritable bowel syndrome (IBS) patient self-management. Web-based programs can help overcome these barriers. METHODS: We developed, assessed, and refined an integrated IBS self-management program (IBS Self-care). We then conducted a 12-week pilot test to assess program utilization, evaluate its association with patients' self-efficacy and quality of life, and collect qualitative feedback to improve the program. KEY RESULTS: 40 subjects with generally mild IBS were recruited via the Internet to participate in a 12-week pilot study. Subjects found the website easy to use (93%) and personally relevant (95%), and 90% would recommend it to a friend. Self-rated IBS knowledge increased from an average of 47.1 on a 100-point VAS scale (SD 22.1) at baseline to 77.4 (SD: 12.4) at week 12 (p < 0.0001). There were no significant changes in patient self-efficacy (Patient Activation Measure) or quality of life (IBS -Quality of Life Scale). CONCLUSIONS & INFERENCES: The IBS Self-Care program was well received by users who after 12 weeks reported improved knowledge about IBS, but no significant changes in self-efficacy or quality of life. If applied to the right population, this low cost solution can overcome some of the deficiencies of medical care and empower individuals to better manage their own IBS.

Chemotherapy and remission status do not alter pre-existing innate immune dysfunction in dogs with lymphoma.

Dogs with lymphoma have altered innate immunity and little is known about the effects of chemotherapy on innate immune function in dogs. Lipopolysaccharide (LPS), lipoteichoic acid (LTA), and peptidoglycan (PG) - induced leukocyte cytokine production capacity, and phagocytosis and respiratory burst were evaluated in dogs prior to and following 6 weeks of chemotherapy. Dogs had decreased TNF production following LPS stimulation and increased IL-10 production following PG stimulation, which did not improve following remission of lymphoma. Dogs also had reduced E. coli-induced respiratory burst function after chemotherapy induced complete or partial remission. Dogs with lymphoma have an imbalance in pro-and anti-inflammatory cytokine production which did not improve with remission, and, following treatment, a decrease in respiratory burst function. Altered immune responses following exposure to bacterial pathogen associated molecular pattern motifs and bacteria may have many implications in the management of canine lymphoma.

Heavy alcohol use as a risk factor for severe outcomes among adults hospitalized with laboratory-confirmed influenza, 2005-2012.

We examined heavy alcohol use as a risk factor for severe influenza (intensive care admission or death) among hospitalized adults. In <65- and ≥65-year-olds, heavy alcohol use increased disease severity [relative risk (RR) 1.34; 95 % confidence interval (CI): 1.04-1.74, and RR 2.47; 95 % CI: 1.69-3.60, respectively]. Influenza vaccination and early, empiric antiviral treatment should be emphasized in this population.

Effect of opioids on CXCL-8 production in healthy cats.

The aim of this study was to evaluate the effect of opioid exposure on CXC chemokine ligand (CXCL)-8 production in cats using whole blood culture. Morphine, buprenorphine, fentanyl, and saline control were administered intravenously to five cats and whole blood pathogen associated molecular pattern motif-induced CXCL-8 production capacity was evaluated. Morphine potentiated CXCL-8 production. To further characterize this effect of morphine, morphine was incubated with whole blood ex vivo and pathogen associated molecular pattern motif-induced CXCL-8 production capacity was measured. There was a time and concentration dependent effect on CXCL-8 production, suggesting the proinflammatory effect of morphine is at least partially mediated by direct stimulatory effects on leukocytes. Additional investigation is indicated to assess the implications of the immunomodulatory actions of opioids in cats.

Methylmalonic acidemia mimicking diabetic ketoacidosis in an infant.

Methylmalonic acidemia (MMA) is an inherited organic acidemia usually present with recurrent episodes of acute illness. A typical episode is ushered in with ketonuria and vomiting, followed by acidosis, dehydration, and lethargy, leading, in the absence of aggressive treatment, to coma and death. We report an infant with MMA presented with diabetes symptoms. A 13-month-old girl complained of polydipsia, diuresis, and loss of weight. She had clinical signs of diabetic ketoacidosis such as dehydration, deep sighing respiration, smell of ketones, lethargy, and vomiting. Laboratory analysis showed hyperglycemia with acidosis and ketonuria. She was treated with parenteral fluid, electrolyte, and insulin infusion. Two days after her discharge, after having a meal rich in protein, she was brought unconscious with hepatomegaly, severe acidosis, ketonuria, and mild hyperammonemia. The absence of hyperglycemia and the presence of neurologic findings suggested organic acidemia. MMA was diagnosed because of methylmalonic aciduria and elevated C3 carnitine esters. Cranial magnetic resonance imaging (MRI) showed increased uptake of radiocontrast material in the basal ganglia bilaterally. A homozygous mutation in exon 4 of the MMAA gene was found in mutation analysis and confirmed the diagnosis of cblA-deficient MMA. Neurologic regression was improved with treatment of low-protein diet, vitamin B12, and l-carnitine. In patients born to consanguineous parents who admit during infancy with severe acidosis refractory to treatment, organic acidemias should be kept in mind, even they have high blood glucose. The definitive diagnosis is important because it may allow a specific treatment and a favorable evolution to prevent the sequelae.

Physiologically based pharmacokinetic (PBPK) tool kit for environmental pollutants--metals.

The Agency for Toxic Substances and Disease Registry (ATSDR) is mandated by the US Congress to identify significant human exposure levels, develop methods to determine such exposures, and design strategies to mitigate them. Physiologically based pharmacokinetic (PBPK) models are increasingly being used to evaluate toxicity of environmental pollutants through multiple exposure pathways. As part of its translational research project, ATSDR is developing a human 'PBPK model tool kit' that consists of a series of published models re-coded in a common simulation language. The tool kit currently consists of models, at various stages of development, for priority environmental contaminants including solvents and persistent organic pollutants. Presented here are results of translational activities of re-coding models for cadmium, mercury, and arsenic. As part of this work, following re-coding each new model was evaluated for fidelity followed by sensitivity analysis. Good agreement was generally obtained for all three models when predictions of original and re-coded model simulations were compared. Also presented is an application of the cadmium toxicokinetic model to interpret biomonitoring data from the National Health and Nutrition Examination Survey (NHANES). The PBPK tool kit will enable ATSDR scientists to perform simulations of exposures from contaminated environmental media at sites of concern and to better interpret site-specific biomonitoring data.

Quality of life following radiofrequency ablation of dysplastic Barrett's esophagus.

BACKGROUND AND STUDY AIMS: The impact of the diagnosis and treatment of dysplastic Barrett's esophagus on quality of life (QoL) is poorly understood. This study assessed the influence of dysplastic Barrett's esophagus on QoL and evaluated whether endoscopic treatment of dysplastic Barrett's esophagus with radiofrequency ablation (RFA) improves QoL. PATIENTS AND METHODS: We analyzed changes in QoL in the AIM Dysplasia Trial, a multicenter study of patients with dysplastic Barrett's esophagus who were randomly allocated to RFA therapy or a sham intervention. We developed a 10-item questionnaire to assess the influence of dysplastic Barrett's esophagus on QoL. The questionnaire was completed by patients at baseline and 12 months. RESULTS: 127 patients were randomized to RFA (n = 84) or sham (n = 43). At baseline, most patients reported worry about esophageal cancer (71 % RFA, 85 % sham) and esophagectomy (61 % RFA, 68 % sham). Patients also reported depression, impaired QoL, worry, stress, and dissatisfaction with the condition of their esophagus. Of those randomized, 117 patients completed the study to the 12-month end point. Compared with the sham group, patients treated with RFA had significantly less worry about esophageal cancer ( P=0.003) and esophagectomy ( P =0.009). They also had significantly reduced depression ( P=0.02), general worry about the condition of their esophagus ( P≤0.001), impact on daily QoL ( P=0.009), stress ( P=0.03), dissatisfaction with the condition of their esophagus ( P≤0.001), and impact on work and family life ( P=0.02). CONCLUSIONS: Inclusion in the treatment group of this randomized, sham-controlled trial of RFA was associated with improvement in disease-specific health-related quality of life. This improvement appears secondary to a perceived decrease in the risk of cancer.