Cobalamin status and its biochemical markers methylmalonic acid and homocysteine in different age groups from 4 days to 19 years

BACKGROUND: Recent data indicate that cobalamin and folate status, including the metabolic markers methylmalonic acid (MMA) and total homocysteine (tHcy), undergo marked changes during childhood, particularly during the first year. METHODS: Serum cobalamin, serum and whole-blood folate, and plasma MMA and tHcy were determined in a cross-sectional study of 700 children, ages 4 days to 19 years. RESULTS: During the first 6 months, serum cobalamin was lower than and plasma MMA, tHcy, and serum folate were higher than the concentrations detected in the other age groups. In infants 6 weeks to 6 months of age, median MMA and tHcy concentrations were >0.78 and >75 micro mol/L, respectively. In older children (>6 months), serum cobalamin peaked at 3-7 years and then decreased, median plasma MMA remained low (<0.26 micro mol/L), median plasma tHcy was low (<6 micro mol/L) and increased from the age of 7 years on, and serum folate gradually decreased. Plasma MMA was inversely associated with cobalamin (r = -0.4) in both age groups, but across the whole range of cobalamin concentrations, MMA was markedly higher in infants (< or =6 months) than in older children. Plasma tHcy showed a strong negative correlation to cobalamin (r = -0.52) but not to serum folate in infants < or =6 months. In older children, tHcy showed the expected association with both cobalamin (r = -0.48) and folate (r = -0.51). CONCLUSIONS: In infants 6 weeks to 6 months, concentrations of the metabolic markers MMA and tHcy were higher than in the other age groups and strongly correlated to cobalamin, whereas in older children, both makers showed correlations to cobalamin and folate concentrations documented in adults. Whether this metabolic profile in infants is explained by impaired cobalamin status, which in turn may have long-term effects on psychomotor development, remains to be addressed in intervention studies.     

Post-traumatic stress reactions among individuals with visual impairments: a systematic review

Purpose: To conduct a systematic review of post-traumatic stress reactions among individuals with visual impairment (VI).

Materials and methods: Qualitative and quantitative studies were identified through searches in MEDLINE, EMBASE, PsycINFO, CINAHL, Web of Science, and Cochrane Libraries. The literature search was limited to humans, of English and Scandinavian languages and publication year between 1980 and 2017. Study quality was assessed for all the included studies and extracted data were synthesized using narrative analysis.

Results: Of 4235 records identified through literature search, eleven were included in the analyses. Results from the qualitative studies illustrated multiple physical, behavioral, emotional, and cognitive manifestations of trauma. Four out of five quantitative studies showed that various types of potentially traumatic events were significantly associated with mental health adversities (p?<?0.05). The prevalence of post-traumatic mental disorders was 4–21.2% for depression, 0.9% for dysthymia, and 32% for substance misuse. The quality of the reviewed studies was considered low to moderate.

Conclusion: Traumatic experiences appear to have a great impact on the mental health in people with visual impairment (VI) and these results highlight their need for mental health care. Future studies with higher methodological rigor are recommended.

• Implications for rehabilitation

• Visual impairment entails a greater susceptibility to some types of potentially traumatic events, especially threats in everyday life. This calls for a greater emphasis on safe community environments and universal design in public spaces.

• In rehabilitation after serious accidents or potentially traumatic events, professionals working with people with vision impairment should be aware of the different manifestations of post-traumatic stress responses and that some stress responses may cause additional disability.

• The high prevalence of traumatic events and their impact on mental health in individuals with visual impairments highlights a need of mental health care.

     

Appearance of a ventricular 5-HT4 receptor-mediated inotropic response to serotonin in heart failure

BACKGROUND: Current pharmacological treatment of congestive heart failure (CHF) addresses changes in neurohumoral stimulation or cardiac responsiveness to such stimulation. Yet, undiscovered neurohumoral changes, adaptive or maladaptive, may occur in CHF and suggest novel pharmacological treatment. Serotonin [5-hydroxytryptamine (5-HT)] enhances contractility and causes arrhythmias through 5-HT(4) receptors in human atrium and ventricle but not through rat ventricular 5-HT(4) receptors. OBJECTIVE: We investigated whether CHF could induce ventricular responsiveness to serotonin. METHODS: Postinfarction CHF was induced in male Wistar rats by coronary artery ligation. Contractility was measured in left ventricular papillary muscles 6 weeks after infarction. Messenger RNA was quantified by RT-PCR and cAMP by RIA. RESULTS: Serotonin caused positive inotropic (-logEC(50)=7.5) and lusitropic effects in CHF but not Sham papillary muscles. The inotropic effect of 10 muM serotonin in CHF (31.3+/-2.2%) was of similar size as the effect of 10 muM isoproterenol (34.0+/-1.7%). The effects of serotonin were antagonised by GR113808 (0.5-5 nM), consistent with mediation through 5-HT(4) receptors. This was further supported by positive inotropic effects of the 5-HT(4)-selective partial agonist RS67506. Carbachol blunted the serotonin responses and serotonin increased ventricular and cardiomyocyte cAMP, consistent with coupling to G(s) and adenylyl cyclase. Quantitative RT-PCR revealed fourfold increased 5-HT(4(b)) mRNA expression in CHF vs. Sham ventricles. CONCLUSION: Functional ventricular 5-HT(4) receptors are induced by myocardial infarction and CHF of the rat heart. We propose that they are a model for ventricular 5-HT(4) receptors of human failing heart and may play a pathophysiological role in heart failure.     

Allele-specific gene expression patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation

To identify genes that are regulated by cis-acting functional elements in acute lymphoblastic leukemia (ALL) we determined the allele-specific expression (ASE) levels of 2, 529 genes by genotyping a genome-wide panel of single nucleotide polymorphisms in RNA and DNA from bone marrow and blood samples of 197 children with ALL. Using a reproducible, quantitative genotyping method and stringent criteria for scoring ASE, we found that 16% of the analyzed genes display ASE in multiple ALL cell samples. For most of the genes, the level of ASE varied largely between the samples, from 1.4-fold overexpression of one allele to apparent monoallelic expression. For genes exhibiting ASE, 55% displayed bidirectional ASE in which overexpression of either of the two SNP alleles occurred. For bidirectional ASE we also observed overall higher levels of ASE and correlation with the methylation level of these sites. Our results demonstrate that CpG site methylation is one of the factors that regulates gene expression in ALL cells.     

Hereditary iron and copper deposition: diagnostics, pathogenesis and therapeutics

Hereditary deposition of iron (primary haemochromatosis) or copper (Wilson's disease) are autosomal recessive metabolic disease characterized by progressive liver pathology and subsequent involvement of various other organs. The prevalence of primary haemochromatosis is approximately 0.5%, about 200 times higher than the prevalence of Wilson's disease. The two diseases are characterized by homozygous occurrences of mutations in the HFE gene on chromosome 6 (primary haemochromatosis) and the ATP7B gene on chromosome 13 (Wilson's disease). Unlike most other inherited conditions, these diseases can be successfully treated, emphasizing the importance of early diagnosis. Serum ferritin values, transferrin saturation and genetic analysis are used when diagnosing haemochromatosis. The diagnostics of Wilson's disease depends on the use of urinary copper values, serum ceruloplasmin and liver biopsy. If untreated, both of these genetic diseases result in rapidly progressing multiorgan damage and early death. The key treatment for haemochromatosis is phlebotomy, for Wilson's disease chelation or Zn treatment. Although the present treatments considerably improve the prognosis of patients, they may be inadequate in patients diagnosed so late that extensive body deposits of metal have been developed. The main research needs in this field are to further clarify molecular mechanisms of disease progression and to develop new chelators that are more effective and less toxic than those presently available.     

The xenoestrogen, 4-nonylphenol, impaired steroidogenesis in previtellogenic oocyte culture of Atlantic cod (Gadus morhua) by targeting the StAR protein and P450scc expressions

The steroidogenic acute regulatory (StAR) protein and cytochrome P450-mediated cholesterol side-chain cleavage (P450scc) have been localized in most steroidogenic organs and are rapidly synthesized in response to acute tropic hormone stimulation. In this study, we present the development of cod previtellogenic oocyte in vitro culture system, histological and molecular methods for evaluating the effects of endocrine disruptors such as nonylphenol (NP) on steroid hormone levels, the StAR protein and P450scc. In addition, expression pattern of cyclin-B was studied, because of cyclin B's role as an indicator of oocyte growth in fish. The in vitro previtellogenic oocyte culture technique was based on an agarose floating method. Tissue was cultured in a humidified incubator at 10 degrees C for 4, 7, 14 and 21 d with different concentrations of nonylphenol (0 (control), 1, 10, 50 and 100 microM) dissolved in ethanol (0.3%). Gene expressions were detected using validated real-time polymerase chain reaction (PCR) with specific primers. Immunohistochemistry of the StAR protein and P450scc were performed using antisera prepared against synthetic peptide for both proteins. Estradiol-17beta (E2) and 11-ketotestosterone (11-KT) tissue levels were estimated using enzyme immunoassay. Our data show that nonylphenol produced a unique and consistent concentration-specific pattern of modulation for the StAR protein, P450scc and cyclin-B gene expression at day 14 after exposure. This pattern is generally described as increasing from 0 (control) to 1 and 10 microM, and decreased at 50 and 100 microM. The observed changes in the StAR protein, P450scc and cyclin-B levels showed a direct relationship with changes in 11-KT levels at day 14 after exposure. Cellular localization of StAR and P450scc were specific to the follicular cells of previtellogenic oocytes, but with no differences in staining intensities. No significant change in oocyte diameter was observed between the exposure groups. Our data reveal some novel aspects of nonylphenol effects on maturation and oocyte growth in teleosts, suggesting impaired steroidogenesis and hormonal imbalance with potential consequences for the vitellogenic process and overt fecundity.     

High-risk hypertrophic cardiomyopathy associated with a novel mutation in cardiac Myosin-binding protein C

Hypertrophic cardiomyopathy is an autosomal dominant inherited disease characterized by ventricular hypertrophy and myofibril disarray. Mutations responsible for hypertrophic cardiomyopathy have been identified in 11 genes that encode for cardiac sarcomere proteins. Traditionally, hypertrophic cardiomyopathy due to mutation of the myosin-binding protein C gene (MYBPC3) has been thought to follow a benign course. We report a family with several members affected by hypertrophic cardiomyopathy in which there was a high incidence of sudden death. Disease was presumably caused by the substitution of cytosine by guanine at nucleotide 269 of MYBPC3 mRNA. This mutation, which has not previously been described, modifies codon 79, which encodes for the incorporation of a tyrosine, and gives rise to a stop codon. The mutation described here appears to confer a higher risk than that previously associated with hypertrophic cardiomyopathy due to MYBPC3 gene mutation.     

Patients' experiences and clinicians' ratings of the quality of outpatient teams in psychiatric care units in Norway

OBJECTIVE: Patients' experiences and satisfaction ratings are increasingly used to evaluate quality of care. This study assessed the extent to which outpatient teams, clinics, and health trusts contributed to patients' experiences and to what extent clinicians' evaluations of quality were related to patients' experiences. METHODS: A questionnaire was mailed to 15,422 outpatients who attended Norwegian clinics in September 2004; 43% responded. Patients' experiences were measured on an 11-item index and three subscales: outcomes, interaction with clinicians, and information. Aggregated responses from clinicians were linked to the data on patients' experiences. Multilevel analyses were used to divide the variance between the different organizational levels and to assess the relationship with clinicians' opinions and individual-level factors. RESULTS: Data were analyzed for 6,570 outpatients within 222 teams derived from 89 outpatient clinics within 33 health trusts. Differences in patients' scores were determined largely at the patient level, with teams accounting for 2% of the total variance and organizational levels of clinics and health trusts not contributing to patients' experiences. Team-level clinician quality scores were not significantly associated with patients' experiences. Better experiences were significantly associated with patients' female gender, older age, better self-perceived health, absence of an inpatient history, longer treatment episodes, frequent consultations, and waiting times perceived as acceptable. CONCLUSIONS: The organizational contributions to patients' experience scores were minimal. Although clinicians' ratings of quality are not a substitute for patients' perceptions of quality, surveys of outpatients' experiences and satisfaction may not be appropriate for cross-sectional comparisons of health care providers.     

Risk factors for mortality in diabetic nephropathy patients accepted for transplantation

BACKGROUND: There is a high incidence of silent coronary artery disease (CAD) in patients with diabetes. We wanted to investigate risk factors for mortality, and especially CAD, in a well-defined cohort of diabetic nephropathy transplant candidates accepted for transplantation. METHODS: From 1999 through 2004, 155 patients underwent work up for living or deceased kidney (KA) or simultaneous pancreas-kidney (SPK) transplantation. The work up included coronary angiography for all patients and 136 were accepted. Mean (SD) age was 50 (12) years, 62% had type 1 diabetes, 73% were males, and 34% were on dialysis. Mean follow-up from time of acceptance for transplantation was 3.6 (1.9) years. RESULTS: Survival of KA transplanted patients was 97% at 1 year, 89% at 3 years, and 76% at 5 years, whereas in SPK patients 100%, 94%, and 90%, respectively (P=0.065). One- and 3- year survival was only 57% and 20% in those remaining wait-listed (P<0.001). In univariate analysis mortality was associated with KA transplantation (hazard ratio [HR]=0.30, P=0.011) and SPK transplantation (HR=0.10, P=0.001), and age (HR=1.04, P=0.014). In multivariable analysis, KA transplantation (HR=0.28, P=0.006), SPK transplantation (HR=0.09, P=0.001), age (HR=1.06, P=0.002), type 2 diabetes (HR=0.14, P=0.003), and duration of diabetes (HR=0.94, P=0.019) were parameters associated with mortality. CONCLUSIONS: The only modifiable risk factor was transplantation with risk reduction up to 90%. CAD was not a risk factor for mortality when medically treated and revascularized according to standard guidelines.     

Similarities in stress physiology among patients with chronic pain and headache disorders: evidence for a common pathophysiological mechanism?

One common feature of chronic musculoskeletal pain and headaches are that they are both influenced by stress. Among these, tension-type headache (TTH), fibromyalgia (FMS) and chronic shoulder/neck pain (SNP) appear to have several similarities, both with regard to pathophysiology, clinical features and demographics. The main hypothesis of the present study was that patients with chronic pain (TTH, FMS and SNP) had stress-induced features distinguishing them from migraine patients and healthy controls. We measured pain, blood pressure, heart rate (HR) and skin blood flow (BF) during (1 h) and after (30 min) controlled low-grade cognitive stressor in 22 migraine patients, 18 TTH patients, 23 FMS patients, 29 SNP patients and 44 healthy controls. FMS patients had a lower early HR response to stress than migraine patients, but no differences were found among FMS, TTH and SNP patients. Finger skin BF decreased more in FMS patients compared to migraine patients, both during and after the test. When comparing chronic pain patients (chronic TTH, FMS and SNP) with those with episodic pain (episodic TTH and migraine patients) or little or no pain (healthy controls), different adaptation profiles were found during the test for systolic and diastolic blood pressure, HR and skin BF in the chronic group. In conclusion, these results suggest that TTH, FMS and SNP patients may share common pathophysiological mechanisms regarding the physiological responses to and recovery from low-grade cognitive stress, differentiating them from episodic pain conditions such as migraine.