A compact x-ray diffraction system for dynamic compression experiments on pulsed-power generators.

Pulsed-power generators can produce well-controlled continuous ramp compression of condensed matter for high-pressure equation-of-state studies using the magnetic loading technique. X-ray diffraction (XRD) data from dynamically compressed samples provide direct measurements of the elastic compression of the crystal lattice, onset of plastic flow, strength-strain rate dependence, structural phase transitions, and density of crystal defects, such as dislocations. Here, we present a cost-effective, compact, pulsed x-ray source for XRD measurements on pulsed-power-driven ramp-loaded samples. This combination of magnetically driven ramp compression of materials with a single, short-pulse XRD diagnostic will be a powerful capability for the dynamic materials' community to investigate in situ dynamic phase transitions critical to equation of states. We present results using this new diagnostic to evaluate lattice compression in Zr and Al and to capture signatures of phase transitions in CdS.

Dynamic changes in RAS gene status in circulating tumour DNA: a phase II trial of first-line FOLFOXIRI plus bevacizumab for RAS-mutant metastatic colorectal cancer (JACCRO CC-11).

BACKGROUND: Few prospective studies have used liquid biopsy testing in RAS-mutant metastatic colorectal cancer (mCRC), and its clinical significance remains unknown. Therefore, this study aimed to carry out a biomarker analysis by liquid biopsy using updated data of the phase II trial of FOLFOXIRI plus bevacizumab as first-line chemotherapy for RAS-mutant mCRC. MATERIALS AND METHODS: A total of 64 patients who received modified FOLFOXIRI regimen (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, and fluorouracil 2400 mg/m2) plus bevacizumab biweekly were enrolled. The primary endpoint was the objective response rate (ORR). Plasma samples were collected at pre-treatment, 8 weeks after treatment, and progression in participants included in the biomarker study. The levels of circulating tumour DNA (ctDNA) and specific KRAS and NRAS variants were evaluated using real-time PCR assays. RESULTS: There were 62 patients (median age: 62.5 years, 92% performance status 0, 27% right side) who were assessable for efficacy and 51 for biomarker analysis. ORR was 75.8% (95% confidence interval 65.1% to 86.5%). The median progression-free survival was 12.1 months, and the median overall survival (OS) was 30.2 months. In 78% of patients, RAS mutations disappeared in the ctDNA at 8 weeks after treatment; these patients tended to have better outcomes than those with RAS mutations. Interestingly, RAS mutations remained undetectable during progression in 62% of patients. Survival analysis indicated that the median OS from progression was significantly longer in patients with RAS mutation clearance than in those with RAS mutation in the ctDNA at disease progression (15.1 versus 7.3 months, hazard ratio: 0.21, P = 0.0046). CONCLUSIONS: Our biomarker study demonstrated no RAS mutations in ctDNA at disease progression in 62% of patients with RAS-mutant mCRC. Both OS and post-progression survival were better in patients with clearance of RAS mutations in ctDNA after triplet-based chemotherapy.

Suicide Ideation and Depression Quality of Life Ratings in a Reservation-Based Community of Native American Youths and Young Adults.

Suicide among adolescents is a significant public health concern in the U.S., especially within American Indian and Alaska Native (AIAN) communities. Lack of quality of life (QoL) estimates for both suicide ideation and depression specific to the AIAN population hinders the ability to compare interventions in cost-effectiveness analysis. We surveyed 200 AI youth and young adults from the Fort Apache Indian Reservation to estimate utility weights for experiencing suicide ideation and depression. Our results indicate that, on a scale of 0-100, with higher scores indicating better health, the general community rates both suicide ideation and depression at 15.8 and 25.1, respectively. These weights are statistically significantly different and lower than for other cultures. Culturally specific QoL values will allow the comparison and identification of the most effective and feasible interventions to reduce the suicide burden among tribal communities.

Data on items of AKUSSI in Alkaptonuria collected over three years from the United Kingdom National Alkaptonuria Centre and the impact of nitisinone.

Alkaptonuria is a rare genetic disorder characterized by a high level of circulating (and urine) homogentisic acid (HGA), which contributes to ochronosis when it is deposited in connective tissue as a pigmented polymer. In an observational study carried out by National AKU Centre (NAC) in Liverpool, a total of thirty-nine AKU patients attended yearly visits in varying numbers. At each visit a mixture of clinical, joint and spinal assessments were carried out and the results calculated to yield an AKUSSI (Alkaptonuria Severity Score Index), see "Nitisinone arrests ochronosis and decreases rate of progression of Alkaptonuria: evaluation of the effect of nitisinone in the United Kingdom National Alkaptonuria Centre" (Ranganath at el., 2018). The aim of this data article is to produce visual representation of the change in the components of AKUSSI over 3 years, through radar charts. The metabolic effect of nitisinone is shown through box plots.

Nitisinone arrests ochronosis and decreases rate of progression of Alkaptonuria: Evaluation of the effect of nitisinone in the United Kingdom National Alkaptonuria Centre.

QUESTION: Does Nitisinone prevent the clinical progression of the Alkaptonuria? FINDINGS: In this observational study on 39 patients, 2 mg of daily nitisinone inhibited ochronosis and significantly slowed the progression of AKU over a three-year period. MEANING: Nitisinone is a beneficial therapy in Alkaptonuria. BACKGROUND: Nitisinone decreases homogentisic acid (HGA), but has not been shown to modify progression of Alkaptonuria (AKU). METHODS: Thirty-nine AKU patients attended the National AKU Centre (NAC) in Liverpool for assessments and treatment. Nitisinone was commenced at V1 or baseline. Thirty nine, 34 and 22 AKU patients completed 1, 2 and 3 years of monitoring respectively (V2, V3 and V4) in the VAR group. Seventeen patients also attended a pre-baseline visit (V0) in the VAR group. Within the 39 patients, a subgroup of the same ten patients attended V0, V1, V2, V3 and V4 visits constituting the SAME Group. Severity of AKU was assessed by calculation of the AKU Severity Score Index (AKUSSI) allowing comparison between the pre-nitisinone and the nitisinone treatment phases. RESULTS: The ALL (sum of clinical, joint and spine AKUSSI features) AKUSSI rate of change of scores/patient/month, in the SAME group, was significantly lower at two (0.32 ±â€¯0.19) and three (0.15 ±â€¯0.13) years post-nitisinone when compared to pre-nitisinone (0.65 ±â€¯0.15) (p < .01 for both comparisons). Similarly, the ALL AKUSSI rate of change of scores/patient/month, in the VAR group, was significantly lower at one (0.16 ±â€¯0.08) and three (0.19 ±â€¯0.06) years post-nitisinone when compared to pre-nitisinone (0.59 ±â€¯0.13) (p < .01 for both comparisons). Combined ear and ocular ochronosis rate of change of scores/patient/month was significantly lower at one, two and three year's post-nitisinone in both VAR and SAME groups compared with pre-nitisinone (p < .05). CONCLUSION: This is the first indication that a 2 mg dose of nitisinone slows down the clinical progression of AKU. Combined ocular and ear ochronosis progression was arrested by nitisinone.

Clinical and biochemical assessment of depressive symptoms in patients with Alkaptonuria before and after two years of treatment with nitisinone.

OBJECTIVE: Concerns exist over hypertyrosinaemia that is observed following treatment with nitisinone. It has been suggested that tyrosine may compete with tryptophan for uptake into the central nervous system, and or inhibit tryptophan hydroxylase activity reducing serotonin production. At the National Alkaptonuria (AKU) Centre nitisinone is being used off-licence to treat AKU, and there is uncertainty over whether hypertyrosinaemia may alter mood. Herein results from clinical and biochemical assessments of depression in patients with AKU before and after treatment with nitisinone are presented. PATIENTS AND METHODS: 63 patients were included pre-nitisinone treatment, of these 39 and 32 patients were followed up 12 and 24 months after treatment. All patients had Becks Depression Inventory-II (BDI-II) assessments (scores can range from 0 to 63, the higher the score the more severe the category of depression), and where possible urinary monoamine neurotransmitter metabolites and serum aromatic amino acids were measured as biochemical markers of depression. RESULTS: Mean (±standard deviation) BDI-II scores pre-nitisinone, and after 12 and 24 months were 10.1(9.6); 9.8(10.0) and 10.5(9.9) (p ≥ 0.05, all visits). Paired scores (n = 32), showed a significant increase at 24 months compared to baseline 10.5(9.9) vs. 8.6 (7.8) (p = 0.03). Serum tyrosine increased at least 6-fold following nitisinone (p ≤ 0.0001, all visits), and urinary 3-methoxytyramine (3-MT) increased at 12 and 24 months (p ≤ 0.0001), and 5-hydroxyindole acetic acid (5-HIAA) decreased at 12 months (p = 0.03). CONCLUSIONS: BDI-II scores were significantly higher following 24 months of nitisinone therapy in patients that were followed up, however the majority of these patients remained in the minimal category of depression. Serum tyrosine and urinary 3-MT increased significantly following treatment with nitisinone. In contrast urinary 5-HIAA did not decrease consistently over the same period studied. Together these findings suggest nitisinone does not cause depression despite some observed effects on monoamine neurotransmitter metabolism.

Serum Amino Acid Profiling in Patients with Alkaptonuria Before and After Treatment with Nitisinone.

BACKGROUND: Alkaptonuria (AKU) is a rare inherited disorder of the tyrosine metabolic pathway. Our group is evaluating the use of the homogentisic acid-lowering agent nitisinone in patients with AKU. A major biochemical consequence of this treatment is hypertyrosinaemia. Herein we report the concentration of 20 serum amino acids over a 36-month period pre- and post-treatment with nitisinone. METHODS: Fasting serum samples were collected at baseline (pre-nitisinone), 3 (2 mg nitisinone every other day), 6, 12, 24 and 36 (2 mg nitisinone daily) months. Amino acids were measured using the Biochrom 30 high-performance liquid chromatography cation exchange system with ninhydrin detection. RESULTS: Fifty patients [21 female, mean age (±standard deviation) 54.1 (15.6) years (range 25-75); 29 male, mean age 49.3 (11.6) years (range 22-70 years)] were included. Following treatment mean tyrosine concentrations increased seven- to eight-fold (baseline, 69.8 µmol/L; 3 months, 670.7 µmol/L; 6 months, 666.4 µmol/L; 12 months, 692.9 µmol/L; 24 months, 649.4 µmol/L; 36 months, 724.8 µmol/L, p = <0.001 for all visits compared to baseline).At baseline mean phenylalanine, aspartic acid and arginine were outside the normal reference range. Following treatment the ratios of phenylalanine/tyrosine, phenylalanine/large neutral amino acids, arginine/branched chain amino acids and branched chain/aromatic amino acids decreased (p = <0.05), and the tyrosine/large neutral amino acid ratio increased (p = <0.0001). CONCLUSIONS: Marked hypertyrosinaemia was observed following treatment with nitisinone. Noteworthy changes were also observed in the ratio of several amino acids following treatment with nitisinone suggesting that the availability of amino acids for neurotransmitter biosynthesis and liver function may be altered following treatment with nitisinone.

Exploitation of sulfonylurea resistance marker and non-homologous end joining mutants for functional analysis in Zymoseptoria tritici.

The lack of techniques for rapid assembly of gene deletion vectors, paucity of selectable marker genes available for genetic manipulation and low frequency of homologous recombination are major constraints in construction of gene deletion mutants in Zymoseptoria tritici. To address these issues, we have constructed ternary vectors for Agrobacterium tumefaciens mediated transformation of Z. tritici, which enable the single step assembly of multiple fragments via yeast recombinational cloning. The sulfonylurea resistance gene, which is a mutated allele of the Magnaporthe oryzae ILV2 gene, was established as a new dominant selectable marker for Z. tritici. To increase the frequency of homologous recombination, we have constructed Z. tritici strains deficient in the non-homologous end joining pathway of DNA double stranded break repair by inactivating the KU70 and KU80 genes. Targeted gene deletion frequency increased to more than 85% in both Z. tritici ku70 and ku80 null strains, compared to ⩽10% seen in the wild type parental strain IPO323. The in vitro growth and in planta pathogenicity of the Z. tritici ku70 and ku80 null strains were comparable to strain IPO323. Together these molecular tools add significantly to the platform available for genomic analysis through targeted gene deletion or promoter replacements and will facilitate large-scale functional characterization projects in Z. tritici.

A suite of Gateway® compatible ternary expression vectors for functional analysis in Zymoseptoria tritici.

Gene overexpression is a widely used functional genomics approach in fungal biology. However, to date it has not been established in Zymoseptoria tritici which is an important pathogen of wheat (Triticum species). Here we report a suite of Gateway® recombination compatible ternary expression vectors for Agrobacterium tumefaciens mediated transformation of Z. tritici. The suite of 32 vectors is based on a combination of four resistance markers for positive selection against glufosinate ammonium, geneticin, hygromycin and sulfonylurea; three constitutive Z. tritici promoters (pZtATUB, pZtGAPDH and pZtTEF) and a nitrogen responsive promoter (pZtNIA1) for controlled expression of the open reading frames. Half of the vectors facilitate expression of proteins tagged with C-terminal EGFP. All 32 vectors allow high frequency targeting of the overexpression cassette into the Ku70 locus and complement the Ku70 gene when transformed into a Z. tritici ku70 null strain, thus circumventing additional phenotypes that can arise from random integration. This suite of ternary expression vectors will be a useful tool for functional analysis through gene overexpression in Z. tritici.

Male hypogonadism: an extended classification based on a developmental, endocrine physiology-based approach.

Normal testicular physiology results from the integrated function of the tubular and interstitial compartments. Serum markers of interstitial tissue function are testosterone and insulin-like factor 3 (INSL3), whereas tubular function can be assessed by sperm count, morphology and motility, and serum anti-Müllerian hormone (AMH) and inhibin B. The classical definition of male hypogonadism refers to testicular failure associated with androgen deficiency, without considering potential deficiencies in germ and Sertoli cells. Furthermore, the classical definition does not consider the fact that low basal serum testosterone cannot be equated to hypogonadism in childhood, because Leydig cells are normally quiescent. A broader clinical definition of hypogonadism that could be applied to male patients in different periods of life requires a comprehensive consideration of the physiology of the hypothalamic-pituitary-testicular axis and its disturbances along development. Here we propose an extended classification of male hypogonadism based on the pathophysiology of the hypothalamic-pituitary-testicular axis in different periods of life. The clinical and biochemical features of male hypogonadism vary according to the following: (i) the level of the hypothalamic-pituitary-testicular axis primarily affected: central, primary or combined; (ii) the testicular cell population initially impaired: whole testis dysfunction or dissociated testicular dysfunction, and: (iii) the period of life when the gonadal function begins to fail: foetal-onset or postnatal-onset. The evaluation of basal testicular function in infancy and childhood relies mainly on the assessment of Sertoli cell markers (AMH and inhibin B). Hypergonadotropism should not be considered a sine qua non condition for the diagnosis of primary hypogonadism in childhood. Finally, the lack of elevation of gonadotropins in adolescents or adults with primary gonadal failure is indicative of a combined hypogonadism involving the gonads and the hypothalamic-pituitary axis.

The DTNBP1 (dysbindin-1) gene variant rs2619522 is associated with variation of hippocampal and prefrontal grey matter volumes in humans.

DTNBP1 is one of the most established susceptibility genes for schizophrenia, and hippocampal volume reduction is one of the major neuropathological findings in this severe disorder. Consistent with these findings, the encoded protein dysbindin-1 has been shown to be diminished in glutamatergic hippocampal neurons in schizophrenic patients. The aim of this study was to investigate the effects of two single nucleotide polymorphisms of DTNBP1 on grey matter volumes in human subjects using voxel-based morphometry. Seventy-two subjects were included and genotyped with respect to two single nucleotide polymorphisms of DTNBP1 (rs2619522 and rs1018381). All participants underwent structural magnetic resonance imaging (MRI). MRI data were preprocessed and statistically analysed using standard procedures as implemented in SPM5 (Statistical Parametric Mapping), in particular the voxel-based morphometry (VBM) toolbox. We found significant effects of the DTNBP1 SNP rs2619522 bilaterally in the hippocampus as well as in the anterior middle frontal gyrus and the intraparietal cortex. Carriers of the G allele showed significantly higher grey matter volumes in these brain regions than T/T homozygotes. Compatible with previous findings on a role of dysbindin in hippocampal functions as well as in major psychoses, the present study provides first direct in vivo evidence that the DTNBP1 SNP rs2619522 is associated with variation of grey matter volumes bilaterally in the hippocampus.

DISC1 (disrupted-in-schizophrenia 1) is associated with cortical grey matter volumes in the human brain: a voxel-based morphometry (VBM) study.

DISC1 (Disrupted-In-Schizophrenia 1), one of the top candidate genes for schizophrenia, has been associated with a range of major mental illnesses over the last two decades. DISC1 is crucially involved in neurodevelopmental processes of the human brain. Several haplotypes and single nucleotide polymorphisms of DISC1 have been associated with changes of grey matter volumes in brain regions known to be altered in schizophrenia and other psychiatric disorders. The aim of the present study was to investigate the effects of two single nucleotide polymorphisms (SNPs) of DISC1 on grey matter volumes in human subjects using voxel-based morphometry (VBM). 114/113 participating subjects (psychiatric patients and healthy controls) were genotyped with respect to two at-risk SNPs of DISC1, rs6675281 and rs821616. All participants underwent structural magnetic resonance imaging (MRI). MRI data was statistically analyzed using voxel-based morphometry. We found significant alterations of grey matter volumes in prefrontal and temporal brain regions in association with rs6675281 and rs821616. These effects of DISC1 polymorphisms on brain morphology provide further support for an involvement of DISC1 in the neurobiology of major psychiatric disorders such as schizophrenia.

Síndrome de Klinefelter en las distintas edades: experiencia multicéntrica / Klinefelter Syndrome at differents ages: multicentric experience

El Síndrome de Klinefelter (SK) es la anormalidad cromosómica más frecuente en los varones, con una prevalencia estimada de 1:600 recién nacidos. El objetivo de este trabajo fue establecer las distintas características de presentación del SK a distintas edades, incluyendo signos y síntomas clínicos, parámetros de laboratorio y otros exámenes complementarios. La franja etaria más frecuente de diagnóstico de SK fue entre los 11 y 20 años (46,8%). En 4 casos el diagnóstico fue prenatal. Los motivos de consulta más frecuentes en forma global fueron la presencia de testículos pequeños, infertilidad y criptorquidia. El cariotipo más prevalente fue el clásico 47,XXY (83,7%), seguido del mosaico 47,XXY/46,XY (7,1%). El promedio de talla de nuestros pacientes prepuberales no mostró diferencia con la población general. Por otro lado, los pacientes puberales presentaron un promedio de talla significativamente más alto, hallándose alrededor de 1 SDS. Hubo correlación entre la edad y el SDS de talla. La media de talla de los adultos fue 178,8 ± 9,0 cm; se observó un 62,5% de sobrepeso/obesidad (IMC ≥ 25,0 kg/m²). El 50% de nuestros pacientes con SK menores de 18 años presentaron trastornos neurocognitivos. El hallazgo clínico más frecuente entre los pacientes prepuberales fue la criptorquidia. En los puberales las consultas y hallazgos clínicos más frecuentes fueron: testículos pequeños, criptorquidia y ginecomastia. Todos nuestros pacientes en estadio de Tanner igual o mayor de III presentaron testículos más pequeños para su grado de desarrollo. Los valores de FSH y LH fueron normales en los pacientes prepuberales y comenzaron a aumentar en la pubertad. Los adultos consultaron más frecuentemente por hipotrofia testicular, infertilidad y en menor grado ginecomastia. Todos los pacientes presentaron testículos hipotróficos, con una mediana de volumen testicular de 3,5 (1-8) ml. El 56,4% presentaron función sexual normal; el resto tuvo algún tipo de disfunción sexual. La testosterona total (TT) fue normal en 45% de los pacientes, con descenso consistente con la edad, donde todos los pacientes mayores de 40 años presentaron TT subnormal. El 10,7% de los pacientes que efectuaron espermograma tuvo oligospermia severa, el resto presentó azoospermia. La densitometría ósea fue anormal en el 46,4% de los adultos estudiados. Sin embargo, no hubo diferencias significativas en la prevalencia de osteopenia y osteoporosis entre los pacientes con TT normal o subnormal.

Klinefelter syndrome (KS) is the most common chromosomal aberration among men, with an estimated prevalence of 1:600 newborns. It is an X chromosome polysomy, with X disomy being the most common variant (47,XXY). The aim of this study was to establish the characteristics of KS presentation at different ages, including signs and symptoms, laboratory parameters and other diagnostic tests. The diagnosis of KS was more frequent in the age group between 11 and 20 years (46.8%). Most of the patients (83.7%) showed the classic 47,XXY karyotype and 7.1% showed a 47,XXY/46,XY mosaicism. While mean prepubertal height was not different from the control population, it was significantly higher at puberty. Patients consulted most frequently for small testes, infertility and cryptorchidism. In four cases the diagnosis was prenatal. 50% of our patients younger than 18 years presented neurocognitive disorders. The more frequent clinical findings were cryptorchidism in prepubertal patients; small testes, cryptorchidism and gynecomastia in pubertal patients. All our patients in Tanner stage III or more presented small testes. FSH and LH levels were normal in prepubertal patients and increased abnormally at puberty. On the other hand, most adults consulted for small testes, infertility and gynecomastia. 43.6% of patients had decreased libido, sexual and/or ejaculatory dysfunction. In adults average height (178.8 ± 9.0 cm) and weight (83.6 ± 21.0 kg), were higher than in the normal population, however 8 patients (19%) had a height less tan 170 cm. There was 62.5% of overweight / obesity (BMI ≥ 25.0 kg/m²) in the whole group of adult patients. 35.2% had eunuchoid proportions. All patients had testicular hypotrophc, with a median testicular volume of 3.5 ml (range 1-8 ml). Total testosterone (TT) levels were normal in 45% of adult patients, showing significant correlation with age. All patients aged 40 or more years had subnormal TT levels. In patients who underwent semen analysis, severe oligospermia and azoospermia were found in 10.7% and 89.3% respectively. Bone mineral densitometry showed low bone mass in 46.4% of cases. No significant differences in the prevalence of osteopenia and osteoporosis were observed among patients with normal or subnormal TT.

Thalamic volumes in patients with bipolar disorder.

There are several hypotheses on functional neuronal networks that modulate mood states and which might form the neuroanatomical basis of bipolar disorder. The thalamus has been reported to be a key structure within the circuits that modulate mood states and might thus play an important role within the aetiology of the bipolar affective disorder. Nevertheless, structural brain imaging studies on the thalamus volume of bipolar patients have shown heterogeneous results. Using structural MRI scanning, we compared the thalamus volume of 41 euthymic bipolar patients to the thalamus volume of 41 well-matched healthy controls. Taking the concomitant medication as a co-variable within the patient group, the analysis of variance revealed a significantly smaller relative volume of the right thalamus in patients not treated with lithium when compared with healthy controls. In contrast, there are no significant differences concerning the thalamus volume between all euthymic bipolar patients and healthy controls. The study only shows findings of a transverse section. No longitudinal analysis was performed. More detailed information on patients' pharmacological histories could not be obtained. In conclusion, this result may be interpreted as an indication of the impact of the thalamus in the pathogenesis of the bipolar I disorder and emphasises the need for further longitudinal studies in bipolar patients with special attention paid to the concomitant medication, in particular to the role of lithium.

Increased right amygdala volume in lithium-treated patients with bipolar I disorder.

OBJECTIVE: The amygdala plays a major role in processing emotional stimuli. Fourteen studies using structural magnetic resonance imaging (MRI) have examined the amygdala volume in paediatric and adult patients with bipolar disorder (BD) compared with healthy controls (HC) and reported inconsistent findings. Lithium has been found to increase grey matter volume, and first evidence points towards an effect on regional brain volume such as the amygdala. METHOD: We examined the amygdala volume of euthymic patients with BD treated with lithium (n = 15), without lithium (n = 24) and HC (n = 41) using structural MRI. RESULTS: Patients treated with lithium exhibited in comparison to HC a larger right absolute (+17.9%, P = 0.015) and relative (+18%, P = 0.017) amygdala volume. There was no significant difference in amygdala volume between patients without lithium treatment and HC. CONCLUSION: Lithium appears to have a sustained effect on a central core region of emotional processing and should therefore be considered in studies examining BD.

Neurochemical pathology in hippocampus in euthymic patients with bipolar I disorder.

OBJECTIVE: Subcortical regions such as hippocampus, thalamus and ventral putamen are assumed to be involved in the pathophysiology of mood regulation. Disturbed hippocampal neuronal function indicated by reduced N-acetyl-aspartate (NAA) levels in bipolar patients was shown by several studies. Results in thalamus and putamen are inconsistent. METHOD: N-acetyl-aspartate, choline (Cho), creatine (Cr) and myo-inositol (Ins) were measured in left hippocampus, left thalamus and left putamen using proton magnetic resonance spectroscopy in 13 euthymic patients with bipolar I disorder and 13 pairwise matched healthy control subjects. Metabolic ratios NAA/Cr, NAA/Cho, Cho/Cr and Ins/Cr were calculated. RESULTS: Patients with bipolar I disorder demonstrated significantly reduced NAA/Cr in the left hippocampus compared with healthy control subjects. No alterations were found in thalamus or putamen. CONCLUSION: We hypothesize that this NAA/Cr reduction might reflect neuronal dysfunction in the left hippocampus in patients with bipolar disorder.

Atypical presentation of a middle age male with severe hypertriglyceridaemia: a case report.

BACKGROUND: Severe hypertriglyceridaemia (HTG) is uncommon but most prevalent in subjects with type 2 diabetes mellitus (T2DM) and excess ethanol intake. CASE PRESENTATION: We describe a case of a middle age male (53 y) presenting to the emergency room with acute atypical central chest pain and severe HTG in the absence of evidence of overt ischaemic heart disease (IHD). Admission ECG and EET (exercise tolerance test) were negative for reversible ischaemic changes. His admission glucose was 12.2 mmol/l, triglycerides (TG) were 103 mmol/l, total cholesterol 37 mmol/l. Cardiac Troponin T could not be measured on three occasions but CK MB mass was normal at 3 mug/l. The patient was started on Bezafibrate 400 mg OD, Simvastatin 20 mg nocte, Omacor (Omega-3 fish oil) 1 gm bd and Metformin 500 mg tds. Four weeks after admission, lipid and liver profiles showed remarkable improvement, TG 2.9 mmol/l, Tchol 6.3 mmol/l and HDLc 1.5 mmol/l, ALAT and GGT were normal. CONCLUSION: A case report of severe hypertriglyceridaemia with atypical presentation demonstrate the role of combined lipid modifying agents in lowering triglycerides and cholesterol as well as improving liver enzymes.

The association of homocysteine and its determinants MTHFR genotype, folate, vitamin B12 and vitamin B6 with bone mineral density in postmenopausal British women.

We studied the association between plasma total homocysteine (tHcy), its determinants folate, vitamin B(12), vitamin B(6) and MTHFR genotype, and bone mineral density (BMD) in 328 postmenopausal British women. When the subjects were assigned to one of 3 groups (control, osteopenic or osteoporotic) according to their BMD at the os calcis, those in the osteoporotic group had, compared with the controls, a significantly lower serum folate concentration, a significantly higher % of current smokers and a significantly higher incidence of recent fracture. In the population as a whole, we found significant associations of BMD with tHcy (r=-0.130, p=0.033, log tHcy) and folate (r=0.132, p=0.025, log folate). The association of folate with BMD was maintained after correction for age, weight and height (r=0.124, p=0.042, log folate), but the association of tHcy with BMD weakened after correction for age, weight, height and creatinine (r=-0.117, p=0.059, log tHcy). Vitamins B(12) and B(6) were not associated with BMD, but were significantly associated with tHcy, vitamin B(12) (r=-0.34, p<0.0001), vitamin B(6) (r=-0.16, p=0.007), as was folate (r=-0.41, p<0.0001). There was an increasing frequency of the MTHFR TT genotype across the 3 BMD groups, but this did not attain significance. Individuals with the TT genotype had significantly higher plasma tHcy but there was no difference between the genotypes (CC, CT, TT) for folate or BMD. Smoking was associated with a highly significant reduction in BMD and lower weight, and a significant reduction in circulating folate and vitamin B(6) concentrations, but no change in tHcy or vitamin B(12) concentrations when compared with non-smokers. We conclude that low serum folate is a significant risk factor for osteoporosis, with plasma tHcy having a lesser effect. Both vitamins B(12) and B(6), by acting through tHcy, may also have an effect on the skeleton, albeit a weaker one than folate. Cigarette smoking is a strong determinant of BMD, and may act through effects on folate and vitamin B(6).

A fuzzy logic-controlled classifier for use in implantable cardioverter defibrillators.

PURPOSE: Implantable cardioverters defibrillators (ICDs) are increasingly used in the management of life-threatening arrhythmias. Correct recognition of a treatable arrhythmia is crucial to this application. However, the computational power of microprocessors currently used in ICDs limits the range of traditional algorithms available for this application. METHODS: Classification based on fuzzy inference systems (FIS) were trained to recognize different cardiac rhythms (AF, VF, SVT, VT) from the Ann Arbor Electrogram Library. The FIS used were designed using adaptive-network-based fuzzy inference methods to optimize the classification procedure. Only computational techniques suitable for ICD design were used. RESULTS: After pretraining with the ANFIS correct rhythm classification was observed for the rhythms studied. CONCLUSION: In this preliminary study, successful rhythm classification was demonstrated using fuzzy logic techniques. In view of the computational efficiency this may have application in ICD design.