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Aims Primary familial brain calcification (PFBC) is a rare disorder characterized by abnormal deposits of calcium in the basal ganglia and cerebellum. PFBC can present with a spectrum of neuropsychiatric symptoms resembling those seen in dementia and schizophrenia. Mutations in a few genes have been identified as causing PFBC: namely, the SLC20A2 gene that codes for the sodium-dependent phosphate transporter and the PDGFRB gene that codes for the platelet-derived growth factor receptor β (PDGF-Rβ). A recent study identified mutations in PDGFB coding for PDGF-B, the main ligand for PDGF-Rβ, in six families with PFBC. Here we report the first Japanese family with PFBC carrying a mutation in PDGFB, which causes the substitution of an arginine with a stop codon at amino acid 149 of the PDGF-B protein (p. Arg149*). Methods Clinical histories and computed tomography scan images were provided. Sanger sequencing was performed for the exome analysis of SLC20A2 and PDGFB genes. Results One family member began to complain of auditory hallucination at 16 years of age and had been treated for schizophrenia. His father suffered from memory and gait disturbances in his late 60s. A computed tomography scan revealed a symmetrical area of calcification over the basal ganglia in both cases. A known mutation in PDGFB (c.445C>T, p.Arg149*) was consistently detected in both PFBC cases by Sanger sequencing. No mutations in SLC20A2 were detected. Conclusions Our findings suggest that this mutation in PDGF-B is responsible for PFBC in this Japanese family and that abnormal PDGF signaling may be involved in the pathophysiology of certain psychiatric disorders.

To date, 3 AIFM1 (apoptosis inducing factor mitochondrial 1, located on Xq26.1) mutations have been reported: 2 missense changes (c.923G>A/p.Gly308Glu; c.1478A>T/p.Glu493Val) and a 3-basepair deletion (c.601delAGA/p.Arg201del). Two mutations have been described in early-onset severe mitochondrial encephalomyopathy related to impaired oxidative phosphorylation.(1,2) A third mutation is associated with Cowchock syndrome, or Charcot-Marie-Tooth X4 (CMTX4), a slowly progressive disorder characterized by axonal neuropathy, hearing loss, and mental retardation.(3,4

Patients with pathogenic truncating mutations in the prion gene (PRNP) usually present with prolonged disease courses with severe neurofibrillary tangle and cerebral amyloidosis pathology, but more atypical phenotypes also occur, including those with dysautonomia and peripheral neuropathy. We describe the neurological, cognitive, neuroimaging, and electrophysiological features of a31-year-old man presenting with an orbitofrontal syndrome, gastrointestinal symptoms, and peripheral neuropathy associated with PRNP Q160X nonsense mutation, with symptom onset at age 27. The mutation was also detected in his asymptomatic father and asymptomatic paternal cousin; several members of prior generations died from early onset dementia. This is the first report of afamily affected with the nonsense PRNP mutation Q160X displaying clear autosomal dominant disease in multiple family members and reduced penetrance. This case strengthens the evidence suggesting an association between PRNP truncating mutations and prion systemic amyloidosis. PRNP gene testing shouldbeconsidered in any patient with atypical dementia, especially with early onset and neuropathy, even in the absence of afamily history.

Predstava Kako sada stvari stoje premijerno je izvedena u Teatru &TD 31. listopada 1994. godine. Režiju potpisuje Ivica Boban, a izvode Ivana Boban, Ivana Buljan (Legati), Saša Buneta, Tarik Filipović, Alen Šalinović i Nina Violić.

Primary familial brain calcification (PFBC) is a neurological disease characterized by calcium phosphate deposits in the basal ganglia and other brain regions and has thus far been associated with SLC20A2, PDGFB or PDGFRB mutations. We identified in multiple families with PFBC mutations in XPR1, a gene encoding a retroviral receptor with phosphate export function. These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC. Lung GO Sequencing Project Lung GO Sequencing Project Women's Health Initiative (WHI) Sequencing Project Broad GO Sequencing Project Seattle GO Sequencing Project Heart GO Sequencing Project United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Neurological Disorders & Stroke (NINDS) Association Francaise contre les Myopathies Ligue Nationale contre le Cancer (Comite de l'Herault) Fondation pour la Recherche Medicale FEDER European Union Languedoc-Roussillon grant National Institute of Neurological Disorders and Stroke Informatics Center for Neurogenetics and Neurogenomics Fondation pour la Recherche Medicale Institut National du Cancer (INCA) France Labex GR-Ex Labex EpiGenMed French National Research Agency (ANR) Institut National de la Sante et de la Recherche Medicale (Inserm) European Commission Instituto de Salud Carlos III (ISCIII) INNOPHARMA project MINECO-USC Servizo Galego de Saúde (SERGAS) National Council for Scientific and Technological Development (CNPq) United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Mental Health (NIMH) United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Neurological Disorders & Stroke (NINDS) University Hospital of Rouen French CNR-MAJ United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Mental Health (NIMH) United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Neurological Disorders & Stroke (NINDS)

Introduction Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease. Results We describe a pedigree presenting with a complex autosomal dominant disease, with a heterogeneous clinical phenotype, comprising unspecified dementia, parkinsonism, frontotemporal dementia and motor neuron disease. Genetic analyses identified a novel P112H TARDBP double variation located in exon 3 coding for the first RNA recognition motif of the protein (RRM1). This double mutation is probably pathogenic based on neuropathological findings, in silico prediction analysis and exome sequencing. The two autopsied siblings described here presented with frontotemporal dementia involving multiple cognitive domains and behavior but lacking symptoms of motor neuron disease throughout the disease course. The siblings presented with strikingly similar, although atypical, neuropathological features, including an unclassifiable TDP-43 inclusion pattern, a high burden of tau-negative β-amyloid neuritic plaques with an AD-like biochemical profile, and an unclassifiable 4-repeat tauopathy. The co-occurrence of multiple protein inclusions points to a pathogenic mechanism that facilitates misfolded protein interaction and aggregation or a loss of TDP-43 function that somehow impairs protein clearance. Conclusions TARDBP mutation screening should be considered in familial frontotemporal dementia cases, even without signs or symptoms of motor neuron disease, especially when other more frequent causes of genetic frontotemporal dementia (i.e. GRN, C9ORF72, MAPT) have been excluded and when family history is complex and includes parkinsonism, motor neuron disease and frontotemporal dementia. Further investigations in this family may provide insight into the physiological functions of TARDBP. Electronic supplementary material The online version of this article (doi:10.1186/s40478-015-0190-6) contains supplementary material, which is available to authorized users.

A familial behavioral variant frontotemporal dementia associated with astrocyte-predominant tauopathy is described in 2 sisters born from consanguineous parents. The neuropathologic examination revealed massive accumulation of abnormally hyperphosphorylated, conformational, truncated tau at aspartic acid 421, ubiquitinated and nitrated tau at Tyr29 in cortical astrocyte (including their perivascular foot processes), and Bergmann glia. Smaller amounts of abnormal tau were observed in neurons and rarely in oligodendrocytes. There was decreased expression of glial glutamate transporter in the majority of tau-positive astrocytes. Gel electrophoresis of sarkosyl-insoluble fractions showed 2 bands of 64 and 60 kDa and a doublet of 67 to 70 kDa (which are different from those seen in Alzheimer disease and in typical 4R and 3R tauopathies) together with several bands of lower molecular weight indicative of truncated tau. Analysis of the expression of MAPT isoforms further revealed altered splicing and representation of tau isoforms involving exons 2, 3, and 10. Genetic testing revealed no known mutations in PSEN1, PSEN2, APP, MAPT, GRN, FUS, and TARDBP and no pathologic expansion in C9ORF72. However, a novel rare heterozygous sequence variant(p.Q140H) of uncertain significance was identified in FUS in both siblings.

We report about a patient with infantile-onset neurodegenerative disease associated with isolated mitochondrial respiratory chain complex III (cIII) deficiency. The boy, now 13 years old, presented with language regression and ataxia at 4 years of age and then showed a progressive course resulting in the loss of autonomous gait and speaking during the following 2 years. Brain MRI disclosed bilateral striatal necrosis. Sequencing of a panel containing nuclear genes associated with cIII deficiency revealed a previously undescribed homozygous rearrangement (c.782_786delinsGAAAAG) in TTC19 gene, which results in a frameshift with premature termination (p.Glu261Glyfs(*)8). TTC19 protein was absent in patient's fibroblasts. TTC19 encodes tetratricopeptide 19, a putative assembly factor for cIII. To date TTC19 mutations have been reported only in few cases, invariably associated with cIII deficiency, but presenting heterogeneous clinical phenotypes. We reviewed the genetic, biochemical, clinical and neuroradiological features of TTC19 mutant patients described to date.

Short-term studies have shown that octreotide, a long-acting somatostatin analog, blunts postprandial glycemic responses and reduces insulin requirement in insulin treated diabetic patients. The aim of our study was to investigate the effects of three single, different doses of octreotide on the glycemic response to a mixed meal in eight insulin treated type 2 diabetic patients after secondary failure with hypoglycemic agents. Previous treatments were substituted by regular insulin, 0.5 U/kg/day divided into three sc injections, for at least seven days. All patients received: (a) regular insulin (0.1 U/kg, sc) at 7.30 am; (b) octreotide 25 micrograms sc or (c) 50 micrograms sc or (d) 100 micrograms sc simultaneously with insulin but injected at different sites. From 8.00 to 8.15 the patients consumed a preconstituted fluid mixed meal of 250 ml. Following insulin alone a significant increase in blood glucose levels was observed after the meal. Abolished and not significantly different blood glucose responses to the meal after each of the three doses of octreotide were observed. Our findings suggest that with a low dose of octreotide (25 micrograms) it is possible to abolish the postprandial glycemic peak in type 2 diabetic patients treated with insulin.

Primary familial brain calcification (PFBC) is a heterogeneous neuropsychiatric disorder, with affected individuals presenting a wide variety of motor and cognitive impairments, such as migraine, parkinsonism, psychosis, dementia, and mood swings. Calcifications are usually symmetrical, bilateral, and found predominantly in the basal ganglia, thalamus, and cerebellum. So far, variants in three genes have been linked to PFBC: SLC20A2, PDGFRB, and PDGFB. Variants in SLC20A2 are responsible for most cases identified so far and, therefore, the present review is a comprehensive worldwide summary of all reported variants to date. SLC20A2 encodes an inorganic phosphate transporter, PiT-2, widely expressed in various tissues, including brain, and is part of a major family of solute carrier membrane transporters. Fifty variants reported in 55 unrelated patients so far have been identified in families of diverse ethnicities and only few are recurrent. Various types of variants were detected (missense, nonsense, frameshift) including full or partial SLC20A2 deletions. The recently reported SLC20A2 knockout mouse will enhance our understanding of disease mechanism and allow for screening of therapeutic compounds. In the present review, we also discuss the implications of these recent exciting findings and consider the possibility of treatments based on manipulation of inorganic phosphate homeostasis.

Primary familial brain calcification (PFBC) is a rare disorder characterized by abnormal deposits of calcium in the basal ganglia and cerebellum. PFBC can present with a spectrum of neuropsychiatric symptoms resembling those seen in dementia and schizophrenia. Mutations in a few genes have been identified as causing PFBC: namely, the SLC20A2 gene that codes for the sodium-dependent phosphate transporter and the PDGFRB gene that codes for the platelet-derived growth factor receptor β (PDGF-Rβ). A recent study identified mutations in PDGFB coding for PDGF-B, the main ligand for PDGF-Rβ, in six families with PFBC. Here we report the first Japanese family with PFBC carrying a mutation in PDGFB, which causes the substitution of an arginine with a stop codon at amino acid 149 of the PDGF-B protein (p. Arg149*).Clinical histories and computed tomography scan images were provided. Sanger sequencing was performed for the exome analysis of SLC20A2 and PDGFB genes.One family member began to complain of auditory hallucination at 16 years of age and had been treated for schizophrenia. His father suffered from memory and gait disturbances in his late 60s. A computed tomography scan revealed a symmetrical area of calcification over the basal ganglia in both cases. A known mutation in PDGFB (c.445CT, p.Arg149*) was consistently detected in both PFBC cases by Sanger sequencing. No mutations in SLC20A2 were detected.Our findings suggest that this mutation in PDGF-B is responsible for PFBC in this Japanese family and that abnormal PDGF signaling may be involved in the pathophysiology of certain psychiatric disorders.

OBJECTIVE The prevalence of neuropathy, a common complication of diabetes, was determined in diabetic patients recruited from 109 outpatient diabetes clinics in Italy. RESEARCH DESIGN AND METHODS Neuropathy was diagnosed using the Diabetic Neuropathy Index (DNI), a standardized examination developed for use in the outpatient setting. A total of 8,757 diabetic patients were studied, 51.2% men and 48.8% women, with average and median ages of 56 and 58 years, respectively. RESULTS Of the 8,757 patients, 32.3% had neuropathy, defined as a positive score of > 2 points on the DNI. A total of 2,033 (49.6% men and 50.4% women) were administered the Diabetic Neuropathy Score (DNS), the second component of the screening program, by a neurologist. This component consists of a quantitative neurological examination and nerve conduction studies that together provide a summated score. A total of 335 patients (16.5%) were not neuropathic, and 395 (19.4%) had borderline, 453 (22.3%) mild, 592 (29.1%) moderate, and 258 (12.7%) severe neuropathy. The concordance between a positive score on the DNI and a DNS indicating neuropathy was 83.5%. The severity of neuropathy increased with both age and disease duration. Of patients with neuropathy, 64.1% had an average age between 58 and 59 years with a disease duration between 12.4 ± 8.4 years (mild neuropathy) and 15.6 ± 9.7 years (severe neuropathy). CONCLUSIONS Neuropathy is a common complication of diabetes and, in this study, was present in 32.3% of all patients. An increased awareness of the high prevalence of neuropathy can lead to early therapeutic intervention and possible prevention of later neuropathic complications, such as infection and foot ulcers.

Glucocorticoids are thought to inhibit growth hormone (GH) secretion through an enhancement of endogenous somatostatin tone. The aim of our study was to evaluate the effect of galanin, a neuropeptide that stimulates GH secretion, on GH-releasing hormone (GHRH)-induced GH secretion in adult patients with nonendocrine diseases who were under daily immunosuppressive glucocorticoid therapy. Six normal subjects (four men, two women) and seven steroid-treated subjects (three men, four women) were studied. GHRH-induced GH secretion was evaluated during a 40-minute intravenous (i.v.) infusion of saline or porcine galanin (12.5 micrograms/min). During saline infusion, steroid-treated patients showed a blunted GH response to GHRH (GH peak, 8.1 +/- 2.8 micrograms/L), as compared with normal subjects (GH peak, 23.8 +/- 3.9 micrograms/L). During galanin infusion, the GH response to GHRH was significantly enhanced (GH peak, 46.6 +/- 9.4 micrograms/L, P less than .05), as compared with saline infusion in normal subjects. In contrast, galanin infusion did not enhance the GH response to GHRH (GH peak, 16.6 +/- 6.5 micrograms/L), as compared with saline infusion in steroid-treated patients. The area under the GH-response curves was also significantly (P less than .05) lower in steroid-treated subjects, as compared with normal subjects. Thus, galanin failed to normalize or enhance the GH response to GHRH in patients treated long-term with glucocorticoids. It can be hypothesized that galanin does not elicit GH secretion by decreasing hypothalamic somatostatin tone.

Adolf Hitler (1889. — 1945.), jedan od najvećih zločinaca u povijesti ljudske civilizacije uspio je gotovo obistiniti svoju fiksnu ideju. Zamišljao je, u budućnosti od stotinjak godina, izgraditi veliku njemačku državu na golemome prostoru (koji bi se pružao prema Afganistanu ili tamo negdje) u kojoj će živjeti 250 milijuna isključivo zdravih i poslušnih Nijemaca. Činjenica je da Hitler nije tajio svoje pomahnitale zamisli, dapače i prije početka Drugoga svjetskog rata bivao je sve eklatantniji u svojemu etnocentrizmu, ksenofobiji i netrpeljivosti svega što je u okolini drugačije. Konačno, svoje je političke i ideološke stavove iznio u svojoj autobiografskoj knjizi Mein Kampf ("Moja borba,) iz 1925. godine, pa uznemiruju sljedeća pitanja: a) kako je moguće da su Europa i svijet mogli misliti da je Hitler bezazlena, skučena politička pojava? b) kako je moguće previdjeti činjenicu da je znanost vrlo često na strani predrasuda? (primjerice, Njemačka je u to doba daleko odmakla u znanosti, a bila je, tim više, barbarskija od mnogih drugih europskih zemalja) c) kako je moguće da, poslije kobnog iskusva s Hitlerom, takvi manipulativni, trovački govori ponovno dižu revolucije? d) je li Hitler samo refleks minulog vremena? Autoritarne su vladavine za sobom ostavile duboki trag, moćno sjemenje koje može proklijati kada se za to stvore društveni, ekonomski i psihološki uvjeti. U ovako specifičnom kontekstu koncentrirala sam se na sadržaj jednog i na izvedbu nekoliko Hitlerovih govora. Zanimljivo je, sa scenskog aspekta, na koji je način svojim govorima zadirao u prostor scenske interpretacije. Političar koji želi zavesti diktaturu i održati poziciju nedvojbeno manipulira govorom. Upravljajući mislima drugih ljudi na neki način čini nasilje, represiju, te mijenja njihovu percepciju, stav i iskustvo

A single administration of the sex-dependent hepatocarcinogenic beta-blocker DL-1-(2-nitro-3-methyl-phenoxy)3-tert-butylamino-propan-2-ol (DL-ZAMI 1305) induces liver DNA damage, as evaluated by alkaline sucrose gradient analysis, in female but not in male Fisher 344 rats. The shift of the methyl-group from the 3-position of the aromatic ring of DL-ZAMI 1305 to the 4- and 5-position causes the progressive decrease of the genotoxic activity of the molecule. No effect on the DNA-damaging capacity of DL-ZAMI 1305 is instead observed when the NO2 group of the aromatic ring is reduced to an NH2 group. Bis-demethylation of the side chain of DL-ZAMI 1305, or its modification to an alpha-hydroxicarboxylic acid or glycol, increases the DNA-damaging capacity of the molecule, which becomes genotoxic also for the liver of the male rat. Thus, modifications of the chemical structure of the aromatic ring or of the side chain of DL-ZAMI 1305 affect the genotoxic activity of the molecule both in male and female rat liver. The modifications of the side chain of DL-ZAMI 1305 investigated in the present work are likely to occur in vivo as a consequence of the hepatic metabolism of the molecule. Sex-dependent differences in the activity of the liver drug-metabolizing system might explain the different genotoxic and oncogenic activity of DL-ZAMI 1305 in the two sexes.

The fuel cell vehicle (FCV) has the potential to revolutionize the world's transportation systems. As choices are made on sources of fuel for FCVs it is important to consider the life-cycle implications of each option or system. This paper summarizes the methodology and results of a joint initiative to evaluate the life-cycle performance of 72 vehicle and fuel scenarios in 3 Canadian cities, comparing Proton Exchange Membrane (PEM) fuel cell vehicles and fuelling infrastructure with conventional and alternative fuel vehicles. The analysis is based on actual performance data of commercial and near-commercial technologies. The specific fuels investigated were gasoline, diesel, natural gas, methanol, hydrogen and electricity. The Pembina Institute's Life-Cycle Value Assessment (LCVA) methodology was used to compare the environmental, economic and social performance of each system. The stressor categories quantified include emissions of greenhouse gases and criteria air contaminants, resource consumption, fuel cost, and vehicle cost. A wide number of other stressor categories were identified as important to vehicle / fuel supply performance and should be considered when comparing systems. This paper details only the air emissions results from the full LCVA report. The conclusions reached within the LCVA highlight that there are considerable differences in the life-cycle performance of vehicle systems and that fuel supply choices play a critical role. collection. Consequently, the project team was required to apply judgment in comparing technologies at different maturity levels and vehicles of different body type and performance. Significant effort has been made to maintain consistency between the systems compared, and, where this was not possible, the inconsistencies have been identified in the report.

Glucocorticoids have been shown to inhibit GH secretion in normal man when administered in large amounts for several days. The aim of our study was 1. to investigate the acute effects of a single dose of glucocorticoids on GH secretion in normal man; 2. to look at the relationship between the increase in serum cortisol concentration and GH response to the stimuli. Six healthy volunteers received on three occasions in random order an iv injection of GHRH (1–29) NH2, 100 μg, alone or 60 min after oral administration of either 25 or 50 mg of cortisone acetate. Mean stimulated GH levels, GH peak and integrated GH concentration were significantly lower after GHRH plus cortisone 25 mg than after GHRH alone. Mean GH levels at 15 and 30 min after GHRH injection and the peak GH level showed a further decrease after GHRH plus cortisone 50 mg. We conclude that acute administration of pharmacological doses of glucocorticoids is able to inhibit GH response to GHRH, probably through enhancement of endogenous somatostatin release. Moreover, this pharmacological effect of glucocorticoids seems to be dose-dependent and thus directly related to serum cortisol concentrations.

In vitro studies have demonstrated that thyroid hormones can enhance basal and stimulated growth hormone secretion by cultured pituitary cells. However, both in man and in the rat the effects of high thyroid hormone levels on GH secretion are unclear. The aim of our study was to test the GH response to human GHRH in hyperthyroid patients and to evaluate the effects on GH secretion of short- and long-term pharmacological decrease of circulating thyroid hormones. We examined 10 hyperthyroid patients with recent diagnosis of Graves' disease. Twelve healthy volunteers served as controls. All subjects received a bolus iv injection of GHRH(1-29)NH2, 100 μg. Hyperthyroid patients underwent a GHRH test one and three months after starting antithyroid therapy with methimazole, 10 mg/day po. GH levels at 15, 30, 45, 60 min and GH peak after stimulus were significantly lower in hyperthyroid patients than in normal subjects. The GH peak was also delayed in hyperthyroid patients. After one month of methimazole therapy, most of the hyperthyroid patients had thyroid hormone levels in the normal range, but they did not show significant changes in GH levels after GHRH, and the GH peak was again delayed. After three months of therapy with methimazole, the hyperthyroid patients did not show a further significant decrease in serum thyroid hormone levels. However, mean GH levels from 15 to 60 min were significantly increased compared with the control study. The GH peak after GHRH was also earlier than in the pretreatment study. In conclusion, the GH response to GHRH is inhibited and delayed by hyperthyroidism and returns to the normal pattern after long-term euthyroidism has been achieved with methimazole.