Psoriasis and the risk of acute coronary syndrome in the elderly.

BACKGROUND: Psoriasis has been associated with a higher prevalence of cardiovascular disease risk factors. However, there is inadequate quantification on the association between psoriasis and acute coronary syndrome (ACS), particularly in the elderly. Therefore, the aim of the present study was to assess the risk of ACS according to history of psoriasis in subjects aged 75 years and older. METHODS: We carried out a case control study based on 1455 cases and 1108 controls. Cases were all the patients admitted in the randomized Elderly ACS 2 trial. Controls were selected from subjects aged ≥75 years included in the Prevalence of Actinic Keratoses in the Italian Population Study (PraKtis), based on a representative sample of the general Italian population. Odds ratios (OR) of ACS according to history of psoriasis were obtained using a multiple logistic regression model including terms for age, sex and smoking. RESULTS: The prevalence of psoriasis was lower among cases (12/1455, 0.8%) than among controls (18/1108, 1.6%). The multivariate OR of ACS according to history of psoriasis was 0.51 (95% confidence interval: 0.23-1.09). CONCLUSIONS: Our data does not support an association between psoriasis and risk of ACS in the elderly.

Features and prognostic impact of distant metastases in 45 dogs with de novo stage IV cutaneous mast cell tumours: A prospective study.

BACKGROUND: Distant metastases in dogs with cutaneous mast cell tumors (cMCT) are rare and incurable. The aims of this prospective study were to clarify the clinico-pathological features of stage IV cMCTs and to identify possible prognostic factors for progression-free interval (PFI) and survival time (ST). MATERIAL AND METHODS: Dogs were eligible for recruitment if they had a previously untreated, histologically confirmed cMCT and if they underwent complete staging demonstrating stage IV disease. Dogs were uniformly followed-up, whereas treatment was not standardized and included no therapy, surgery, radiation therapy, chemotherapy, tyrosine-kinase inhibitors or a combination of these. RESULTS: 45 dogs with stage IV cMCT were enrolled. All dogs had distant metastatic disease, and 41 (91.1%) dogs had also metastasis in the regional lymph node. Histopathological grade and mutational status greatly varied among dogs. Median ST was 110 days. Notably, PFI and ST were independent of well-known prognostic factors, including anatomic site, histological grade, and mutational status. Conversely, tumor diameter >3 cm, more than 2 metastatic sites, bone marrow infiltration, and lack of tumor control at the primary site were confirmed to be negative prognostic factors by multivariate analysis. CONCLUSION: Currently, there is no satisfactory treatment for stage IV cMCT. Asymptomatic dogs with tumor diameter <3 cm and a low tumor burden, without bone marrow infiltration may be candidates for multimodal treatment. Stage IV dogs without lymph node metastasis may enjoy a surprisingly prolonged survival. The achievement of local tumor control seems to predict a better outcome in dogs with stage IV cMCT.

Early-onset epileptic encephalopathy in a girl carrying a truncating mutation of the ARX gene: rethinking the ARX phenotype in females.

Severe early-onset epilepsy is due to a number of known causes, although a clear etiology is not identifiable in up to a third of all the cases. Pathogenic sequence variations in the ARX gene have been described almost exclusively in males, whereas heterozygous female relatives, such as mothers, sisters and even grandmothers have been largely reported as asymptomatic or mildly affected. To investigate the pathogenic role of ARX in refractory epilepsy of early onset even in females, we have screened the ARX sequence in a population of 50 female subjects affected with unexplained epileptic encephalopathy with onset in the first year of life. We report the identification of a novel truncating mutation of the coding region of the ARX gene in a girl with a structurally normal brain. Our findings confirm the role of ARX in the pathogenesis of early epilepsy and underline the importance of screening of the ARX gene in both male and female subjects with otherwise unexplained early onset epileptic encephalopathy.

Congenital muscular dystrophies with cognitive impairment. A population study.

BACKGROUND: Cognitive impairment has been reported in a significant proportion of patients with congenital muscular dystrophies (CMD), generally associated with brain changes. OBJECTIVES: The aim of this study was to establish 1) the overall prevalence of CMD and cognitive impairment in the Italian population; 2) the frequency of individual genetically defined forms; and 3) the presence of distinct phenotypes not associated with mutations in the known genes. METHODS: We included all patients with CMD and cognitive impairment followed in all the Italian tertiary neuromuscular centers. Clinical, brain MRI, and morphologic data were collected. Genetic screening of the known genes was performed according to clinical and muscle biopsy findings. RESULTS: Ninety-two of the 160 (58%) patients with CMD followed in our centers had cognitive impairment. alpha-Dystroglycan (alpha-DG) reduction on muscle biopsy was found in 73/92 (79%), with 42/73 carrying mutations in the known genes. Another 6/92 (7%) showed a laminin alpha2 deficiency on muscle biopsy and 5 of the 6 carried mutations in LAMA2. The remaining 13/92 (14%) patients had normal alpha-DG and laminin alpha2 expression on muscle. CONCLUSIONS: This is the first population study establishing the prevalence of CMD and cognitive impairment and providing a classification on the basis of clinical, MRI, and genetic findings. We also showed that cognitive impairment was not always associated with alpha-DG or laminin alpha2 reduction or with structural brain changes.

Expression of endothelin-1 and endothelin receptor a in canine ovarian tumours.

Ovarian tumours have a low incidence in bitch. Endothelin (ET-1) and endothelin A receptor (ET-A) are overexpressed in human ovarian cancer. Twenty canine ovarian tumours and five normal samples were first evaluated by western blotting and then immunohistochemically for ET-1 and ET-A expression. Seventeen out of twenty tumours were ET-1 positive. Eight out of twenty tumours were ET-A immunohistochemically positive. At molecular level both proteins were proven to be expressed in normal as well as in tumour samples. Our results show that ET-1 and ET-A are overexpressed in canine ovarian tumours, suggesting a potential role of these two molecules in canine ovarian carcinogenesis.

Visual evoked potentials in succinate semialdehyde dehydrogenase (SSADH) deficiency.

In mammals, increased GABA in the central nervous system has been associated with abnormalities of visual evoked potentials (VEPs), predominantly manifested as increased latency of the major positive component P100. Accordingly, we hypothesized that patients with a defect in GABA metabolism, succinate semialdehyde dehydrogenase (SSADH) deficiency (in whom supraphysiological levels of GABA accumulate), would manifest VEP anomalies. We evaluated VEPs on two patients with confirmed SSADH deficiency. Whereas the P100 latencies and amplitudes for binocular VEP analyses were within normal ranges for both patients, the P100 latencies were markedly delayed for left eye (OS) (and right eye (OD), patient 1) and monocular OS (patient 2): 134-147 ms; normal <118 ms. We hypothesize that elevated GABA in ocular tissue of SSADH patients leads to a use-dependent downregulation of the major GABAergic receptor in eye, GABA(C), and that the VEP recordings' abnormalities, as evidenced by P100 latency and/or amplitude measurements, may be reflective of abnormalities within visual systems. This is a preliminary finding that may suggest the utility of performing VEP analysis in a larger sample of SSADH-deficient patients, and encourage a neurophysiological assessment of GABA(C) receptor function in Aldh5a1(-/-) mice to reveal new pathophysiological mechanisms of this rare disorder of GABA degradation.

Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study.

BACKGROUND: Congenital muscular dystrophies (CMD) with reduced glycosylation of alpha-dystroglycan (alpha-DG) are a heterogeneous group of conditions associated with mutations in six genes encoding proven or putative glycosyltransferases. OBJECTIVES: The aim of the study was to establish the prevalence of mutations in the six genes in the Italian population and the spectrum of clinical and brain MRI findings. METHODS: As part of a multicentric study involving all the tertiary neuromuscular centers in Italy, FKRP, POMT1, POMT2, POMGnT1, fukutin, and LARGE were screened in 81 patients with CMD and alpha-DG reduction on muscle biopsy (n = 76) or with a phenotype suggestive of alpha-dystroglycanopathy but in whom a muscle biopsy was not available for alpha-DG immunostaining (n = 5). RESULTS: Homozygous and compound heterozygous mutations were detected in a total of 43/81 patients (53%), and included seven novel variants. Mutations in POMT1 were the most prevalent in our cohort (21%), followed by POMT2 (11%), POMGnT1 (10%), and FKRP (9%). One patient carried two heterozygous mutations in fukutin and one case harbored a new homozygous variant in LARGE. No clear-cut genotype-phenotype correlation could be observed with each gene, resulting in a wide spectrum of clinical phenotypes. The more severe phenotypes, however, appeared to be consistently associated with mutations predicted to result in a severe disruption of the respective genes. CONCLUSIONS: Our data broaden the clinical spectrum associated with mutations in glycosyltransferases and provide data on their prevalence in the Italian population.

POMT1 and POMT2 mutations in CMD patients: a multicentric Italian study.

Mutations in POMT1 and POMT2 genes were originally identified in Walker-Warburg syndrome (WWS) and subsequently reported in patients with milder phenotypes characterised by mental retardation with or without brain abnormalities and without ocular malformations. As part of a multicentric Italian study we screened the POMT1 and POMT2 genes in 61 congenital muscular dystrophy (CMD) patients with alpha-dystroglycan reduction on muscle biopsy and/or clinical and radiological findings suggestive of the known forms of CMD with alpha-dystroglycan deficiency. The aim of the study was to establish how frequently mutations in POMT1 and POMT2 occur in CMD patients in the Italian population and to evaluate the spectrum of associated phenotypes. Thirteen patients showed mutations in POMT1 and five harboured mutations in POMT2, accounting for a total of 20 different mutations, eight of which were novel (two in POMT1 and six in POMT2). Normal brain MRI associated with mental retardation and microcephaly was the most frequent finding in patients with mutations in POMT1 (six out of 13), but was also found in a patient with POMT2 mutations. Predominant cerebellar hypoplasia was also frequent both in patients with POMT1 (three out of 13) and POMT2 (three out of 5) mutations. A MEB phenotype with frontal cortical dysplasia and pons abnormalities was found in two patients with POMT1 and in one with POMT2 mutations, while a WWS phenotype was only found in a case with mutations in POMT1. Mutations causing frameshifts and stop codons were responsible for the more severe phenotypes. Our results provide further evidence that, as previously reported for FKRP, the array of mutations in POMT1 and POMT2 is ample and the spectrum of associated phenotypes is wider than initially thought.

Multiplex ligation-dependent probe amplification detects DCX gene deletions in band heterotopia.

BACKGROUND: Subcortical band heterotopia (SBH, or double cortex syndrome) is a neuronal migration disorder consisting of heterotopic bands of gray matter located between the cortex and the ventricular surface, with or without concomitant pachygyria. Most cases show diffuse or anteriorly predominant (A>P) migration abnormality. All familial and 53% to 84% of sporadic cases with diffuse or A>P SBH harbor a mutation of the DCX gene, leaving the genetic causes unexplained, and genetic counseling problematic, in the remaining patients. Our purpose was to verify the extent to which exonic deletions or duplications of the DCX gene would account for sporadic SBH with A>P gradient but normal gene sequencing. METHODS: We identified 23 patients (22 women, 1 man) with sporadic, diffuse, or anteriorly predominant SBH. After sequencing the DCX gene and finding mutations in 12 (11 women, 1 man), we used multiplex ligation-dependent probe amplification (MLPA) to search for whole-exon deletions or duplications in the 11 remaining women. We used semiquantitative fluorescent multiplex PCR (SQF-PCR) and Southern blot to confirm MLPA findings. RESULTS: MLPA assay uncovered two deletions encompassing exons 3 to 5, and one involving exon 6, in 3 of 11 women (27%) and raised the percentage of DCX mutations from 52% to 65% in our series. SQF-PCR performed in all three women and Southern blot analysis performed in two confirmed the deletions. CONCLUSIONS: MLPA uncovers large genomic deletions of the DCX gene in a subset of patients with SBH in whom no mutations are found after gene sequencing. Deletions of DCX are an underascertained cause of SBH.

[Neurobiology of autism: Study of a sample of autistic children]. / Neurobiologia dell'autismo: studio di un campione di soggetti autistici in età evolutiva.

AIM: Recent studies on the neuroanatomic, neurofunctional and/or neurochemical features of the autistic disorder (AD) gave many evidences suggesting the hypothesis that different organic factors may lead to a disruption of the cerebral development finally expressing with an autistic pattern. The aim of this study was to study a sample of subjects with AD with a wide protocol, including neurophysiological and radiological investigations as well as laboratory investigations in order to investigate the neurobiologic basis of the syndrome. METHODS: The patients group included 80 subjects diagnosed as having AD. All were examined with a protocol of investigations including: brain MRI; wakefulness and sleep EEG; VEP, ABR; karyotype and search of the fragile X; serum and urinary levels of serotonin, catecolamines, omovanillic acid, aminoacids, ammonium, lactic acid, creatine kinase, piruvic acid, calcium, uric acid, total proteins, antibodies against neurotrophic agents. RESULTS: Eighty-eight percent of subjects had at least one pathologic neurobiological parameter. CONCLUSIONS: This study highlights the different noxae involved in the etiopathogenesis of AD and the percentage that every biological factor has in the development of the autistic phenotype. Furthermore, it confirms that AD corresponds to an atypical behavioural phenotype expression of a cerebral dysfunction with heterogeneous etiology.

Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder in developed countries.

Over a period of almost 10 yr, we carried out a prospective study of the neuropsychological development of the offspring of 16 women from a moderately iodine-deficient area (area A) and of 11 control women from a marginally iodine-sufficient area (area B) whose thyroid function had been monitored during early gestation. Attention deficit and hyperactivity disorder (ADHD) was diagnosed in 11 of 16 area A children (68.7%) but in none from area B. Total intelligence quotient score was lower in area A than in area B children (92.1 +/- 7.8 vs. 110 +/- 10) and in ADHD children when compared with both non-ADHD children from the same area and control children (88.0 +/- 6.9 vs. 99.0 +/- 2.0 and 110 +/- 10, respectively). Seven of 11 ADHD children (63.6%) were born to the seven of eight area A mothers who became hypothyroxinemic at early gestation, whereas only one of five non-ADHD children was born to a woman who was hypothyroxinemic at 20 wk of gestation. So far, a similar prevalence of ADHD has been reported only in children with generalized resistance to thyroid hormones. This might suggest a common ADHD pathogenetic mechanism consisting either of reduced sensitivity of the nuclear receptors to thyroid hormone (generalized resistance to thyroid hormones) or reduced availability of intracellular T3 for nuclear receptor binding. The latter would be the ultimate consequence of maternal hypothyroxinemia (due to iodine deficiency), resulting in a critical reduction of the source of the intracellular T3 available to the developing fetal brain.

Familial periventricular heterotopia: missense and distal truncating mutations of the FLN1 gene.

OBJECTIVE: To examine the clinical and MRI associations in bilateral periventricular nodular heterotopia (BPNH) (MIM # 300049) in two families segregating a missense mutation and a C-terminal deletion of the filamin 1(FLN1) gene. BACKGROUND: Classical familial BPNH, an X-linked dominant disorder, has been associated with protein truncations or splicing mutations, which tend to cluster at the N-terminal of the FLN1 protein, causing severe predicted loss of the protein function. The clinical syndrome includes symmetrical contiguous nodular heterotopia lining the lateral ventricles, epilepsy, mild retardation to normal cognitive level in affected females, and prenatal lethality in hemizygous boys. METHODS: Clinical examination, cognitive testing, MRI, mutation analysis (direct sequencing, single-strand conformation polymorphism) in seven patients from two families with BPNH. RESULTS: In Family 1, harboring an A > T change in exon 2 (E82V), heterotopic nodules were few, asymmetric, and noncontiguous. Five boys born from affected females had died unexpectedly early in life. In Family 2, harboring an 8 base pair deletion in exon 47 (7627_7634del TGTGCCCC), heterotopic nodules were thick and contiguous. Affected females in both families showed normal to borderline IQ and epilepsy. CONCLUSION: Missense mutations and distal truncations consistent with partial loss of FLN1 function cause familial BPNH with the classical clinical phenotype including epilepsy and mild mental retardation, if any. However, missense mutations have milder anatomic consequences in affected females and are possibly compatible with live birth but short survival of boys.

Diagnostic and prognostic value of vasodilator stress echocardiography in asymptomatic Type 2 diabetic patients with positive exercise thallium scintigraphy: a pilot study.

AIM: To assess the diagnostic and prognostic value of vasodilator stress echocardiography in Type 2 diabetic patients with positive exercise perfusion scintigraphy. METHODS: Of an initial cohort of 50 asymptomatic Type 2 diabetic patients undergoing exercise single photon emission computed tomography (SPECT) thallium scintigraphy, 24 had a positive thallium scan, with a reversible perfusion defect. All these 24 underwent high dose (up to 0.84 mg/kg in 10 min) dipyridamole echocardiography and coronary angiography independently of stress echocardiography results. All patients were then followed for 61+/-22 months. RESULTS: Coronary angiography showed normal coronary arteries in 11 patients and significant (> 50% visually assessed diameter reduction in a major vessel) coronary artery disease in 13. Stress echocardiography showed 92% sensitivity and 100% specificity for non-invasive detection of coronary artery disease. During follow-up, five patients experienced cardiac events: heart failure in one, angina with subsequent revascularization in two, and myocardial infarction in two. Event-free survival was 100% in the 12 patients with negative and 58% in the 12 patients with positive stress echocardiography (P = 0.08 by Mantel-Cox test). CONCLUSIONS: In asymptomatic Type 2 diabetic patients with stress-induced perfusion defects, vasodilator stress echocardiography is an excellent diagnostic and prognostic tool proven with long-term follow-up.