Prevalence and phenotype of the c.1529C>T SPG7 variant in adult-onset cerebellar ataxia in Italy.

BACKGROUND AND PURPOSE: Hereditary ataxias are heterogeneous groups of neurodegenerative disorders, characterized by cerebellar syndromes associated with dysarthria, oculomotor and corticospinal signs, neuropathy and cognitive impairment. Recent reports have suggested mutations in the SPG7 gene, causing the most common form of autosomal recessive spastic paraplegia (MIM#607259), as a main cause of ataxias. The majority of described patients were homozygotes or compound heterozygotes for the c.1529C>T (p.Ala510Val) change. We screened a cohort of 895 Italian patients with ataxia for p.Ala510Val in order to define the prevalence and genotype-phenotype correlation of this variant. METHODS: We set up a rapid assay for c.1529C>T using restriction enzyme analysis after polymerase chain reaction amplification. We confirmed the diagnosis with Sanger sequencing. RESULTS: We identified eight homozygotes and 13 compound heterozygotes, including two novel variants affecting splicing. Mutated patients showed a pure cerebellar ataxia at onset, evolving in mild spastic ataxia (alternatively) associated with dysarthria (~80% of patients), urinary urgency (~30%) and pyramidal signs (~70%). Comparing homozygotes and compound heterozygotes, we noted a difference in age at onset and Scale for the Assessment and Rating of Ataxia score between the two groups, supporting an earlier and more severe phenotype in compound heterozygotes versus homozygotes. CONCLUSIONS: The SPG7 c.1529C>T (p.Ala510Val) mutants accounted for 2.3% of cerebellar ataxia cases in Italy, suggesting that this variant should be considered as a priority test in the presence of late-onset pure ataxia. Moreover, the heterozygous/homozygous genotype appeared to predict the onset of clinical manifestation and disease progression.

HrQoL in hair loss-affected patients with alopecia areata, androgenetic alopecia and telogen effluvium: the role of personality traits and psychosocial anxiety.

BACKGROUND: Illness impact on HrQoL has been widely studied in hair loss-affected patients, yet no study has addressed whether individual differences modulate HrQoL in patients with alopecia areata (AA), androgenetic alopecia (AGA) and telogen effluvium (TE). OBJECTIVE: To identify the personality dimensions most predictive of the impact of disease on HrQoL. METHOD: A single-site cross-sectional study was carried out in the Dermatology Unit of Sant'Orsola-Malpighi Hospital, Bologna between September 2016 and September 2017. The study included 143 patients (105 females, ages 18-60 years) diagnosed with AA (n = 27), AGA (n = 80) and TE (n = 36). Illness severity, alopecia type, age, gender, education and civil status were documented. Health-related quality of life (HrQoL), personality traits, trait anxiety, emotional intelligence, social anxiety and social phobia were also measured. RESULTS: AA, AGA and TE groups differed significantly for illness severity with most severe patients falling in AA type. For HrQoL, Gender × Group interaction resulted significant with AGA females reporting a higher impact of hair loss on quality of life than males, while TE males were more impacted by hair loss than AA and AGA males. Lower scores were obtained by AGA females than males on emotional intelligence while no significant differences were evidenced on other groups. A significant Gender × Group interaction was also found for trait anxiety, social phobia and social anxiety: consistently, AGA females reported higher scores than AGA males in all three measures. Finally, discriminant analysis evidenced that anxiety-related traits can contribute to reliably predict hair loss impact on HrQoL, regardless of illness severity and alopecia type. CONCLUSIONS: We recommend that gender and individual differences in anxiety-related dimensions be considered as key factors in gaining a deeper understanding of hair loss impact on quality of life as well as in reducing the burden of illness in alopecia-affected patients.

Clinical characteristics of juvenile idiopathic arthritis in an area of central Italy: a population-based study.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and an important cause of short and long-term disability. In a recent systematic review of population based studies, the epidemiology of JIA is variable worldwide with incidence rates ranging between 1.6 and 23.0/100,000, and prevalence rates between 3.8 and 400.0/100,000. We investigate the incidence and describe the characteristics of juvenile idiopathic arthritis in the pediatric population of the central Italy, in the period 2000-2009. METHODS: A retrospective study was conducted in the Marche region to identify patients with a diagnosis of juvenile idiopathic arthritis according to ILAR criteria, between January 1, 2000 and December 31, 2009. JIA was classified according to the ILAR criteria, that is, arthritis of unknown etiology that persisted for > 6 weeks with onset before the age of 16 years. The pooled global ascertainment of cases was estimated by capture-recapture methods and two independent information sources of ascertainment of new cases of JIA were considered. RESULTS: We studied 151 patients (56 males, 37.1% and 95 females, 62.9%) meeting the ILAR criteria of juvenile idiopathic arthritis. Mean age at presentation was 6.8 ± 3.7 years for males and 6.0 ± 4.0 years for females (p=0.22). The overall incidence rate was 6.34 per 100,000/year (C.I. 6.26-7.35) and the total incidence rate increase from 2000-2009 was 8.16%. Oligoarthritis was the most common onset type (n=98, 65.0%) with 62.5% of ANA-positive patients in at least two determinations. CONCLUSIONS: Our results indicate that juvenile idiopathic arthritis incidence rates in Italy are comparable to previous data from southern Europe, with a higher frequency of oligoarthritis. To the best of our knowledge, this is the first population-based epidemiological study carried out in Italy focusing on the incidence of juvenile idiopathic arthritis.

Copy number variants analysis in a cohort of isolated and syndromic developmental delay/intellectual disability reveals novel genomic disorders, position effects and candidate disease genes.

BACKGROUND: Array-comparative genomic hybridization (array-CGH) is a widely used technique to detect copy number variants (CNVs) associated with developmental delay/intellectual disability (DD/ID). AIMS: Identification of genomic disorders in DD/ID. MATERIALS AND METHODS: We performed a comprehensive array-CGH investigation of 1,015 consecutive cases with DD/ID and combined literature mining, genetic evidence, evolutionary constraint scores, and functional information in order to assess the pathogenicity of the CNVs. RESULTS: We identified non-benign CNVs in 29% of patients. Amongst the pathogenic variants (11%), detected with a yield consistent with the literature, we found rare genomic disorders and CNVs spanning known disease genes. We further identified and discussed 51 cases with likely pathogenic CNVs spanning novel candidate genes, including genes encoding synaptic components and/or proteins involved in corticogenesis. Additionally, we identified two deletions spanning potential Topological Associated Domain (TAD) boundaries probably affecting the regulatory landscape. DISCUSSION AND CONCLUSION: We show how phenotypic and genetic analyses of array-CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects.

RPL5 on 1p22.1 is recurrently deleted in multiple myeloma and its expression is linked to bortezomib response.

Chromosomal region 1p22 is deleted in ⩾20% of multiple myeloma (MM) patients, suggesting the presence of an unidentified tumor suppressor. Using high-resolution genomic profiling, we delimit a 58 kb minimal deleted region (MDR) on 1p22.1 encompassing two genes: ectopic viral integration site 5 (EVI5) and ribosomal protein L5 (RPL5). Low mRNA expression of EVI5 and RPL5 was associated with worse survival in diagnostic cases. Patients with 1p22 deletion had lower mRNA expression of EVI5 and RPL5, however, 1p22 deletion status is a bad predictor of RPL5 expression in some cases, suggesting that other mechanisms downregulate RPL5 expression. Interestingly, RPL5 but not EVI5 mRNA levels were significantly lower in relapsed patients responding to bortezomib and; both in newly diagnosed and relapsed patients, bortezomib treatment could overcome their bad prognosis by raising their progression-free survival to equal that of patients with high RPL5 expression. In conclusion, our genetic data restrict the MDR on 1p22 to EVI5 and RPL5 and although the role of these genes in promoting MM progression remains to be determined, we identify RPL5 mRNA expression as a biomarker for initial response to bortezomib in relapsed patients and subsequent survival benefit after long-term treatment in newly diagnosed and relapsed patients.

Galectin-1 suppression delineates a new strategy to inhibit myeloma-induced angiogenesis and tumoral growth in vivo.

Galectin-1 (Gal-1) is involved in tumoral angiogenesis, hypoxia and metastases. Actually the Gal-1 expression profile in multiple myeloma (MM) patients and its pathophysiological role in MM-induced angiogenesis and tumoral growth are unknown. In this study, we found that Gal-1 expression by MM cells was upregulated in hypoxic conditions and that stable knockdown of hypoxia inducible factor-1α significantly downregulated its expression. Therefore, we performed Gal-1 inhibition using lentivirus transfection of shRNA anti-Gal-1 in human myeloma cell lines (HMCLs), and showed that its suppression modified transcriptional profiles in both hypoxic and normoxic conditions. Interestingly, Gal-1 inhibition in MM cells downregulated proangiogenic genes, including MMP9 and CCL2, and upregulated the antiangiogenic ones SEMA3A and CXCL10. Consistently, Gal-1 suppression in MM cells significantly decreased their proangiogenic properties in vitro. This was confirmed in vivo, in two different mouse models injected with HMCLs transfected with anti-Gal-1 shRNA or the control vector. Gal-1 suppression in both models significantly reduced tumor burden and microvascular density as compared with the control mice. Moreover, Gal-1 suppression induced smaller lytic lesions on X-ray in the intratibial model. Overall, our data indicate that Gal-1 is a new potential therapeutic target in MM blocking angiogenesis.

Galaxy evolution. Evidence for mature bulges and an inside-out quenching phase 3 billion years after the Big Bang.

Most present-day galaxies with stellar masses ≥10(11) solar masses show no ongoing star formation and are dense spheroids. Ten billion years ago, similarly massive galaxies were typically forming stars at rates of hundreds solar masses per year. It is debated how star formation ceased, on which time scales, and how this "quenching" relates to the emergence of dense spheroids. We measured stellar mass and star-formation rate surface density distributions in star-forming galaxies at redshift 2.2 with ~1-kiloparsec resolution. We find that, in the most massive galaxies, star formation is quenched from the inside out, on time scales less than 1 billion years in the inner regions, up to a few billion years in the outer disks. These galaxies sustain high star-formation activity at large radii, while hosting fully grown and already quenched bulges in their cores.

Thyroid gland and pulmonary hypertension. What's the link?

Both hyperthyroidism and hypothyroidism produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic or pulmonary vascular resistance. In almost all cases these cardiovascular changes are reversible when the underlying thyroid disorder is recognized and treated. Pulmonary hypertension (PAH) has been associated with thyroid dysfunction, but primarily with hyperthyroidism. The vast majority of patients with this form of PAH are usually older with toxic multinodular goitre. Data currently available suggest a direct influence of TH on pulmonary vasculature. Possible mechanisms include: 1) enhanced catecholamine sensitivity, causing pulmonary vasoconstriction, a reduction in pulmonary vascular compliance and an increase in vascular resistance; 2) increased metabolism of intrinsic pulmonary vasodilating substances (prostacyclin, nitric oxide); 3) decreased or impaired metabolism of vascontrictors (serotonin, endothelin 1 and tromboxane). In some cases (Graves's and Hashimoto's disease) and an autoimmune process inducing endothelial damage may play a key role. Future studies should focus on discovering the immunogenetic overlap between autoimmune thyroid diseases and PAH: common human leukocyte antigen alleles, susceptibility loci and so on. Such an understanding of the genetic and immune factors may ultimately lead to novel effective approaches in the treatment of PAH. At present, thyroid function tests should be considered in the investigation of all patients with PAH.

Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction.

Hypoxia-inducible transcription factor-1 (HIF-1α) is overexpressed in multiple myeloma (MM) cells within the hypoxic microenvironment. Herein, we explored the effect of persistent HIF-1α inhibition by a lentivirus short hairpin RNA pool on MM cell growth either in vitro or in vivo and on the transcriptional and pro-angiogenic profiles of MM cells. HIF-1α suppression did not have a significant impact on MM cell proliferation and survival in vitro although, increased the antiproliferative effect of lenalidomide. On the other hand, we found that HIF-1α inhibition in MM cells downregulates the pro-angiogenic genes VEGF, IL8, IL10, CCL2, CCL5 and MMP9. Pro-osteoclastogenic cytokines were also inhibited, such as IL-7 and CCL3/MIP-1α. The effect of HIF-1α inhibition was assessed in vivo in nonobese diabetic/severe combined immunodeficiency mice both in a subcutaneous and an intratibial MM model. HIF-1α inhibition caused a dramatic reduction in the weight and volume of the tumor burden in both mouse models. Moreover, a significant reduction of the number of vessels and vascular endothelial growth factors (VEGFs) immunostaining was observed. Finally, in the intratibial experiments, HIF-1α inhibition significantly blocked bone destruction. Overall, our data indicate that HIF-1α suppression in MM cells significantly blocks MM-induced angiogenesis and reduces MM tumor burden and bone destruction in vivo, supporting HIF-1α as a potential therapeutic target in MM.

Psychopathological chronic sequelae of the 2009 earthquake in L'Aquila, Italy.

BACKGROUND: To date, there are no data available among the general adult population on the long-term psychological sequelae of the earthquake that occurred in the town of L'Aquila, Italy in 2009. We investigated the prevalence of post-traumatic stress disorder (PTSD) and major depression (MD) and identified risk factors for these disorders among adult survivors more than one year after the earthquake. METHODS: Telephone interviews were conducted among a random sample of 957 resident adults. The interviews were performed using a questionnaire on exposure to the earthquake, the Mini-International Neuropsychiatric Interview for PTSD, and the Patient Health Questionnaire 8 for MD. Univariate and multivariate logistic regression analyses were conducted to assess potential risk factors. RESULTS: The prevalence rates of PTSD and MD were 4.1% (95% CI=3.0-5.5) and 5.8% (95% CI=4.5-7.5), respectively. The risk factors for PTSD were economic difficulties not necessarily related to the earthquake, chronic disease, death of a relative or friend, and serious economic difficulties as consequence of the earthquake, whereas those for MD were female gender, economic difficulties not necessarily related to the earthquake, not having a permanent job and living in L'Aquila. LIMITATIONS: The major limitations were the cross sectional design and the uncertain accuracy of the diagnoses compared with clinical diagnoses. CONCLUSIONS: Psychological symptoms are frequent even 14-19 months after the L'Aquila earthquake. The mental health care providers in the area of L'Aquila should be aware of the possibility of PTSD or MD among their users.

A new type of Hypersensitivity Pneumonitis: salami brusher's disease.

We observed five consecutive cases of Hypersensitivity Pneumonitis in subjects working in a salami factory. The workers had to clean the white mould growing on salami surface using a manual wire brush. The five patients (four female) had a mean age of 39 +/- 15 years; two were smokers. Three patients had an acute clinical presentation with fever, dyspnoea, dry cough, oxygen desaturation, and presented at the emergency department with suspected diagnosis of community acquired pneumonia. The mean latency for developing respiratory symptoms was 11.6 days. Pulmonary function test demonstrated a reduction in diffusing capacity (DLCO) in all 5 patients (60 +/- 15% of predicted value). Skin prick test was positive for Penicillium spp in 3 cases and for Cladosporium and Aspergillus spp in 2 others. Specific IgG antibodies against Penicillium spp were positive in 3 subjects; 2 were positive for Aspergillus Fumigatus. The prevailing radiological pattern was a ground glass appearance in the three patients with acute clinical onset and a centrilobular one in patients with subacute onset. All patients were advised to avoid exposure to the antigens. Follow-up visits including pulmonary function testing, and DLCO measurement were conducted at one, three and six months. HRCT was performed at six month. Four subjects had a complete radiological and clinical resolution after changing work. Only one patient was treated with oral steroids for severe dyspnoea and progressive reduction of DLCO, gaining a complete radiological and clinical stability at six months.

Invasive pulmonary aspergillosis in non-neutropenic patients: analysis of a 14-month prospective clinical experience.

Invasive pulmonary aspergillosis (IPA) is one of the major causes of morbidity and mortality in severely immunocompromised patients, but recently several authors have reported the occurrence of IPA in liver cirrhosis, chronic obstructive pulmonary disease (COPD) patients, most of whom, but not all, were receiving steroid treatment, with a very high mortality rate. The detection of galactomannan performed in respiratory specimens is a new valuable test for the diagnosis of probable IPA, even in non-neutropenic high risk patients. Since the frequency and clinical impact of IPA in non-hematologic patients is not well known, it seemed rational to us to attempt a prospective study evaluating all patients hospitalized in a university hospital for whom an infectious Diseases consultation was required. This 14-month survey in our hospital, using recently recommended diagnostic criteria, seems to suggest an emerging role of IPA in these patients who may have a higher mortality rate than their neutropenic peers, and provides preliminary evidence that early diagnosis and prompt initiation of antifungal therapy may improve the ultimate outcome of their IPA.

HOXB7 expression by myeloma cells regulates their pro-angiogenic properties in multiple myeloma patients.

The deregulation of the homeobox genes as homeoboxB (HOXB)-7 has been previously associated to tumor progression and angiogenesis; here we investigated the potential role of HOXB7 in the pro-angiogenic properties of multiple myeloma (MM) cells. We found that HOXB7 was expressed in 10 out of 22 MM patients analyzed at the diagnosis related to high bone marrow angiogenesis and overexpressed in about 40% of myeloma cell lines compared with normal plasma cells. Enforced HOXB7 expression in MM cells by a lentiviral vector significantly modified their transcriptional and angiogenic profile, checked by combined microarray and angiogenesis PCR analyses, upregulating VEGFA, FGF2, MMP2, WNT5a and PDGFA and downregulating thrombospoindin-2. The pro- and anti-angiogenic HOXB7-related gene signature was also validated in a large independent dataset of MM patients. Accordingly, MM-induced vessel formation was significantly increased by HOXB7 overexpression both in vitro angiogenic and chorioallantoic membrane assays, as well as the HOXB7 silencing by small interfering RNA inhibited the production of angiogenic factors, and the pro-angiogenic properties of MM cells. Finally, in SCID-NOD mice we confirmed that HOXB7 overexpression by MM cells stimulated tumor growth, increased MM-associated angiogenesis and the expression of pro-angiogenic genes by microarray analysis supporting the critical role of HOXB7 in the angiogenic switch in MM.

EBV-associated leukoencephalopathy with late onset of central nervous system lymphoma in a kidney transplant recipient.

Central nervous system (CNS) lymphoma is a rare posttransplant lymphoproliferative disorder (PTLD), which usually has a poor outcome. To date, no specific conditions predisposing to this complication have been identified. We here describe the case of a renal transplant patient who was initially diagnosed as having Epstein-Barr virus (EBV)-associated leukoencephalopathy and ultimately developed EBV-positive CNS lymphoma. The patient was a young lady who, 2 years after transplantation, presented with focal neurological and electroencephalographic abnormalities and diffuse white matter lesions on brain magnetic resonance imaging. EBV-DNA was detected in the cerebrospinal fluid (CSF) by polymerase chain reaction. After acyclovir therapy and immunosuppressive drug tapering, the symptoms and electroencephalographic abnormalities subsided, and EBV-DNA disappeared from the CSF. Ten years later, a bulky cerebral mass was found. After excision, a diagnosis of EBV-positive, Hodgkin-like monomorphic B-cell PTLD was made. This case illustrates the potential pathophysiological relationships between EBV infection, leukoencephalopathy and CNS lymphoma; although a long time elapsed from the initial neurological illness to CNS lymphoma, a link between these two conditions cannot be excluded. Therefore, a careful long-term follow-up of EBV-related encephalopathy is advisable.

Prolonged bacteraemia caused by VIM-1 metallo-beta-lactamase-producing Proteus mirabilis: first report from Italy.

Persistent bacteraemia arising from a case of post-operative mediastinitis as a result of a Proteus mirabilis isolate, possessing two class 1 integrons carrying bla(VIM-1) and aadA2 gene cassettes located on chromosomal and plasmidic DNA, respectively, is reported. Despite the in vitro susceptibility to carbapenems, meropenem therapy failed, whereas the patient responded to treatment with cefepime plus amikacin. To our knowledge, this is the first report of metallo-beta-lactamase production in a clinical isolate of P. mirabilis in Italy.

Multidrug-resistant Acinetobacter baumannii outbreak in an intensive care unit.

Carbapenem-resistant Acinetobacter baumannii was isolated from 15 colonized or infected patients (carriers) between April and July 2004, in a teaching hospital ICU in Rome, Italy. All isolated strains were susceptible only to gentamicin, ampicillin-sulbactam and colistin and displayed the same Random Amplified Polymorphic DNA (RAPD) 1 pattern. Twelve out of 15 strains were susceptible to tigecycline, whereas the remaining three showed intermediate susceptibility. Although infection control measures were reinforced and carriers isolated in separate rooms, A. baumannii transmission continued. Therefore, finally A. baumannii carriers were moved to another available subintensive unit, which was re-equipped, and cared for by dedicated personnel, whereas only the non infected/colonized patients remained in the ICU. This study shows that during an outbreak by multiresistant A. baumannii it may be indispensable to geographically isolate not only patients but also dedicated staff.

HEV prevalence in the general population and among workers at zoonotic risk in Latium Region.

Hepatitis E Virus (HEV) infections are responsible for large waterborne outbreaks in developing countries. Sporadic cases in the developed world are mainly imported from endemic areas. HEV has been suggested to be a zoonotic infection, for which pigs may be the reservoir; specific swine strains of HEV have been identified. Humans are susceptible to infections with swine strains. The aim of this study was to analyse whether Italian pig farmers, veterinarians and abattoir workers are more exposed than persons with other occupations. A total of 92 workers at zoonotic risk and 3511 controls from the general population of two Latium cities, Rome and Rieti, were tested for IgG-HEV antibodies. No significant difference in anti-HEV prevalence was observed between the two groups. The prevalence of general population was 2.9% against 3.3% of pig breeders, while there was a statistically significant difference (p = .0004) between subjects recruited in Rome (prevalence 2.5%) and those recruited in Rieti (prevalence 5.5%). Moreover, in some subgroups of general population and in a subgroup of pig breeders, the prevalence was higher than that previously reported in Italy and in other European countries. The highest value (33%) was found in male housekeepers enrolled in Rome; an analogous value was found in the employees of abattoirs (33%). Further studies are needed to elucidate the transmission routes.

Identification of respiratory isolates of Stenotrophomonas maltophilia by commercial biochemical systems and species-specific PCR.

One hundred strains of Stenotrophomonas maltophilia isolates from respiratory specimens were biochemically identified using the API 20NE strip and the VITEK2 ID-GNB card. The identification was confirmed by a species-specific PCR using two primers specific for the 23S rRNA gene. The API 20NE showed only 1 strain with "low discrimination" whereas the VITEK2 gave 12. In any case, the two biochemical systems showed good reliability compared to SS-PCR.