Comprehensive germline mutation analysis and clinical profile in a large cohort of Brazilian xeroderma pigmentosum patients.

BACKGROUND: Xeroderma pigmentosum (XP) patients present a high risk of developing skin cancer and other complications at an early age. This disease is characterized by mutations in the genes related to the DNA repair system. OBJECTIVES: To describe the clinical and molecular findings in a cohort of 32 Brazilian individuals who received a clinical diagnosis of XP. METHODS: Twenty-seven families were screened for germline variants in eight XP-related genes. RESULTS: All patients (N = 32) were diagnosed with bi-allelic germline pathogenic or potentially pathogenic variants, including nine variants previously undescribed. The c.2251-1G>C XPC pathogenic variant, reported as the founder mutation in Comorian and Pakistani patients, was observed in 15 cases in homozygous or compound heterozygous. Seven homozygous patients for POLH/XPV variants developed their symptoms by an average age of 7.7 years. ERCC2/XPD, DDB2/XPE and ERCC5/XPG variants were found in a few patients. Aside from melanoma and non-melanoma skin tumours, a set of patients developed skin sebaceous carcinoma, leiomyosarcoma, angiosarcoma, mucoepidermoid carcinoma, gastric adenocarcinoma and serous ovarian carcinoma. CONCLUSIONS: We reported a high frequency of XPC variants in 32 XP Brazilian patients. Nine new variants in XP-related genes, unexpected non-skin cancer lesions and an anticipation of the clinical manifestation in POLH/XPV cases were also described.

Cross-sectional serosurvey of Coxiella burnetii in healthy cattle and sheep from extensive grazing system in central Italy.

A cross-sectional survey was carried out to estimate the seroprevalence of Coxiella burnetii in extensively grazed cattle and sheep from central Italy and to identify the related risk factors. Data on notified human Q fever cases in the area were also collected and described. A two-stage cluster sampling was performed. A total of 5083 animals (2210 cattle; 2873 sheep) belonging to 186 farms (92 herds; 94 flocks) were tested for the presence of antibodies against C. burnetii using a commercial enzyme-linked immunosorbent assay kit. The prevalence at the animal-level resulted three times higher in sheep compared to cattle (37.8% vs. 12.0%; χ2 = 270.10, P < 0.001). The prevalence at the herd-level was also higher in sheep than in cattle (87.2% vs. 68.5%; χ2 = 9.52, P < 0.01). The multivariate analysis showed a higher risk of seropositivity for cattle aged 67-107 months (OR 2.79, 95% CI 1.86-4.18), cattle >107 months of age (OR 2.07, 95% CI 1.36-3.14) and mixed breed cattle (OR 1.74, 95% CI 1.11-2.72). A herd size >92 animals was recognized as herd-level risk factor in cattle (OR 6.88, 95% CI 1.67-28.37). The risk of being seropositive was double in sheep belonging to flocks >600 animals (odds ratio (OR) 2.04, 95% CI 1.63-2.56). Sheep were confirmed to be the most exposed species. Nevertheless, the prevalence observed in cattle also suggests the potential involvement of this species in the circulation of the pathogen in the area. Seven confirmed human Q fever cases were reported. In five out of seven cases there was at least one exposed herd within a 5 km buffer. Even though the source of the infection was not identified, the possibility of C. burnetii circulating in the livestock and human population in the study area cannot be overlooked. The integration between veterinary and human surveillance will be crucial to understand the spread of this zoonosis and to support the adoption of appropriate control measures.

A CACNA1D mutation in a patient with persistent hyperinsulinaemic hypoglycaemia, heart defects, and severe hypotonia.

Congenital hyperinsulinaemic hypoglycaemia (HH) can occur in isolation or it may present as part of a wider syndrome. For approximately 40%-50% of individuals with this condition, sequence analysis of the known HH genes identifies a causative mutation. Identifying the underlying genetic aetiology in the remaining cases is important as a genetic diagnosis will inform on recurrence risk, may guide medical management and will provide valuable insights into ß-cell physiology. We sequenced the exome of a child with persistent diazoxide-responsive HH, mild aortic insufficiency, severe hypotonia, and developmental delay as well as the unaffected parents. This analysis identified a de novo mutation, p.G403D, in the proband's CACNA1D gene. CACNA1D encodes the main L-type voltage-gated calcium channel in the pancreatic ß-cell, a key component of the insulin secretion pathway. The p.G403D mutation had been reported previously as an activating mutation in an individual with primary hyper-aldosteronism, neuromuscular abnormalities, and transient hypoglycaemia. Sequence analysis of the CACNA1D gene in 60 further cases with HH did not identify a pathogenic mutation. Identification of an activating CACNA1D mutation in a second patient with congenital HH confirms the aetiological role of CACNA1D mutations in this disorder. A genetic diagnosis is important as treatment with a calcium channel blocker may be an option for the medical management of this patient.

Genetic profile of Brazilian patients with dystrophinopathies.

Different types of mutations in the DMD gene underlie Duchenne muscular dystrophies (DMD) and Becker muscular dystrophies (BMD). Large deletions and duplications are the most frequent causative genetic alterations worldwide, but little is known about DMD/BMD genetic profile in Brazil. Hence, we recruited patients with DMD and BMD from 8 neuromuscular reference centers along the country, and performed a comprehensive molecular investigation that included Multiplex Ligation-dependent Probe Amplification and Next generation sequencing (NGS) analyses. We evaluated 199 patients from 177 unrelated families: 166 with DMD, 32 with BMD and 1 1.5 years old asymptomatic patient with persistent hiperCKemia. Overall, large deletions (58.2%) followed by nonsense mutations (12.4%) and large duplications (11.3%) were the most frequent variants in Brazilian families. Large deletions were less frequent in BMD than in DMD (44.8% vs 60.8%). We identified 19 new DMD variants. Nonsense mutations were significantly more frequent in patients from northeastern region than from southern/southeastern regions of Brazil (27.7% vs 8.5%, P < .05). Genetic profile of Brazilian patients with DMD/BMD is similar to previously reported cohorts, but it is not uniform across the country. This information is important to plan rational clinical care for patients in face of the new coming mutation-specific therapies.

Post-caesarean section surgical site infections at a Tanzanian tertiary hospital: a prospective observational study.

Few data are available on the determinants and characteristics of post-caesarean section (CS) surgical site infections (SSIs) in resource-limited settings. We conducted a prospective observational cohort study to evaluate the rates, determinants, and microbiological characteristics of post-CS SSI at the Dodoma Regional Referral Hospital (DRRH) Gynaecology and Obstetrics Department in Tanzania. Spanning a three-month period, all pregnant women who underwent CS were enrolled and followed up for 30 days. SSI following CS occurred in 224 (48%) women. Only 10 (2.1%) women received pre-incision antibiotic prophylaxis. Urgent intervention is needed to prevent and control infections and contain the rising rate of post-CS SSI at the DRRH.

Glucocerebrosidase gene variants in parkinsonian patients with Machado Joseph/spinocerebellar ataxia 3.

UNLABELLED: Machado-Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3) may rarely presents a parkinsonian phenotype. Considering that mutations in the glucocerebrosidase (GBA) gene have been associated with Parkinson disease, we investigated whether these would be more prevalent in MJD/SCA3 patients with parkinsonian manifestations than in those without them. METHODS: MJD/SCA3 patients with parkinsonian features were identified and compared to relatives and to a MJD/SCA3 control group with no such features. The GBA gene was sequenced and, in a subset of patients and in normal volunteers, GBA enzyme activity was measured. RESULTS: We have identified nine index MJD/SCA3 patients with parkinsonian manifestations. Overall, GBA sequence variations were found in 3/9 MJD/SCA3 index cases with parkinsonian manifestations (33%) and in 0/40 MJD/SCA3 controls without parkinsonism (p=0.03, Fisher exact test). The GBA sequence variations found were p.K(-27)R, p.E326K, and p.T369M. The latter two sequence variations were also found in two symptomatic relatives with no parkinsonian manifestations. A MJD/SCA3 relative belonging to the first positive pedigree and carrier of the p.K(-27)R mutation also presented parkinsonian manifestations. GBA activity in MJD/SCA3 patients was similar to those found in the normal control group. CONCLUSION: Sequence variations at the GBA gene may play a role as a minor, modifying gene of MJD/SCA3 phenotype. This hypothetical role was not related to changes in GBA activity in peripheral leukocytes.

The prevalence of antibodies to human herpesvirus 8 and hepatitis B virus in patients in two hospitals in Tanzania.

The aim of this study was to determine the seroprevalence of human herpesvirus 8 (HHV-8) and the immunization status for hepatitis B virus (HBV) infection in febrile patients in two districts of the United Republic of Tanzania. Between February and March 2007, blood samples were collected in Pemba Island and Tosamaganga from 336 outpatients and sent to the Virology Laboratory in Rome (Italy) for testing. HHV-8 DNA and HBV-DNA were amplified by two in-house molecular methods, anti-HHV-8 antibody titers were determined by an immunofluorescence assay (IFA), and anti-HCV, HBsAg, anti-HBs, and anti-HBc were evaluated by microplate enzyme immunoassay (MEIA). The seroprevalence of HHV-8 was 30.7% (96/313). In Pemba Island, the prevalence was lower than in Tosamaganga (14.4% vs. 46.3%). A higher prevalence of low titers of HHV-8 IgG (<1:80, 81%) was found among those under 5 years of age. HHV-8 DNA was detected in six seropositive patients (6.7%). The prevalence of HBsAg, anti-HBs, and anti-HBc was 4.3%, 37.6%, and 29.3%, respectively. Out of 277 patients, 70 had had a previous infection (25.3%). One case of occult hepatitis was found. The cover of hepatitis B vaccination was higher among children born after 2002 (66.7%) than in patients born before 2002. HHV-8 infection is endemic in Tanzania and the seroprevalence rate was higher in the mainland than on Pemba Island. The 3.9% percentage of HBsAg in children younger than 4 years of age suggests that increased efforts are required in order to achieve universal and compulsory immunization of children against HBV.

[Dolichoarteriopathy (kinking, coiling,tortuosity) of the carotid arteries and cardiovascular risk factors]. / Dolicoarteriopatie (kinking, coiling, tortuosità) delle arterie carotidi e fattori di rischio cardiovascolare.

BACKGROUND AND AIMS: The clinical significance of dolichoarteriopathies (kinking, coiling, tortuosity) and their prognosis have not yet been clearly defined. A study was performed in outpatients in order to evaluate the cardiovascular risk factors of dolichoarteriopathies. METHODS: A total of 1220 subjects (620 males and 600 females, aged between 25 and 89 years old) were examined using color Doppler ultrasonography of the extracranial carotid arteries with an Acuson 128 XP-5 scan and 7 MHz linear probe. The reason for the test was the presence of clinical symptoms or cardiovascular risk factors. The risk factors studied included: arterial hypertension [systolic (> 140 mmHg) and/or diastolic arterial pressure (> 90 mmHg)], hypercholesterolemia (total cholesterol > 200 mg/dl), diabetes mellitus, cigarette smoking. Patients were divided as follows: patients with arterial hypertension alone, patients with arterial hypertension associated with other cardiovascular risk factors (hypercholesterolemia, diabetes mellitus, smoking), patients with other cardiovascular risk factors (hypercholesterolemia, diabetes mellitus, smoking), patients without risk factors. RESULTS: In 316 (25.9%) patients with dolichoarteriopathies, arterial hypertension alone was present in 98 (31%), arterial hypertension associated with other cardiovascular risk factors in 85 (26.3%) and other cardiovascular risk factors in 54 (17%), whereas 75 (25%) did not present cardiovascular risk factors. In the 904 subjects without dolichoarteriopathies, arterial hypertension alone was present in 254 (28%), arterial hypertension associated with other cardiovascular risk factors in 213 (23.6%) and other cardiovascular risk factors in 191 (21.1%), whereas 241 (27.2%) did not present cardiovascular risk factors. In 316 subjects with dolichoarteriopathies, cardiovascular risk factors were equally present in the two sexes without statistically significant differences. In cases with kinking and tortuosity, cardiovascular risk factors were equally present in the two sexes, whereas colling was more frequently associated with arterial hypertension alone in males and with arterial hypertension associated with other risk factors in females, showing a statistically significant difference. CONCLUSIONS: The findings of this study reveal that the presence of risk factors in patients with dolichoarteriopathies is comparable to that in subjects without dolichoarteriopathies. Also in the three types of dolichoarteriopathies (kinking, coiling and tortuosity), cardiovascular risk factors were equally present. Therefore, these results appear to lay the role of arterial hypertension or other cardiovascular risk factors in the genesis of diolichoarteriopathies open to question.

[Dolicho-arteriopathies (kinking, coiling, tortuoosity) of the carotid arteries: study by color Doppler ultrasonography]. / Dolicoarteriopatie (kinking, coiling, tortuosità) delle arterie carotidi: studio con esame eco color Doppler.

BACKGROUND: This work aimed to study extracranial carotid dolichoarterial disease in outpatients using color Doppler ultrasonography. METHODS: A total of 1220 outpatients, 620 males and 600 females, aged between 25 and 89 years old, were enrolled in the study. Subjects were divided into three groups according to age: under 60, between 60 and 70, over 70. Color Doppler ultrasonography was performed on the extracranial carotid using Acuson 128 XP/5 ultrasonograph and linear 7 MHz probe. Reference was made to Weibel and Field's classification for kinking, coiling and tortuosity for the classification of dolichoarterial disease. RESULTS: Of the 1220 subjects examined, 316 (25.9%) presented dolichoarterial disease, 126 males (39.9%) and 190 females (60.1%) with a male/female ratio of 1:1.5. Of the 316 cases of dolichoarterial disease, 171 (54.1%; 14% of the patients examined) showed kinking, 36 (11.4%; 2.9% of the patients examined) showed coiling, 109 (34.5%; 8.9% of the patients examined) showed tortuosity. Females were predominantly affected by kinking (male/female ratio: 1:1.8) and coiling (male/female ratio: 1:1.8), whereas the two sexes were equally affected by tortuosity (male/female ratio: 1:1). 76 out of 387 subjects (19.6%) presented dolichoarterial disease in the under-60 group, 128 out of 441 subjects (29.3%) in the 60-70-year-old group, and 112 out of 392 subjects (28.6%) in the over-70 group. The prevalence of dolichoarterial disease remained stationary after the age of 70, as the result of different findings in the two sexes, but continued to increase in males, while it diminished in females. This trend was clearly evident for kinking and coiling, whereas the prevalence of the two sexes was comparable with regard to tortuosity, slightly higher in females under the age of 70 and slightly higher in males after the age of 70. Of the 316 cases of dolichoarterial disease diagnosed, 297 (94%) were localised at the level of the internal carotid artery, with a predominance for the left (47.8%) artery compared to the right (22.1%), 14 (4.4%) at the level of the external carotid artery and 5 (1.6%) affecting the common carotid. Dolichoarterial disease was monolateral in 239 subjects (75.6%) and bilateral in 77 (24.4%). Of the bilateral cases, only one affected the common carotid, 76 the internal carotid with much higher presence of kinking and coiling compared to tortuosity. As far as concerns the site of dolichoarterial disease, no difference was observed between the sexes. CONCLUSIONS: In conclusion, non-invasive color Doppler ultrasonography, which is easily repeatable, can provide useful data for the morphological evaluation of dolichoarterial disease. Further studies in large populations which will enable the anatomofunctional aspects obtained using color Doppler ultrasonography to be correlated with clinical symptoms and possible effects on the central nervous system are now required for an improved clinical and prognostic assessment of dolichoarterial disease.

[New hybrid composite resin for anterior restorations]. / Una nuova resina composita ibrida nei restauri del settore anteriore.

The Authors examine a new hybrid composite resin used in restoration and in veneering of the frontal group. They describe the method of use of the new composite with clinical cases, expressing a positive evaluation.

[Foreign body in the palate. A clinical case]. / Corpo estraneo in sede palatina. Caso clinico.

An unusual clinical case of a foreign body (a toy fragment) adhering by section to the palatine mucosa of a child is repeated. Greater attention is called for to prevent this kind of accident.

[Amalgam gingival tatoo]. / Tatuaggio gengivale da amalgama.

The Authors present (5) cases of gingival tattooing resulted by rapport between argentum amalgam and prosthetic reconstruction with aurum or combination. Theu concluded is opportune to substitute the stumps reconstructions in amalgam with other materials not cause of electrogalvanism. So we avaid principally the antiaesthetic aspect of pigmentation.