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OBJECTIVEThree to five days of external lumbar drainage (ELD) of CSF is a test for ventriculoperitoneal shunt (VPS) selection in idiopathic normal pressure hydrocephalus (iNPH). The accuracy and complication rates of a shorter (1-day) ELD procedure were analyzed.METHODSData of patients with iNPH who underwent 1-day ELD to be selected to undergo VPS placement with a programmable valve in the period from 2005 to 2015 were reviewed. Patients experiencing VPS complications, valve malfunctioning, or with less than 1 year of follow-up were excluded. The ability of 1-day ELD to predict VPS outcome at 1- and 12-month follow-up was assessed by calculating sensitivity, specificity, and positive and negative predictive values.RESULTSOf 93 patients who underwent 1-day ELD, 3 did not complete the procedure. Of the remaining 90 patients, 2 experienced transient nerve root irritation. Twenty-four patients had negative test outcomes and 66 had positive test outcomes. Nine negative-outcome patients had intraprocedural headache, which showed 37.5% sensitivity (95% confidence interval [CI] 19.5%–59.2%) and 100% specificity (95% CI 93.1%–100%) as predictors of negative 1-day ELD outcome. Sixty-eight patients (6 with negative and 62 with positive outcomes) underwent VPS insertion, which was successful in 0 and 58 patients, respectively, at 1-month follow-up. Test sensitivity and specificity in predicting surgical outcome at 1-month follow-up were 100% (95% CI 92.3%–100%) and 60% (95% CI 27.4%–86.3%), respectively, with 94.1% accuracy (95% CI 85.6–98.4%). Among the 1-day ELD–positive patients, 2 showed no clinical benefit at 12 months follow-up. Test sensitivity and specificity in predicting surgical outcome at 12-month follow-up was 100% (95% CI 92.5%–100%) and 75.0% (95% CI 35.6%–95.5%), respectively, with 97.1% (95% CI 89.8%–99.6%) accuracy.CONCLUSIONSOne-day ELD is a reliable tool in iNPH management, with low complication risk and short trial duration. The test is very consistent in predicting who will have a positive outcome with VPS placement, given the high chance of successful outcome at 1- and 12-month follow-up; negative-outcome patients have a high risk of unsuccessful surgery. Intraprocedural headache is prognostic of 1-day ELD negative outcome.

CSF shunting with adjustable valve is the treatment of idiopathic normal pressure hydrocephalus. The opening pressure valve setting is left to the neurosurgeon’s experience. Aqueductal CSF stroke volume by phase-contrast magnetic resonance measures the CSF passing through the Sylvian aqueduct and it changes with intracranial hydrodynamics. We sought to identify a window of stroke volume differences associated with the best clinical outcome and lowest rate of complications. The records of 69 patients were reviewed. At every clinical check, stroke volume, opening pressure valve, clinical outcome, and CSF overdrainage were analyzed. The correlation between stroke volume differences and negative outcome was also analyzed. The median follow-up was 2.3 years (range 0.3–10.4 years). The odds of negative outcome between two consecutive checks significantly increased by 16% (95%CI 4–28%, p = 0.006). Taking the lowest risk group as reference, the odds ratio of negative outcome was 1.16 (95%CI 0.51–2.63, p = 0.726) for SV differences less than − 37.6 µL, while it was 1.96 (95%CI 0.97–3.98, p = 0.062) for stroke volume changes above + 23.1 µL. Maintaining stroke volume values within a definite range might help maximize clinical benefit and avoid the risk of CSF overdrainage.

Importance The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participants Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Results Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P

We present a 24-year-old female patient affected by neurofibromatosis type 1 (NF1) who developed a malignant phyllodes tumor of the breast. The molecular studies showed that the patient carried a heterozygous inactivating deleterious variant in BRCA1 inherited from the father associated with a germline de novo pathogenic alteration in NF1; the tumor presented a biallelic inactivation of both genes. Therefore, tumor analyses helped to establish that the germline NF1 and BRCA1 variants were in cis on the paternal chromosome. This last information is important to provide adequate genetic counselling regarding the risk of recurrence in the offspring, as well as opportunity for early intervention. In conclusion, we present the first case of a malignant phyllodes tumor of the breast in patient carrying pathogenic variants in NF1 and BRCA1. Further studies will be necessary to understand if the phyllodes histotype represents a very rare component of NF1-associated breast cancer.

~10% of dementia patients have idiopathic normal pressure hydrocephalus (iNPH), an expansion of the cerebrospinal fluid (CSF)-filled brain ventricles. iNPH and Alzheimer’s disease (AD) both exhibit sleep disturbances, build-up of brain metabolic wastes and Aβ plaques, perivascular reactive astrogliosis, and mislocalization of astrocyte Aquaporin-4 (AQP4). The glymphatic system facilitates brain fluid clearance and waste removal during sleep via glia-supported perivascular channels. Human studies have implicated impaired glymphatic function in both AD and iNPH. Continued investigation into the role of glymphatic system biology in AD and iNPH models could lead to new strategies to improve brain health by restoring homeostatic brain metabolism and CSF dynamics.

OBJECTIVEChanges in the pressure gradient between intraocular and intracranial compartments at the lamina cribrosa level are a possible explanation of normal tension glaucoma (NTG). Shunt-treated normal pressure hydrocephalus (NPH) is a model for testing whether the increase (time from disease onset to CSF shunt placement, i.e., “protection period”) and decrease (time from shunt placement to observation, i.e., “exposure period”) in intracranial pressure (ICP) are glaucoma protective or risk factors, respectively. The authors estimated the prevalence of NTG in patients with shunt-treated NPH and calculated the extent of optic nerve exposure to changes in the trans–lamina cribrosa gradient.METHODSData obtained in patients with NPH who had undergone ventriculoperitoneal (VP) shunt placement were analyzed. Patients with more than 6 months’ follow-up, no pathologies associated with ICP changes or CSF dynamics disturbances, and no surgical or valve-related complications were scheduled for ophthalmic evaluation.RESULTSNine of 22 patients had NTG, which is about a 40-fold increase in rate compared with the rate in the general elderly population without hydrocephalus (p < 0.001). The median protection period was 12.0 months in patients with NTG and 18.0 months in those without NTG (p = 0.033). The median ICP decrease multiplied by duration of exposure in months was 76.0 mm Hg × months in the NTG group and 24.1 mm Hg × months in the no-NTG group (p = 0.048). The patients’ median adjusted age (adjusted for “protection” and “exposure” times) was 85.1 years in the NTG group and 78.8 years in the no-NTG group (p = 0.001).CONCLUSIONSA crucial risk factor for development of NTG in patients with shunt-treated NPH is the duration of optic nerve exposure to the lowering of ICP. Patients with NPH who are candidates for CSF shunting should be informed of the risk of incurring glaucoma. Longitudinal studies could provide estimates of tolerated times for a given ICP decrease.

Fetal grafting in a human diseased brain was thought to be less immunogenic than other solid organ transplants, hence the minor impact on the efficacy of the transplant. How much prophylactic immune protection is required for neural allotransplantation is also debated. High-sensitive anti-HLA antibody screening in this field has never been reported. Sixteen patients with Huntington's disease underwent human fetal striatal transplantation in the frame of an open-label observational trial, which is being carried out at Florence University. All patients had both brain hemispheres grafted in two separate robotic-stereotactic procedures. The trial started in February 2006 with the first graft to the first patient (R1). R16 was given his second graft on March 2011. All patients received triple immunosuppressive treatment. Pre- and posttransplant sera were analyzed for the presence of anti-HLA antibodies using the multiplexed microsphere-based suspension array Luminex xMAP technology. Median follow-up was 38.5 months (range 13-85). Six patients developed anti-HLA antibodies, which turned out to be donor specific. Alloimmunization occurred in a time window of 0–49 months after the first neurosurgical procedure. The immunogenic determinants were non-self-epitopes from mismatched HLA antigens. These determinants were both public epitopes shared by two or more HLA molecules and private epitopes unique to individual HLA molecules. One patient had non-donor-specific anti-HLA antibodies in her pretransplant serum sample, possibly due to previous sensitization events. Although the clinical significance of donor-specific antibodies is far from being established, particularly in the setting of neuronal transplantation, these findings underline the need of careful pre- and posttransplant immunogenetic evaluation of patients with intracerebral grafts.

Summary Microsomal epoxide hydrolase gene ( EPHX1 ) is polymorphic and encodes an enzyme involved in both the activation and detoxification of several tobacco carcinogens. Therefore, a contribution of EPHX1 enzymatic activity on lung cancer risk is possible. A genetic component of early-onset lung cancer has been suggested but variations in enzyme activity and polymorphisms in EPHX1 have seldom been studied in young patients with lung cancer. Primary lung cancer cases of both sexes and under age 45 at diagnosis were considered for this study. Controls fulfilled the following criteria: over 60 years old, smoking history of at least 40 years, no malignancies. Because of these criteria, they are referred to as super controls. The polymorphisms at exons 3 (Tyr113His) and 4 (His139Arg) as well as at the 5′-UTR-290T/G of the EPHX1 gene were genotyped by minisequencing. The association of these three polymorphisms with the development of early-onset lung cancer and the group of the super controls was evaluated by means of 2×2 tables using Yate's X 2 test or Fisher's exact test. Overall, data were obtained from 42 cases and 72 super controls. There was a significant association between early-onset lung cancer and the presence of the EPHX1 exon 4 variant (OR=3.33, 95% CI=1.50–7.41). This was confirmed at the phenotypic level when the data of both patients and super controls were stratified according to the predicted enzymatic activity ( X 2 for linear trend=7.23, p =0.007). This analysis of lung cancer in subjects under age 45 supports the hypothesis that EPHX1 polymorphisms may have a role in cancer susceptibility in this age group.

OBJECTIVE Post-streptococcal reactive arthritis (PSReA) may be a variant of acute rheumatic fever (ARF), but there still is debate on the relationship between the 2 entities. Possible associations with HLA class II antigens of PSReA (DRB1*01) and ARF (DRB1*16) were described previously in white Americans. To confirm these findings, we studied DRB1 alleles in a group of Italian children with PSReA and ARF. METHODS We performed low-resolution HLA-DRB1 typing by a sequence-specific primer polymerase chain reaction method in 33 children with PSReA and 25 children with ARF. We also compared the DRB1 genotypes of our patients with 200 normal subjects from the same geographic area and typed in the same laboratory with the same methods. RESULTS The allele distributions at the DRB1 locus observed in PSReA patients, ARF patients, and controls were not significantly different from each other (chi-square test with small numbers, P = .65). The positivity for each of the 13 HLA-DRB1 alleles was compared in disease groups (PSReA and ARF) and controls, and failed to show any significant association. Comparisons of the frequency of the DRB1*01 allele among PSReA, ARF, and controls did not show any statistical differences. No significant difference in the frequency of DRB1*16 was present between ARF vs the control group, between ARF vs PSReA, and in PSReA patients when compared with controls. CONCLUSIONS Our data do not confirm in Italian patients the previously reported associations of DRB1*01 and DRB1*16 with PSReA and ARF, respectively.

Objectives To describe the clinical presentation and course of a relatively large group of Italian adult patients screened for mutation of the homogentisate dioxygenase gene causing alkaptonuria (AKU) and ochronosis, and to review typical and atypical facets of this condition. Methods We reviewed the medical records of 9 patients affected by ochronotic arthropathy who were observed in our institutions between 1979 and 2001. All patients were diagnosed as having AKU through a rapid urine test with alkali. Mutation screening was performed by single-strand conformation analysis of all homogentisate dioxygenase exons, followed by sequencing of altered conformers. Results Our 9 cases had similar clinical features and they reflected those described in the literature: a progressive degenerative arthropathy mainly affecting axial and weight-bearing joints associated with extraarticular manifestation. Musculoskeletal symptoms began in most of our patients around the age of 30 years with back pain and stiffness: involvement of the large peripheral joints usually occurred several years after spinal changes. Ochronotic peripheral arthropathy generally was degenerative, but joint inflammation was observed in some cases; this could be attributed to an inflammatory reaction of the ochronotic shard in the synovial membrane. Conclusions Ochronosis is a model of arthropathy with known etiologic factors. Over time, AKU, the genetically determined metabolic defect, leads to the accumulation of pigment and the development of this crippling condition. Most of the clinical findings may be explained by inhibition of collagen crosslinks, but some require additional interpretation. For example, inflammatory features of the ochronotic joint only occur in a minority of cases, and may be attributable to ochronotic shards. Further studies are needed to establish the genotype-phenotype correlation to identify mutations that are predictive of severe disease. For this purpose, the Italian Study Group on Alkaptonuria (www.dfc.unifi.it/aku) is enrolling affected patients in an on-line database to characterize the molecular defects and their relationship to clinical data.

Objective. – To investigate the association between the HLA-DRB1 alleles sharing the epitope (Q/R)(K/R)RAA and rheumatoid arthritis (RA) in a large sample of Italian patients ( N = 264) recruited from a single centre over the last 5 years. Methods. - Patients’ classification according to the ACR criteria. DNA typing of HLA-DRB1 alleles by conventional polymerase chain reaction sequence specific oligonucleotide probing techniques. Results. – Low-resolution DRB1 “generic” typing showed a significantly higher frequency of DR4+ RA patients as compared to normal controls. Both DR1 and DR10 specificities were over-represented in our patients, but neither reached the statistically significant P level of 0.05 after Bonferroni’s correction. However, direct search of Q(K/R)RAA epitopes, which are present in most DR4+ and DRl+ samples, demonstrated that these motifs were found at increased frequencies in RA patients. Stratification according to gender did not show differences in the proportion of disease-associated HLA alleles. Conclusions. – Our study confirms the association of HLA-DR4, and -DR1 alleles, and more generally speaking of the shared epitopes Q(K/R)RAA, with disease susceptibility in Italian patients.

Development of six large nodules of solid tissue after bilateral human fetal striatal transplantation in four Huntington's disease patients has raised concern about the safety of this experimental therapy in our setting. We investigated by serial MRI-based volumetric analysis the growth behaviour of such grafts. After 33-73 months from transplantation the size of five grafts was stable and one graft showed a mild decrease in size. Signs neither of intracranial hypertension nor of adjuctive focal neurological deficit have ever been observed. This supports long-term safety of the grafting procedure at our Institution.

EDITOR: We read with interest the paper by Wostyn and colleagues2016 on ‘Fast circulation of cerebrospinal fluid: an alternative perspective on the protective role of high intracranial pressure in ...

Background. Head and neck non-Hodgkin's lymphomas in HIV positive patients are highly related with Epstein-Barr virus (EBV) infection. In general, viral agents can alter p53 protein levels by enhancing degradation of cellular p53 or by increasing its half-life by viral protein-p53 interaction. Moreover, it has been reported that modifications of p53 gene can modulate tumor cells' response to radio- and chemotherapy. Methods. To assess a possible role of EBV infection, p53 protein deregulation, and p53 gene alterations in exons 5 to 8, we have studied six cases of HIV-related primary oral large B-cell lymphoma. We used in situ hybridization (ISH) for EBV-DNA and EBV-encoded nuclear RNA-1 (EBER-1), immunohistochemistry (IHC) for EBV latent membrane protein -1 (LMP-1) and p53 proteins expression, and single strand conformational polymorphism (SSCP) analysis to screen p53 gene mutations in exons 5 to 8. Results. The EBV-DNA was present in all specimens, according to conventional DNA-ISH. No evidence for EBER-1 was found by ISH. The presence of EBV-DNA was correlated with the LMP-1 expression in all but one case. Moreover, p53 protein expression was negative in three cases and strongly positive in the others. However, mutational analysis of p53 gene in exons 5-8 showed no alteration. Conclusions. Our data may suggest that both EBV infection and LMP-1 expression may cause p53 loss of function even in the absence of p53 gene mutations, as assessed by SSCP. We speculate that the presence of EBV-infection and p53 protein deregulation may be responsible for radio- and chemotherapy resistance, by influencing apoptosis of cancer cells.

An in vitro system has been set up to study the possible genetic effects of diagnostic ultrasound (US) on the developing fetus. Amniotic cells were cultured by the in situ technique. Well established clones were exposed to US for various lengths of time using a linear array transducer within a sound transparent apparatus. Cells were then grown in the presence of 5-bromo-2'-deoxyuridine and processed for scoring the number of sister chromatid exchanges (SCE) as the cytogenetic endpoint. There was no linear relationship between the SCE frequency and the duration of US exposure. Variance analysis showed that only interindividual variability was a significant component of total variation. Neither the main effect of treatment nor the interaction effect were statistically significant. The data suggest that US delivered from a diagnostic unit to actively growing cultured fetal cells in a system closely mimicking the conditions of US exposure during amniocentesis does not induce SCE.

Rebuilding brain structure and neural circuitries by transplantation of fetal tissue is a strategy to repair the damaged nervous system and is currently being investigated using striatal primordium in Huntington's disease (HD) patients. Four HD patients underwent bilateral transplantation with human fetal striatal tissues (9-12 week gestation). Small blocks of whole ganglionic eminencies were processed to obtain cell suspension and then stereotactically grafted in the caudate head and in the putamen. Follow-up period ranged between 18 and 34 months (mean, 24.7 months). Surgery was uneventful. Starting from the fourth month after grafting, neo-generation of metabolically active tissue with striatal-like MRI features was observed in 6 out of 8 grafts. The increase in D2 receptor binding suggested striatal differentiation of the neo-generated tissue in 3 patients. New tissue, connecting the developing grafts with the frontal cortex and, in one case, with the ventral striatum, was also observed. The new tissue growth halted after the ninth month post transplantation. All patients showed stabilization or improvement in some neurological indices. No clinical and imaging signs, suggestive of graft uncontrolled growth, were seen. This study provides the first evidence in humans that neuroblasts of a striatal primordium can develop and move into the brain after neurotransplantation. Primordium development resulted in the building of a new structure with the same imaging features as the corresponding mature structure, combined with short- and long-distance targeted migration of neuroblasts. The results of this study support both the reconstructive potential of fetal tissue and the remarkably retained plasticity of adult brain. Further studies are necessary to assess the clinical efficacy of the human fetal striatal transplantation.

We report on a 2-year-old male child with both nemaline myopathy and hypertrophic cardiomyopathy (HCM). Sequencing of the ACTA1 gene showed a "de novo" missense heterozygous mutation a>g in exon 7 (Lys336Glu). Two-dimensional electrophoresis showed 28% mutant actin present in his muscle biopsy. Actin was isolated from the muscle biopsy and examined by in vitro motility assay. The sliding speed was 13+/-3% less than normal and the affinity of actin for the Z-line protein alpha-actinin was reduced 10 fold. This is the first report on a hypertrophic cardiomyopathy associated with nemaline myopathy and an ACTA1 mutation.