Congenital afibrinogenaemia caused by uniparental isodisomy of chromosome 4 containing a novel 15-kb deletion involving fibrinogen Aalpha-chain gene

Among rare inherited deficiencies of coagulation factors, congenital afibrinogenaemia is characterised by the lack of fibrinogen in plasma. In the last few years, several genetic defects underlying afibrinogenaemia (mostly point mutations) have been described in the fibrinogen gene cluster. In this study, the molecular basis responsible for afibrinogenaemia in a Thai proband was defined. Point mutation screening was accomplished by directly sequencing the three fibrinogen genes. The impossibility to amplify fibrinogen Aalpha-chain gene (FGA) exons 5 and 6 suggested the presence of a homozygous deletion. A specific long-range PCR assay enabled the identification of a novel 15-kb deletion, representing the largest afibrinogenaemia-causing deletion described so far. Direct sequencing of the deletion junction allowed mapping of the breakpoints in FGA intron 4 and in the intergenic region between Aalpha- and Bbeta-chain genes. Since the mutation was inherited only from the mother and nonpaternity was ruled out, a maternal uniparental disomy (UPD) was hypothesised. UPD test, carried out with markers covering the whole chromosome 4, revealed that maternal isodisomy was responsible for homozygosity of the 15-kb deletion in the proband. The apparently normal phenotype of the proband, except for afibrinogenaemia, suggests that UPD for chromosome 4 is clinically silent. This represents the first case of a documented complete isodisomy of chromosome 4 causing the phenotypic expression of a recessive disorder. In silico analyses of the regions surrounding the breakpoints suggested that the 15-kb deletion might have originated from an inappropriate repair of a double-strand break by the nonhomologous end joining mechanism.     

Comparison of two abdominal training devices with an abdominal crunch using strength and EMG measurements

BACKGROUND: The purpose of this study was to compare the training effects of the Ab-Flex (F), Ab-Roller (R) and standard crunch (C) on EMG production, isometric maximum voluntary contraction (MVC), and isokinetic average peak torque at 30 degrees/sec (ISO) of the abdominal muscles. It was hypothesized that the training devices would have similar value in a strength training program. METHODS: Experimental design: this was a prospective study involving 18 training sessions of progressively increasing repetitions. Setting: Neuromuscular Research Laboratory, University of Pittsburgh. Subjects: thirty-two subjects volunteered for this study, but only 26 completed the training. Each subject participated in recreational activity, but had not performed any abdominal training prior to starting this study. Each subject was randomly assigned to either the control group or one of the treatment groups. Interventions: there were three interventions: two training devices (Ab-Flex and Ab-Roller) and the standard crunch, considered a control group. Measures: the pretest consisted of skin fold measurements (%), EMG activity (V) during the three interventions, and peak torque (Nm) plus EMG during the MVC and ISO tasks. The 18 training sessions over three weeks consisted of three sets of exercise with increasing repetitions from 10 to 20, by 2, every three sessions. The difference in pretest/posttest scores were compared using a One-way ANOVA on the mean differences (Mdiff) for each of: MVC, ISO (peak torque), and EMG for upper rectus (UR), lower rectus (LR), internal oblique (IO), and external oblique (EO). A T-Test was used to detect significance for the body fat measures. RESULTS: Mean differences (Mdiff) were normally distributed about zero for both MVC and ISO (MVC = -0.55, ISO = 4.57). The analysis by group showed no difference (p = 0.596) on the reported means (Nm) -3.16 (C), 5.84 (F) and -4.83 (R). The change associated to the treatment during MVC was only 4% (eta = 0.04). For the ISO the Mdiff (Nm) were 1.39 (C), 13.66 (F) and -2.06 (R) which were not significant (p = 0.127). The Ab-Flex was the only group to have a 95% confidence interval above zero, increasing by an average of 16.5%. There were no significant differences for the EMG activity for Mdiff or between group scores. CONCLUSIONS: No significant differences were found with this study. These results would suggest that using these devices does not add significantly to overall abdominal strength development, or reduction of body fat. A suggestion could be made that certain devices influence muscles differently.     

The effects of cochlear implantation on quality of life in the elderly

The purpose of this study was to evaluate the benefits of unilateral cochlear implant (CI) in patients over 60 on speech perception and quality of life, comparing the results obtained with a control group of younger CI recipients. Twenty CI users (mean age 72 years), postlingually deafened, were included in this study. Audiological performance was evaluated using bisyllabic words and sentences recognition tests in a quiet and a noise environment. Moreover, we administered two questionnaires to evaluate the health status (SF-36), CI-related effects on daily activities and personal satisfaction (Questionnaire for self-evaluation of CI benefit with SADL scale modification). Performance measures of the geriatric population showed a significant benefit on speech recognition tests compared to pre-implantation condition, even if younger CI users scored significantly better in both bisyllabic words and sentences recognition test. All study patients reported being able to have a normal conversation with an acquaintance. No significant difference was found between the study and control group in physical and mental health status, conversation with an outsider, use of TV and phone. A significant difference (p < 0.05) was noticed, instead, between elderly and younger adult patients about the overall satisfaction derived from CI. Our findings confirm the indisputable utility of CI and provide evidence that elderly patients derive a substantial benefit from it on quality of life, as demonstrated by health status, success in the common activities of daily living and perceived satisfaction after this procedure.     

Congenital hypofibrinogenemia: characterization of two missense mutations affecting fibrinogen assembly and secretion

Congenital hypofibrinogenemia is a rare bleeding disorder characterized by abnormally low levels of fibrinogen in plasma, generally due to heterozygous mutations in one of the three fibrinogen genes (FGA, FGB, and FGG, coding for Aα, Bβ, and γ chain, respectively). Hypofibrinogenemic patients are usually asymptomatic, whereas individuals bearing similar mutations in the homozygous or compound heterozygous state develop a severe bleeding disorder: afibrinogenemia. The mutational spectrum of these quantitative fibrinogen disorders includes large deletions, point mutations causing premature termination codons, and missense mutations affecting fibrinogen assembly or secretion, distributed throughout the 50-kb fibrinogen gene cluster. In this study, we report the mutational screening of two unrelated hypofibrinogenemic patients leading to the identification of two missense mutations, one hitherto unknown (αCys45Phe), and one previously described (γAsn345Ser). The involvement of αCys45Phe and γAsn345Ser in the pathogenesis of hypofibrinogenemia was investigated by in-vitro expression experiments. Both mutations were demonstrated to cause a severe impairment of intracellular fibrinogen processing, either by affecting half-molecule dimerization (αCys45Phe) or by hampering hexamer secretion (γAsn345Ser).     

Delirium in COVID-19 patients: a multicentric observational study in Italy

Neurological Sciences - Although recent data show that SARS-CoV-2 infection seems to affect the central nervous system (CNS), little is known about the neuropsychiatric effects resulting from this...     

Purely subcortical tumors in eloquent areas: Awake surgery and cortical and subcortical electrical stimulation (CSES) ensure safe and effective surgery

Objective

To analyze the efficacy and safety of cortical and subcortical electrical stimulation CSES and awake surgery to approach purely subcortical tumors in highly functional locations, particularly in guiding the choice of the best transcortical path.

Patients and methods

Prospective analysis of the surgical, neurological, and radiological outcome of patients harboring supratentorial, subcortically located brain tumors or vascular malformations who are operated on through awake surgery and CSES. Functional magnetic resonance (fMRI; either sensory-motor or language, based on the location) was performed in order to confirm the proximity to functional cortical areas. Major white matter tracts were investigated by MRI diffusion tensor fiber tracking (DTI-ft). The Rankin modified score was chosen to express the pre and postoperative functional neurological status. Immediate postoperative MRI was used to evaluate the extent of resection.

Results

Seventeen patients were selected. The main distance of the tumors from the cortical surface was 18.2 mm (range 9–48 mm). Neuronavigation was used to show the most direct route to the tumor (transsulcal or transgyral), but CSES was fundamental to adapt the surgical corridor to the functional topography both cortically and subcortically. If the transgyral route was chosen, CSES helped to detect a non-eloquent area. When a transsulcal route was preferred, CSES documented the presence or absence of function in the deep sulcus. The transient postoperative morbidity was 76.4%, but at last follow-up (range 4–20 months), all the patients regained preoperative status and 2 improved. Postoperative MRI demonstrated complete resection in all cases.

Conclusions

Approaching purely subcortical tumors requires microsurgical skills, but in eloquent areas, functional topography monitoring is mandatory to allow safe surgery. CSES in an awake patient is a method that produces very good results in terms of resection and neurological outcome.     

Analysis of Iranian patients allowed the identification of the first truncating mutation in the fibrinogen Bbeta-chain gene causing afibrinogenemia

BACKGROUND AND OBJECTIVES: Congenital afibrinogenemia is a rare coagulation disorder whose molecular basis is still poorly characterized. Most mutations have been identified in the fibrinogen Aalpha- and gamma-chain genes, whereas only two missense mutations have been reported in the Bbeta-chain gene. The aim of this work was to widen knowledge about the mutational spectrum of this disease by analyzing the molecular bases of congenital afibrinogenemia in three unrelated Iranian patients. DESIGN AND METHODS: All patients showed unmeasurable levels of clottable fibrinogen in plasma. Mutational screening was performed by sequencing the whole coding region, including exon-intron boundaries and part of the promoter region of the three fibrinogen genes. RESULTS: Sequencing in one patient revealed the presence of a novel nonsense mutation (3282C-->T) in exon 2 of the fibrinogen Bbeta-chain gene, causing a severe truncation of the corresponding polypeptide (R17X). In the remaining probands, two already known small deletions (4209delA and 4220delT), both located in exon 5 of the fibrinogen Aalpha-chain gene, were identified, and their effect at the protein level explored by computer-assisted analysis. INTERPRETATION AND CONCLUSIONS: The identification of the first truncating mutation in the fibrinogen Bbeta-chain gene confirms the involvement of all three fibrinogen genes in the pathogenesis of congenital afibrinogenemia and widens the mutational spectrum of the disease. This knowledge is clinically essential in order to carry out prenatal diagnosis in families at risk.     

The link between genetic variation and variability in vaccine responses: Systematic review and meta-analyses

Although immune response to vaccines can be influenced by several parameters, human genetic variations are thought to strongly influence the variability in vaccine responsiveness. Systematic reviews and meta-analyses are needed to clarify the genetic contribution to this variability, which may affect the efficacy of existing vaccines. We performed a systematic literature search to identify all studies describing the associations of allelic variants or single nucleotide polymorphisms in immune response genes with vaccine responses until July 2013. The studies fulfilling inclusion criteria were meta-analyzed.