Design and testing of a virtual environment to train stroke patients with unilateral spatial neglect to cross a street safely

Virtual reality (VR) entails the use of advanced technologies, including computers and various multimedia peripherals, to produce a simulated (that is, virtual) environment that users perceive as comparable to real world objects and events. In recent years, virtual reality technologies have begun to be used as an assessment and treatment tool in occupational therapy, in part because of the ability to create environments that provide patients with opportunities to engage in meaningful, purposeful tasks that are related to real-life interests and activities. The objective of this study was to determine the suitability and feasibility of using a PC-based, non-immersive, VR system (that is, a system in which the user has a reduced sense of actual presence in and control over the simulated environment) for training individuals with unilateral spatial neglect to cross streets in a safe and vigilant manner. A virtual environment, consisting of a typical city street, was programmed using Superscape's 3D-Webmaster, a 3D web-authoring tool. Twelve subjects, aged 55 to 75 years, participated in the initial feasibility study and, to date, a further eight subjects have participated in the intervention study. Six of the initial subjects and all eight of the intervention subjects had sustained a right hemispheric stroke at least 6 weeks prior to the study. The remaining subjects were healthy age-matched adults who were independently mobile and had no difficulty in crossing streets. The results show that this virtual environment was suitable in both its cognitive and motor demands for the targeted population and indicate that the virtual reality training is likely to prove beneficial to people who have difficulty with crossing streets. The generalizability of these results, and recommendations regarding the use of virtual reality as an occupational therapy intervention, must be substantiated by further studies using a range of VR platforms with people with different cognitive and motor disabilities.     

Complete Freund's adjuvant immunization prolongs survival in experimental prion disease in mice

We recently reported that immunization of mice with certain self-prion protein peptides induced specific T-cell and B-cell immune responses; importantly, this immunization was associated with a decrease in the number of protease-resistant PrP(Sc) particles recoverable in a transplanted, scrapie-infected syngeneic tumor. The present study was carried out to determine whether immunization with the immunogenic PrP peptides might influence the natural history of experimental scrapie in mice. We immunized C57BL/6 mice with self-prion peptides in complete Freund's adjuvant (CFA) or with CFA alone as a control and then infected the mice with mouse-adapted scrapie by injection either intraperitoneally or intracerebrally. We report here that immunization with CFA, irrespective of whether prion peptides were present in the inoculum, resulted in marked prolongation of survival of the mice, whether the challenge was intracerebral or intraperitoneal. Mice in the immunized and control groups that died contained equivalent amounts of PrP(Sc). Thus, CFA immunization has a therapeutic effect in experimental scrapie in mice, possibly by reducing the rate of PrP(Sc) accumulation in the brain.     

Comparison between three memory tests: cued recall,priming and saving closed-head injured patients and controls

Twenty closed-head injured (CHI) patients and 20 matched controls were tested with three different memory tasks: cued recall, word stem completion (WSC), and saving. Saving is defined as the advantage of relearning of a list of word pairs, in terms of the number of learning trials to the criterion of one errorless trial, over the original learning of the same list. It was predicted that CHI patients' explicit memory (i.e., cued recall), but not implicit memory (i.e., WSC), would be impaired. The question addressed in this study is whether the memory of CHI patients will be impaired when memory is tested with a saving task, with 2 weeks delay between original learning and relearning. The findings confirm impairment of CHI patients in explicit memory, although the learning rate is preserved. Implicit memory is preserved in CHI patients only when based on reactivation of preexisting knowledge, but not when dependent on forming new associations. Finally, the CHI patients, even after 2 weeks delay, demonstrated a significant saving in relearning old, as compared to new, pairs of words. The clinical contribution of this study is the delineation of those aspects of memory that are impaired and those that are preserved in CHI patients. The theoretical implications of the finding that memory could be preserved in CHI patients when measured by saving, are discussed in terms of the relationship between implicit memory and saving.     

Perceived benefit after participating in positive or negative/neutral heart failure trials: the patients' perspective

BACKGROUND: Clinical trials, the gold standard for the evaluation of new therapeutic strategies, may prove a drug to be beneficial, harmful or neutral according to its effect on the end-point(s) under study. AIMS: To study the reaction and perspective of the patients participating in a clinical heart failure trial, particularly in relation to whether the trial subsequently proved to be positive, negative or neutral. METHODS: Anonymous self-completed questionnaire was sent to 78 and returned by 70 consecutive patients 1--6 months after participating in six clinical heart failure trials. The trial was neutral or negative regarding the primary end-point in four (47 patients) of the six studies (MACH-1 trial of mibefradil, REACH trial of bosentan, CASCO trial of calcium sensitizer, ecadotril trial of neutral endopeptidase inhibitor) and positive in two (23 patients) (ICARUS Israel carvedilol study, exercise study of candesartan cilexetil). RESULTS: Most patients reported subjective global clinical benefit (78% for positive, 74% for negative or neutral trial, NS) after participating in a clinical trial. After adjustment for age, sex, level of education, previous research, perceived comprehension, and treatment allocation (active drug/placebo) in a stepwise regression model, perceived global improvement was greater in older patients (P=0.02), after participation in a positive trial (P=0.05) and in females (P=0.07). The major reason given by the patient for perceived clinical improvement was better follow-up, some believed it was due to change in medication, particularly those who had participated in a positive trial. CONCLUSIONS: More than 70% of patients participating in clinical trials of new drugs for heart failure reported perceived global improvement. Clinical improvement was greater in, but not limited to, patients who participated in positive trials. These salutary findings support the continued recruitment of patients to clinical heart failure trials.     

Lateral Paracapsular GABAergic Synapses in the Basolateral Amygdala Contribute to the Anxiolytic Effects of ��3 Adrenoceptor Activation

Norepinephrine (NE) is known to play an integral role in the neurobiological response to stress. Exposure to stressful stimuli increases NE levels in brain regions that regulate stress and anxiety, like the basolateral amygdala (BLA). NE is thought to increase excitability in these areas through α- and β-adrenoceptors (ARs), leading to increased anxiety. Surprisingly, recent studies have shown that systemic β3-AR agonist administration decreases anxiety-like behaviors, suggesting that β3-ARs may inhibit excitability in anxiety-related brain regions. Therefore, in this study we integrated electrophysiological and behavioral approaches to test the hypothesis that the anxiolytic effects of β3-AR agonists may be mediated by an increase in BLA GABAergic inhibition. We examined the effect of a selective β3-AR agonist, BRL37344 (BRL), on GABAergic synapses arising from local circuit interneurons and inhibitory synapses originating from a recently described population of cells called lateral paracapsular (LPCS) interneurons. Surprisingly, BRL selectively enhanced LPCS-evoked inhibitory postsynaptic currents (eIPSCs) with no effect on local GABAergic inhibition. BRL also had no effect on glutamatergic synaptic excitation within the BLA. BRL potentiation of LPCS eIPSCs was blocked by the selective β3-AR antagonist, SR59230A, or by intracellular dialysis of Rp-CAMPS (cAMP-dependent protein kinase inhibitor), and this enhancement was not associated with any changes in spontaneous IPSCs or LPCS paired-pulse ratio. BRL also increased the amplitude of unitary LPCS IPSCs (uIPSCs) with no effect on uIPSC failure rate. Finally, bilateral BLA microinjection of BRL reduced anxiety-like behaviors in an open-field assay and the elevated plus-maze. Collectively, these data suggest that β3-AR activation selectively enhances LPCS, but not local, BLA GABAergic synapses, and that increases in LPCS-mediated inhibition may contribute to the anxiolytic profile of β3-AR agonists.     

Peripheral corneal edema following excision of a corneal keloid

A 49-year-old man presented with the rare finding of corneal keloid after corneal penetrating injury. The keloid was totally excised by lamellar keratectomy and was disconnected from a stromal scar, probably the perforation site. Symptomatic peripheral corneal edema developed postoperatively, extending 180°. The keloid had an effect similar to an avascular pannus in chronic bullous keratopathy. As long as the keloid was under the epithelium, the patient remained asymptomatic.     

Factors influencing diagnosis delay in children with Tourette syndrome.

BACKGROUND: Tourette syndrome (TS) is a chronic disorder characterized by motor and vocal tics. Previous studies reported a substantial lag period between disease onset and diagnosis ranging from 3 to 11.9 years. AIMS: To determine the lag period and factors associated with diagnosis delay of TS. METHODS: All files of 185 children with TS attending one neuropediatric unit in Jerusalem were reviewed. Lag time between disease onset, according to DSM criteria, and diagnosis was determined and the contributions of the disease course, comorbidities and epidemiological factors were assessed. RESULTS: A relatively short lag to diagnosis following the onset of diagnosable TS was documented (mean 13.2+/-15.9 months, median 6 months). A relatively longer gap was associated with older age at TS onset (r=0.161, p<0.05) and vocal tics as the first manifestation rather than motor or combined motor and vocal tics (mean=20.3+16.3 months vs 11.9+16.5 and 12.6+15.2, respectively, p<0.05). A relatively shorter gap was associated with tic severity (r=0.13, p<0.05) and presence of comorbid obsessive-compulsive disorder (OCD) (9.5+14.7 months vs. 14.1+16 without OCD, p<0.05). CONCLUSIONS: Lag time to diagnosis is relatively short in our population. Factors associated with a shorter lag (early age of TS onset, motor tics as the first manifestation, greater tics severity and the presence of OCD) may be perceived as disruptive, prompting patient and families to seek medical care. Conversely, vocal tics as the first manifestation, associated with a longer lag, may be misdiagnosed as features of common pediatric conditions, thus delaying diagnosis.     

Three-dimensional Nuclear Telomere Architecture Is Associated with Differential Time to Progression and Overall Survival in Glioblastoma Patients

The absence of biological markers allowing for the assessment of the evolution and prognosis of glioblastoma (GBM) is a major impediment to the clinical management of GBM patients. The observed variability in patients'' treatment responses and in outcomes implies biological heterogeneity and the existence of unidentified patient categories. Here, we define for the first time three GBM patient categories with distinct and clinically predictive three-dimensional nuclear-telomeric architecture defined by telomere number, size, and frequency of telomeric aggregates. GBM patient samples were examined by three-dimensional fluorescent in situ hybridization of telomeres using two independent three-dimensional telomere-measurement tools (TeloView program [P₁] and SpotScan system [P₂]). These measurements identified three patients categories (categories 1–3), displaying significant differences in telomere numbers/nucleus (P₁ = .0275; P₂ ≤ .0001), telomere length (P₁ and P₂ = .0275), and number of telomeric aggregates (P₁ = .0464; P₂ ≤ .0001). These categories corresponded to patients with long-term, intermediate, and short-term survival, respectively (P = .0393). The time to progression analyses showed significant differences between the three categories (P = .0167). There was a correlation between time to progression, median survival, and nuclear telomere architecture. Our study suggests a link between patient outcome and three-dimensional nuclear-telomere organization and highlights the potential clinical power of telomere signatures as a new prognostic, predictive, and potentially pharmacodynamic biomarker in GBM. Furthermore, novel automated three-dimensional high-throughput scanning as developed here permits to obtain data from 300 nuclei in 20 minutes. This method is applicable to any cell type and scanning application.     

Cor pulmonale as a complication of methylmalonic acidemia and homocystinuria (Cb1-C type)

We report an infant with a bronchiolitis-like illness and rapid deterioration who developed a cor pulmonale-like picture with a dilated right ventricle. Urinary organic acid assays established a probable diagnosis of Cbl-C-type methylmalonic aciduria, later confirmed by complementation studies. Despite medical intervention and cyanocobalamin treatment the patient died on his tenth hospital day. Postmortem examination showed the presence of thromboemboli in the pulmonary circulation. We hypothesize that acute cor pulmonale developed in this infant secondary to thromboembolism of his pulmonary circulation. A review of the literature shows that thromboembolism may be a part of this disease process.