The use of wearable/portable digital sensors in Huntington’s disease: a systematic review

In chronic neurological conditions, wearable/portable devices have potential as innovative tools to detect subtle early disease manifestations and disease fluctuations for the purpose of clinical diagnosis, care and therapeutic development. Huntington’s disease (HD) has a unique combination of motor and non-motor features which, combined with recent and anticipated therapeutic progress, gives great potential for such devices to prove useful. The present work aims to provide a comprehensive account of the use of wearable/portable devices in HD and of what they have contributed so far. We conducted a systematic review searching MEDLINE, Embase, and IEEE Xplore. Thirty references were identified. Our results revealed large variability in the types of sensors used, study design, and the measured outcomes. Digital technologies show considerable promise for therapeutic research and clinical management of HD. However, more studies with standardized devices and harmonized protocols are needed to optimize the potential applicability of wearable/portable devices in HD

Conflict of Norms in the Brazilian Bankruptcy Law

[extract] In 2005, Brazil implemented a new Bankruptcy Law (Law No. 11.101, dated February 9, 2005), modeled largely after the Title 11 of the United States Code, also known as the United States Bankruptcy Code.The current Brazilian system provides three alternatives for insolvent legal entities: (i) judicial reorganization, a court-supervised reorganization proceeding; (ii) bankruptcy, a court-supervised liquidation proceeding; and (iii) extrajudicial reorganization, an out-of-court reorganization proceeding.The possibility of recovery of an activity momentarily in crisis, with the possibility of implementing a corporate restructuring plan, renegotiation of liabilities with creditors and business continuity was undoubtedly the innovative point of the Law.Unfortunately, the Brazilian Bankruptcy Law embodies within itself serious contradictions – legal antinomies – which prevent the fulfillment of the objective of the Law. One of the most serious antinomies is the conflict between Article 47 and Article 49, Paragraph 3. This antinomy has the potential to impair the judicial recovery of the economically viable company. For this reason, this antinomy must be widely discussed, as well as the cause and the nature of this conflict of norms

The Modified Five-Point Test (MFPT): normative data for a sample of Italian elderly

INTRODUCTION: Non-verbal figural fluency is related to executive functions and specifically to the ability to create as many unique designs as possible, while minimizing their repetitions. An Italian version of figural fluency is the Modified Five-Point Test (MFPT), which is highly employed in the clinical practice of neuropsychologists. To date, reference data of Italian population are limited to a sample aged between 16 and 60 years old. Thus, the current study aims to provide normative data of the MFPT in the context of a population-based setting, conducted in Southern Italy. MATERIAL AND METHODS: We collected N = 340 Italian healthy subjects, aged over 65 years old (range: 65-91), pooled across subgroups for age, sex, and education. Multiple regression analyses were performed to estimate the effect of age, education, and sex on the participant's performance. Equivalent scores and cut-off scores were also defined for the number of unique designs (UDs) and the number of strategies (CSs). RESULTS: Multiple regression analyses revealed that UDs increase with decreasing age and increasing educational level. CSs are influenced by higher educational levels but neither by age nor sex. A significant inverse correlation between the UDs and percentage of errors occurred, suggesting that a higher number of UDs are associated with a fewer number of errors and higher CSs employed. CONCLUSION: The MFPT provides a measure of cognitive functioning in terms of the ability to initiate and realize designs, affording useful hints for clinical settings. The MFPT may represent a handy and useful tool with a specific focus in the differentiation of healthy versus pathological aging

Cortical thinning and clinical heterogeneity in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) has heterogeneous clinical features that could be translated into specific patterns of brain atrophy. In the current study we have evaluated the relationship between different clinical expressions of classical ALS and measurements of brain cortical thickness. Cortical thickness analysis was conducted from 3D-MRI using FreeSurfer software in 29 ALS patients and 20 healthy controls. We explored three clinical traits of the disease, subdividing the patients into two groups for each of them: the bulbar or spinal onset, the higher or lower upper motor neuron burden, the faster or slower disease progression. We used both a whole brain vertex-wise analysis and a ROI analysis on primary motor areas. ALS patients showed cortical thinning in bilateral precentral gyrus, bilateral middle frontal gyrus, right superior temporal gyrus and right occipital cortex. ALS patients with higher upper motor neuron burden showed a significant cortical thinning in the right precentral gyrus and in other frontal extra-motor areas, compared to healthy controls. ALS patients with spinal onset showed a significant cortical thinning in the right precentral gyrus and paracentral lobule, compared to healthy controls. ALS patients with faster progressive disease showed a significant cortical thinning in widespread bilateral frontal and temporal areas, including the bilateral precentral gyrus, compared to healthy controls. Focusing on the primary motor areas, the ROI analysis revealed that the mean cortical thickness values were significantly reduced in ALS patients with higher upper motor neuron burden, spinal onset and faster disease progression related to healthy controls. In conclusion, the thickness of primary motor cortex could be a useful surrogate marker of upper motor neuron involvement in ALS; also our results suggest that cortical thinning in motor and non motor areas seem to reflect the clinical heterogeneity of the disease. © 2013 Mezzapesa et al

Brain-derived neurotrophic factor in cerebrospinal fluid and plasma is not a biomarker for Huntington’s disease

Brain-derived neurotrophic factor (BDNF) is implicated in the survival of striatal neurons. BDNF function is reduced in Huntington’s disease (HD), possibly because mutant huntingtin impairs its cortico-striatal transport, contributing to striatal neurodegeneration. The BDNF trophic pathway is a therapeutic target, and blood BDNF has been suggested as a potential biomarker for HD, but BDNF has not been quantified in cerebrospinal fluid (CSF) in HD. We quantified BDNF in CSF and plasma in the HD-CSF cohort (20 pre-manifest and 40 manifest HD mutation carriers and 20 age and gender-matched controls) using conventional ELISAs and an ultra-sensitive immunoassay. BDNF concentration was below the limit of detection of the conventional ELISAs, raising doubt about previous CSF reports in neurodegeneration. Using the ultra-sensitive method, BDNF concentration was quantifiable in all samples but did not differ between controls and HD mutation carriers in CSF or plasma, was not associated with clinical scores or MRI brain volumetric measures, and had poor ability to discriminate controls from HD mutation carriers, and premanifest from manifest HD. We conclude that BDNF in CSF and plasma is unlikely to be a biomarker of HD progression and urge caution in interpreting studies where conventional ELISA was used to quantify CSF BDNF

Episodic memory and learning rates in amyotrophic lateral sclerosis without dementia

In amyotrophic lateral sclerosis (ALS), memory deficits may be primary or secondary to executive dysfunction. We assessed episodic memory and executive function of nondemented ALS patients, comparing episodic memory profiles and learning rates of ALS patients with those of mild cognitive impairment (MCI) subjects and cognitively healthy controls (HC). In a multidisciplinary tertiary centre for motor neuron disease, 72 nondemented ALS patients, 57 amnestic MCI (aMCI), 89 single non amnestic MCI with compromised executive functions (dysexecutive MCI), and 190 HC were enrolled. They were screened using the Frontal Assessment Battery and Mini Mental State Examination. Episodic memory performances and learning rates were tested using the Rey Auditory Verbal Learning Test (RAVLT). Episodic memory dysfunction (immediate recall) was found in 14 ALS patients (19.4%). The ALS group had lower performance than HC on immediate recall, without differences in learning rate, and better performance than aMCI subjects on all RAVLT measures. Compared to dysexecutive MCI subjects, ALS patients had only better verbal learning abilities. ALS patients with executive dysfunction had a lower score on immediate and delayed recalls, verbal learning, and primacy effect than ALS patients without executive dysfunction. The immediate recall among couples of diagnostic groups differed in a statistically significant way except for the ALS/dysexecutive MCI groups. In ALS patients, episodic memory performances and learning rates appeared to be better than in aMCI subjects and similar to those with dysexecutive MCI, suggesting also a secondary functional damage due to executive impairment

Age-Related Central Auditory Processing Disorder, MCI, and Dementia in an Older Population of Southern Italy

Objective: We explored the associations of age-related central auditory processing disorder (CAPD) with mild cognitive impairment (MCI) and dementia in an older population-based cohort in Apulia, Southern Italy (GreatAGE Study). / Study Design: Cross-sectional data from a population-based study. / Setting: Castellana Grotte, Bari, Italy. / Subjects and Methods: Between 2013 and 2018, MCI, dementia, age-related CAPD (no disabling hearing loss and 65 years. / Results: The prevalences of age-related CAPD, MCI, and dementia were 14.15%, 15.79%, and 3.58%, respectively. Among the subjects with MCI and dementia, 19.61% and 42.37% had age-related CAPD. In the regressive models, age-related CAPD was associated with MCI (odds ratio, 1.50; 95% CI, 1.01-2.21) and dementia (odds ratio, 2.23; 95% CI, 1.12-4.42). Global cognition scores were positively associated with increasing SSI-ICM scores in linear models. All models were adjusted for demographics and metabolic serum biomarkers. / Conclusion: The tight association of age-related CAPD with MCI and dementia suggests the involvement of central auditory pathways in neurodegeneration, but it is not clear which is the real direction of this association. However, CAPD is a possible diagnostic marker of cognitive dysfunction in older patients

Associations between the vaginal microbiome and Candida colonization in women of reproductive age

Background The composition of bacteria within the vaginal microbiome has garnered a lot of recent attention and has been associated with reproductive health and disease. Despite the common occurrence of yeast (primarily Candida) within the vaginal microbiome, there is still an incomplete picture of relationships between yeast and bacteria (especially lactobacilli), as well as how such associations are governed. Such relationships could be important to a more holistic understanding of the vaginal microbiome and its connection to reproductive health. Objective To perform molecular characterization of clinical specimens to define associations between vaginal bacteria (especially Lactobacillus species) and Candida colonization. In vitro studies were conducted to test the two most common dominant Lactobacillus species (Lactobacillus crispatus and Lactobacillus iners) in their ability to inhibit Candida growth and to examine the basis for such inhibition. Study Design A nested cross-sectional study of reproductive age women from the Contraceptive CHOICE Project was conducted. Vaginal swabs from 299 women were selected to balance race and BV status, resulting in similar representation of black and white women in each of the three Nugent score categories [normal (0-3), intermediate (4-6), and bacterial vaginosis (7-10)]. Sequencing of the 16S ribosomal gene (V4 region) was used to determine the dominant Lactobacillus species present (primarily L. iners and L. crispatus), defined as >50% of the community. Subjects without dominance by a single Lactobacillus species were classified as Diverse. A Candida-specific qPCR targeting the internally transcribed spacer 1 (ITS1) was validated using vaginal samples collected from a second cohort of women and used to assess Candida colonization. 255 nonpregnant women with sufficient bacterial biomass for analysis were included in the final analysis. Generalized linear models were employed to evaluate associations between Lactobacillus dominance, sociodemographic and risk characteristics and vaginal Candida colonization. In separate in vitro studies, the potential of cell-free supernatants from L. crispatus and L. iners cultures to inhibit Candida growth was evaluated. Results Forty-two women (16%) were vaginally colonized with Candida. Microbiomes characterized as Diverse (38%), L. iners-dominant (39%), and L. crispatus-dominant (20%) were the most common. The microbiome, race and Candida colonization co-varied with a higher prevalence of Candida among black women and L. iners-dominant communities compared to white women and L. crispatus-dominant communities. L. iners-dominant communities were more likely to harbor Candida than L. crispatus-dominant communities (OR = 2.85, 95% CI: 1.03 to 7.21; Fisher’s Exact, p = 0.048). In vitro, L. crispatus produced greater concentrations of lactic acid and exhibited significantly more pH-dependent growth inhibition of C. albicans, suggesting a potential mechanism for the clinical observations. Conclusion In nonpregnant women, L. iners-dominant communities were significantly more likely to harbor Candida than L. crispatus-dominant communities, suggesting that Lactobacillus species have different relationships with Candida. In vitro experiments indicate that L. crispatus may impede Candida colonization more effectively than L. iners through a greater production of lactic acid

Combinations of QT-prolonging drugs: towards disentangling pharmacokinetic and pharmaco-dynamic effects in their potentially additive nature.

Background: Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug–drug interactions. Methods: In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses. Results: Drugs attributing a ‘known’ risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for ‘known’ risk drugs + 0.93 ms (–8.88;10.75)]. Estimates for the ‘conditional’ risk class increased upon refinement with relative drug exposure and coadministration of a ‘known’ risk drug as a further risk factor. Conclusions: These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs