Lactose intolerance (LI) is characterized by diarrhea, abdominal pain, or bloating occurring after lactose consumption in patients with lactose malabsorption. The National Institute of Health (NIH) ...proposed a double-blind placebo testing to identify LI individuals correctly. However, until now, no study used this approach in a real-life setting. We aimed to assess double-blind placebo challenge accuracy in diagnosing LI in patients with self-reported symptoms of LI. 148 patients with self-reported LI were consecutively enrolled and blindly underwent hydrogen breath test (HBT) after 25 g lactose or 1 g glucose (placebo) load. One week later, the subjects were challenged with the alternative substrate. Each subject completed a validated questionnaire, including five symptoms (diarrhea, abdominal pain, vomiting, bowel sounds, and bloating) scored on a 10-cm visual analog scale. Home questionnaire (HQ) referred to symptoms associated with the consumption of dairy products at home, while lactose questionnaire (LQ) and placebo questionnaire (PQ) referred to symptoms perceived throughout the 4-h after the administration of the substrates, respectively. After lactose load, HBT was positive in 81 patients (55%), of whom 60 (74%) reported relevant symptoms at LQ (lactose malabsorbers, LM). After placebo challenge, 45 out of 60 with a positive lactose challenge did not complain of symptoms and therefore were diagnosed as lactose intolerant, according to NIH definition. The blinded oral challenges with lactose and placebo accurately diagnose LI and identify patients who will likely benefit from a lactose-free diet.
Two analogues of the MS3 aptamer, which was previously shown to have an exquisite capability to selectively bind and modulate the activity of mutant huntingtin (mHTT), have been here designed and ...evaluated in their physicochemical and biological properties. Featured by a distinctive propensity to form complex G-quadruplex structures, including large multimeric aggregates, the original 36-mer MS3 has been truncated to give a 33-mer (here named MS3-33) and a 17-mer (here named MS3-17). A combined use of different techniques (UV, CD, DSC, gel electrophoresis) allowed a detailed physicochemical characterization of these novel G-quadruplex-forming aptamers, tested in vitro on SH-SY5Y cells and in vivo on a Drosophila Huntington’s disease model, in which these shorter MS3-derived oligonucleotides proved to have improved bioactivity in comparison with the parent aptamer.
•Morphology and autophagic process are impaired in VTA DA neurons of Tg2576 mice.•Tg2576 DA neurons show increased excitability and changes in neuronal conductances.•Midbrain of Tg2576 mice shows ...increased activation of c-Abl tyrosine kinase.•Nilotinib, a c-Abl inhibitor, ameliorates DA neuron loss and cell deficits.•Nilotinib restores hippocampal DA levels and cognitive functions.
What happens precociously to the brain destined to develop Alzheimer’s Disease (AD) still remains to be elucidated and this is one reason why effective AD treatments are missing. Recent experimental and clinical studies indicate that the degeneration of the dopaminergic (DA) neurons in the Ventral Tegmental Area (VTA) could be one of the first events occurring in AD. However, the causes of the increased vulnerability of DA neurons in AD are missing.
Here, we deeply investigate the physiology of DA neurons in the VTA before, at the onset, and after onset of VTA neurodegeneration. We use the Tg2576 mouse model of AD, overexpressing a mutated form of the human APP, to identify molecular targets that can be manipulated pharmacologically. We show that in Tg2576 mice, DA neurons of the VTA at the onset of degeneration undergo slight but functionally relevant changes in their electrophysiological properties and cell morphology. Importantly, these changes are associated with accumulation of autophagosomes, suggestive of a dysfunctional autophagy, and with enhanced activation of c-Abl, a tyrosine kinase previously implicated in the pathogenesis of neurodegenerative diseases.
Chronic treatment of Tg2576 mice with Nilotinib, a validated c-Abl inhibitor, reduces c-Abl phosphorylation, improves autophagy, reduces Aβ levels and – more importantly – prevents degeneration as well as functional and morphological alterations in DA neurons of the VTA. Interestingly, the drug prevents the reduction of DA outflow to the hippocampus and ameliorates hippocampal-related cognitive functions.
Our results strive to identify early pathological brain changes in AD, to provide a rational basis for new therapeutic interventions able to slow down the disease progression.
A set of guanine-rich aptamers able to preferentially recognize full-length huntingtin with an expanded polyglutamine tract has been recently identified, showing high efficacy in modulating the ...functions of the mutated protein in a variety of cell experiments. We here report a detailed biophysical characterization of the best aptamer in the series, named MS3, proved to adopt a stable, parallel G-quadruplex structure and show high nuclease resistance in serum. Confocal microscopy experiments on HeLa and SH-SY5Y cells, as models of non-neuronal and neuronal cells, respectively, showed a rapid, dose-dependent uptake of fluorescein-labelled MS3, demonstrating its effective internalization, even in the absence of transfecting agents, with no general cytotoxicity. Then, using a well-established
model for Huntington's disease, which expresses the mutated form of human huntingtin, a significant improvement in the motor neuronal function in flies fed with MS3 was observed, proving the in vivo efficacy of this aptamer.
Endosomal trafficking is essential for cellular homeostasis. At the crossroads of distinct intracellular pathways, the endolysosomal system is crucial to maintain critical functions and adapt to the ...environment. Alterations of endosomal compartments were observed in cells from adult individuals with Down syndrome (DS), suggesting that the dysfunction of the endosomal pathway may contribute to the pathogenesis of DS. However, the nature and the degree of impairment, as well as the timing of onset, remain elusive. Here, by applying imaging and biochemical approaches, we demonstrate that the structure and dynamics of early endosomes are altered in DS cells. Furthermore, we found that recycling trafficking is markedly compromised in these cells. Remarkably, our results in 18-20 week-old human fetal fibroblasts indicate that alterations in the endolysosomal pathway are already present early in development. In addition, we show that overexpression of the polyphosphoinositide phosphatase synaptojanin 1 (Synj1) recapitulates the alterations observed in DS cells, suggesting a role for this lipid phosphatase in the pathogenesis of DS, likely already early in disease development. Overall, these data strengthen the link between the endolysosomal pathway and DS, highlighting a dangerous liaison among Synj1, endosomal trafficking and DS.
Summary Background Depression is the third leading contributor to the worldwide burden of disease. We assessed the nature and severity of experienced and anticipated discrimination reported by adults ...with major depressive disorder worldwide. Moreover, we investigated whether experienced discrimination is related to clinical history, provision of health care, and disclosure of diagnosis and whether anticipated discrimination is associated with disclosure and previous experiences of discrimination. Methods In a cross-sectional survey, people with a diagnosis of major depressive disorder were interviewed in 39 sites (35 countries) worldwide with the discrimination and stigma scale (version 12; DISC-12). Other inclusion criteria were ability to understand and speak the main local language and age 18 years or older. The DISC-12 subscores assessed were reported discrimination and anticipated discrimination. Multivariable regression was used to analyse the data. Findings 1082 people with depression completed the DISC-12. Of these, 855 (79%) reported experiencing discrimination in at least one life domain. 405 (37%) participants had stopped themselves from initiating a close personal relationship, 271 (25%) from applying for work, and 218 (20%) from applying for education or training. We noted that higher levels of experienced discrimination were associated with several lifetime depressive episodes (negative binomial regression coefficient 0·20 95% CI 0·09–0·32, p=0·001); at least one lifetime psychiatric hospital admission (0·29 0·15–0·42, p=0·001); poorer levels of social functioning (widowed, separated, or divorced 0·10 0·01–0·19, p=0·032; unpaid employed 0·34 0·09–0·60, p=0·007; looking for a job 0·26 0·09–0·43, p=0·002; and unemployed 0·22 0·03–0·41, p=0·022). Experienced discrimination was also associated with lower willingness to disclose a diagnosis of depression (mean discrimination score 4·18 SD 3·68 for concealing depression vs 2·25 2·65 for disclosing depression; p<0·0001). Anticipated discrimination is not necessarily associated with experienced discrimination because 147 (47%) of 316 participants who anticipated discrimination in finding or keeping a job and 160 (45%) of 353 in their intimate relationships had not experienced discrimination. Interpretation Discrimination related to depression acts as a barrier to social participation and successful vocational integration. Non-disclosure of depression is itself a further barrier to seeking help and to receiving effective treatment. This finding suggests that new and sustained approaches are needed to prevent stigmatisation of people with depression and reduce the effects of stigma when it is already established. Funding European Commission, Directorate General for Health and Consumers, Public Health Executive Agency.
Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent ...clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability.
A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed.
A total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61,
= 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20,
< 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83,
< 0.001). Overall, 186 different variants in the
gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%,
< 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%,
= 0.001), cerebral atrophy (11.2% vs 3.4%,
= 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%,
< 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%,
< 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3).
The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense
variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability.
No study has so far explored differences in discrimination reported by people with major depressive disorder (MDD) across countries and cultures.
To (a) compare reported discrimination across ...different countries, and (b) explore the relative weight of individual and contextual factors in explaining levels of reported discrimination in people with MDD.
Cross-sectional multisite international survey (34 countries worldwide) of 1082 people with MDD. Experienced and anticipated discrimination were assessed by the Discrimination and Stigma Scale (DISC). Countries were classified according to their rating on the Human Development Index (HDI). Multilevel negative binomial and Poisson models were used.
People living in 'very high HDI' countries reported higher discrimination than those in 'medium/low HDI' countries. Variation in reported discrimination across countries was only partially explained by individual-level variables. The contribution of country-level variables was significant for anticipated discrimination only.
Contextual factors play an important role in anticipated discrimination. Country-specific interventions should be implemented to prevent discrimination towards people with MDD.
ObjectiveWhereas employment has been shown to be beneficial for people with Major Depressive Disorder (MDD) across different cultures, employers’ attitudes have been shown to be negative towards ...workers with MDD. This may form an important barrier to work participation. Today, little is known about how stigma and discrimination affect work participation of workers with MDD, especially from their own perspective. We aimed to assess, in a working age population including respondents with MDD from 35 countries: (1) if people with MDD anticipate and experience discrimination when trying to find or keep paid employment; (2) if participants in high, middle and lower developed countries differ in these respects; and (3) if discrimination experiences are related to actual employment status (ie, having a paid job or not).MethodParticipants in this cross-sectional study (N=834) had a diagnosis of MDD in the previous 12 months. They were interviewed using the Discrimination and Stigma Scale (DISC-12). Analysis of variance and generalised linear mixed models were used to analyse the data.ResultsOverall, 62.5% had anticipated and/or experienced discrimination in the work setting. In very high developed countries, almost 60% of respondents had stopped themselves from applying for work, education or training because of anticipated discrimination. Having experienced workplace discrimination was independently related to unemployment.ConclusionsAcross different countries and cultures, people with MDD very frequently reported discrimination in the work setting. Effective interventions are needed to enhance work participation in people with MDD, focusing simultaneously on decreasing stigma in the work environment and on decreasing self-discrimination by empowering workers with MDD.
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