Mutant huntingtin impairs immune cell migration in Huntington disease

In Huntington disease (HD), immune cells are activated before symptoms arise; however, it is unclear how the expression of mutant huntingtin (htt) compromises the normal functions of immune cells. Here we report that primary microglia from early postnatal HD mice were profoundly impaired in their migration to chemotactic stimuli, and expression of a mutant htt fragment in microglial cell lines was sufficient to reproduce these deficits. Microglia expressing mutant htt had a retarded response to a laser-induced brain injury in vivo. Leukocyte recruitment was defective upon induction of peritonitis in HD mice at early disease stages and was normalized upon genetic deletion of mutant htt in immune cells. Migration was also strongly impaired in peripheral immune cells from pre-manifest human HD patients. Defective actin remodeling in immune cells expressing mutant htt likely contributed to their migration deficit. Our results suggest that these functional changes may contribute to immune dysfunction and neurodegeneration in HD, and may have implications for other polyglutamine expansion diseases in which mutant proteins are ubiquitously expressed.     

Metacognitive Interpersonal Therapy in group (MIT-G) for young adults with personality disorders: A pilot randomized controlled trial

Young adults with personality disorders (PD) other than borderline are in urgent need of validated treatments to help them in managing important life transitions. Therapeutic interventions focused upon social and interpersonal difficulties may facilitate these individuals in maximizing opportunities for employment, forming stable romantic relationships, and belong to social groups. It is also important that they are offered evidence-based, first-line time-limited treatments in order to maximize effectiveness and reduce costs. We developed a 16-session programme of group-based Metacognitive Interpersonal Therapy (MIT-G) including psychoeducation on the main interpersonal motives, an experiential component enabling practice of awareness of mental states; and use of mentalistic knowledge for purposeful problem-solving. We report a feasibility, acceptability, and clinical significance randomized clinical trial. Participants meeting inclusion criteria were randomized to receive MIT-G (n = 10) or waiting list+TAU (n = 10). Dropout rate was low and session attendance high (92.19%). Participants in the MIT-G arm had symptomatic and functional improvements consistent with large effect sizes. In the MIT-G arm similarly large effects were noted for increased capacity to understand mental states and regulate social interactions using mentalistic knowledge. Results were sustained at follow-up. Our findings suggest potential for applying MIT-G in larger samples to further test its effectiveness in reducing PD-related symptoms and problematic social functioning.     

Right hemispheric dysfunction in a case of pure progressive aphemia: fusion of multimodal neuroimaging

This article describes the unusual case of a 60-year-old woman suffering from pure progressive aphemia. The fusion of multimodal neuroimaging (MRI, perfusion SPECT) implicated the right frontal lobe, especially the inferior frontal gyrus. This area also showed the greatest functional MRI activation during the performance of a covert phonemic fluency task. Results are discussed in terms of bihemispheric language representation. The fusion of three sets of neuroimages has aided in the interpretation of the patient's cognitive brain dysfunction.     

High prevalence of (99m)tc-tetrofosmin reverse perfusion pattern in patients with myocardial infarction and angiographically smooth coronary arteries

Background: There are no published data in the literature on the scintigraphic perfusion pattern in patients with myocardial infarction (MI) and normal coronary arteries (NCA) Objectives: To evaluate myocardial perfusion imaging in a series of patients with MI and NCA. Methods: Twenty-seven patients who had developed a MI and had NCA were studied. As a control group we included 27 patients with a recent MI and coronary artery disease (CAD). All patients underwent stress/rest tetrofosmin myocardial perfusion SPECT within 6 months from MI. Results: In patients with NCA tetrofosmin stress images revealed 41 hypoperfused segments in 17 patients (63%). On rest images, 13 segments remained unchanged, 4 showed partial reperfusion, 10 normalized and 14 worsened. Additionally, there were 18 new hypoperfused segments in nine patients. Therefore, perfusion worsened at rest in 18 patients (67%) (32 segments). Overall, at rest there were 49 hypoperfused segments in 22 patients (81%). In patients with CAD, stress images revealed 71 hypoperfused segments. On rest images, 39 segments remained unchanged, 16 showed partial reperfusion and 12 normalized. Four segments worsened at rest and only four patients (15%) showed new perfusion defects at rest. Conclusions: Myocardial perfusion with tetrofosmin might appear considerably worse at rest than at stress in patients with MI and NCA. Specifically, a reverse perfusion pattern in the infarct area is a frequent finding and is likely to be due to residual tissue viability. We postulate that in these patients the hyperemic response to exercise may mask resting underperfusion areas.     

Influence of indigenous microbiota on experimental toxoplasmosis in conventional and germ‐free mice

Toxoplasmosis represents one of the most common zoonoses worldwide. Its agent, Toxoplasma gondii, causes a severe innate pro‐inflammatory response. The indigenous intestinal microbiota promotes host animal homoeostasis and may protect the host against pathogens. Germ‐free (GF) animals provide an important tool for the study of interactions between host and microbiota. In this study, we assessed the role of indigenous microorganisms in disease development utilizing a murine toxoplasmosis model, which includes conventional (CV) and GF NIH Swiss mice. CV and GF mice orally inoculated with T. gondii had similar survival curves. However, disease developed differently in the two animal groups. In CV mice, intestinal permeability increased and levels of intestinal pro‐inflammatory cytokines were altered. In GF animals, there were discrete epithelial degenerative changes and mucosal oedema, but the liver and lungs displayed significant lesions. We conclude that, despite similar survival curves, CV animals succumb to an exaggerated inflammatory response, whereas GF mice fail to produce an adequate systemic response.     

Citizens and family doctors facing awareness and management of traditional cardiovascular risk factors: results from the Global Cardiovascular Risk Reduction Project (Help Your Heart Stay Young Study)

BACKGROUND AND AIM: The numerous guidelines and multiple approaches to managing cardiovascular risk factors have reduced the number of fatal events but not the incidence of cardiovascular disease (CVD). One rarely explored aspect is the extent to which individuals perceive their own risk in relation to their education and history of CVD. Furthermore, Italy has a State-based Health System, in which family doctors (FDs) may be an extremely useful and relatively low cost resource for risk management, but the degree of their involvement in individual CVD risk management has not been previously assessed. METHODS AND RESULTS: The Department of Clinical and Experimental Medicine of Federico II University, Naples, Italy, and the Neapolitan Section of the Italian Society of Family Doctors (SIMG), developed an epidemiological survey to evaluate the level and awareness of CVD risk in subjects in the urban area of Naples, and the degree of involvement of FDs in CVD risk management. During a period of a few months, the subjects who visited their FDs were invited to respond to a standard self-explanatory questionnaire, and the FDs were required to provide quantitative information concerning the CVD risk factors of each enrolled subject from their databases in order to assess global CVD risk. The data included cholesterol and blood pressure (BP) levels, and had to be collected within six months of the visit; if the date were missing, the fact was recorded. The present analysis was based on data concerning the 5,687 subjects who had entered the study by January 2002, 7.6% of whom reported CVD (myocardial infarction (MI), stroke, angina, cerebral transient ischemic attack: CD+) and 92.4% did not (CVD-). MI was the most frequent CVD, and 18% of the CVD+ cases reported more than one non-fatal cardiovascular event. On average, the CVD+ subjects were older and more often men. After adjusting for age and FD, they also had a higher body mass index (BMI) and prevalence of obesity, higher self-reported BP, a lower education level, and more often referred high cholesterol levels, hypertension and diabetes. On the contrary, the proportion of smokers was higher in the CVD- group. Among the subjects who declared that they did not have a high cholesterol level, 11% reported recent values of > 200 mg/dL. The FDs of 36% of the cases were unable to assess the individual global CV risk level using quantitative data from their electronic databases. The most frequently missing information was the level of total cholesterol. Missing data were more frequent in the CVD- than the CVD+ subjects, regardless of age and FD. CONCLUSIONS: The results of our study suggest that the awareness of CVD risk among subjects is somewhat vague. The FDs were generally able to provide a quantitative assessment of CVD risk in their patients. CVD risk prevention programmes may be more successful if they stress knowledge and awareness in the population, and stimulate FDs to undertake more stringent quantitative assessments of CVD risk factors.     

Fusion of Semliki Forest virus infected aedes albopictus cells at low pH is a fusion from within

Summary Herein, it is shown for the first time that the mechanism of fusion followed in Aedes albopictus cells infected with Semliki Forest virus induced by low pH exposure is a fusion from within. Several parameters were studied disclosing that the development of the fusion capacity of the cells is directly related to the synthesis of viral specific products. These findings were further substantiated by utilizing various chemicals to inhibit viral specific events during infection, protein synthesis and maturation. Removal of exogenous virions produced at 16 hours post infection by proteinase K digestion clearly revealed that the viral proteins located at the cell surface and not the exogenous virions were responsible for the fusogenic activity. The presence of these viral proteins at the cell surface was disclosed by immunofluorescence employing anti-SFV antibodies elicited in rabbits. Additional evidence for the participation of the viral proteins at the cell surface in the fusion reaction was obtained by Bromelaine digestion which inhibited the fusion and tunicamycin treatment which only partially inhibited the fusion but revealed the inevitable presence of the E₁ protein.With 2 Figures     

Silica-based mesoporous materials as drug delivery system for methotrexate release

Antineoplastic methotrexate has been loaded through different soaking procedures on silica-based mesoporous materials and, successively, released mimicking an oral administration. The materials were prepared using a self-assembly mechanism in the presence of cationic surfactants with alkyl chain of 16, 12, and 10 carbon atoms in the synthesis mixture to obtain different pore diameter in the porous structure. Mesoporous materials were prepared as pure silica sample and in the presence of Al(OH)₃ in the synthesis mixture. Only alumina-silica samples were able to load methotrexate. The amounts of drug loaded and the in vitro release kinetics are a function of the pore size of the materials.     

Rab11 rescues synaptic dysfunction and behavioural deficits in a Drosophila model of Huntington's disease

Synapse abnormalities in Huntington's disease (HD) patients can precede clinical diagnosis and neuron loss by decades. The polyglutamine expansion in the huntingtin (htt) protein that underlies this disorder leads to perturbations in many cellular pathways, including the disruption of Rab11-dependent endosomal recycling. Impairment of the small GTPase Rab11 leads to the defective formation of vesicles in HD models and may thus contribute to the early stages of the synaptic dysfunction in this disorder. Here, we employ transgenic Drosophila melanogaster models of HD to investigate anomalies at the synapse and the role of Rab11 in this pathology. We find that the expression of mutant htt in the larval neuromuscular junction decreases the presynaptic vesicle size, reduces quantal amplitudes and evoked synaptic transmission and alters larval crawling behaviour. Furthermore, these indicators of early synaptic dysfunction are reversed by the overexpression of Rab11. This work highlights a potential novel HD therapeutic strategy for early intervention, prior to neuronal loss and clinical manifestation of disease.     

Metabolic effects of contraceptive implants in adolescents

Background

This prospective study analyzed the metabolic effects of an etonogestrel implant used for 1 year by adolescents.

Study Design

The study population comprised 47 postpartum adolescents (mean 17.2 years old) managed at the Family Planning Sector of São Paulo Federal University. Participants received an implant containing etonogestrel (68 mg) within 6 months of delivery (on average 102 days after giving birth) and were followed for 1 year. Blood was collected at baseline and 12 months later to assess total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), hemogram, urea, creatinine, sodium, potassium, fasting glucose, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and bilirubin.

Results

Three adolescents did not return after receiving the implant despite telephone messages and a telegram and were excluded from the clinical and final laboratory analyses. All 44 patients completed the 12 months of follow-up, resulting in a study discontinuation rate of 0%. No implants were removed. Laboratory analyses were completed in 37 adolescents. After 1 year of using the implant, there was a significant increase in mean hemoglobin, hematocrit and indirect bilirubin concentrations and of the HDL-C/TC and HDL-C/LDL-C ratios. Additionally, there was a significant decrease in mean TC level as well as LDL-C, very low-density lipoprotein cholesterol, TG, SGOT and SGPT. These results suggest that the etonogestrel implant does not interfere directly with the risk of cardiovascular diseases because it improves the lipid profile. There were no pregnancies during the study.

Conclusion

Our results indicate that an etonogestrel implant used by adolescents for 1 year is associated with changes in the lipid profile and hepatic function without adverse clinical effects.