PEG-metronidazole conjugates: synthesis, in vitro and in vivo properties

Metronidazole (MTZ), a drug used for the treatment of protozoal infections caused by protozoa and anaerobic microorganisms, was conjugated to linear or branched poly(ethylene glycol) of 5,000, 10,000 and 20,000 Da. An ester linkage between polymer and drug was used in the coupling to yield a polymeric prodrug. The modification allowed overcoming the known MTZ solubility problem leading us to obtain a bioconjugate more suitable for parental administration. The conjugates of various molecular weight polymers have been tested in vitro toward chemical degradation and digestive enzymes. It was found that molecular weight and shape of PEG is critical for the prodrugs stability. Good resistance in the stomach acidic media was found and a slow release of the drug in the large intestinal fluid may take place. In vivo studies carried out following i.v. or s.c. administration to mice revealed improved pharmacokinetics properties upon conjugation.     

Interactions between hippocampal activity and striatal dopamine in people at clinical high risk for psychosis: relationship to adverse outcomes

Preclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CHR) for psychosis and investigated its association with subsequent clinical and functional outcomes. Ninety-five participants (67 CHR and 28 healthy controls) underwent arterial spin labeling MRI and ¹⁸F-DOPA PET imaging at baseline. CHR participants were followed up for a median of 15 months to determine functional outcomes with the global assessment of function (GAF) scale and clinical outcomes using the comprehensive assessment of at-risk mental states (CAARMS). CHR participants with poor functional outcomes (follow-up GAF < 65, n = 25) showed higher rCBF in the right hippocampus compared to CHRs with good functional outcomes (GAF ≥ 65, n = 25) (p_fwe = 0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (p_fwe = 0.035); the association was negative in CHR with poor outcomes (p_fwe = 0.012), but non-significant in CHR with good outcomes. Furthermore, the correlation between right hippocampal rCBF and striatal dopamine function predicted a longitudinal increase in the severity of positive psychotic symptoms within the total CHR group (p = 0.041). There were no differences in rCBF, dopamine, or their associations in the total CHR group relative to controls. These findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of adverse outcomes in the CHR state.Subject terms: Predictive markers, Psychosis     

Anti-cancer PEG-enzymes: 30 years old, but still a current approach

PEGylation (i.e. the covalent link of PEG strands) is a well known technique used to improve pharmaceutical properties of bioactive proteins and peptides. Even in cancer therapy some proteins, in particular enzymes, can find many applications, because of their antiproliferative action or ability to reduce side effects of chemotherapies, but to do so they need to be properly formulated. Unfortunately, formulation alone can not fulfil all the requirements to yield a safe and successful protein preparation for therapeutic applications. In particular, for many proteins fast clearance from the body and potential immunogenicity are severe limitations, which can not be easily overcome without taking into consideration a purposely designed drug delivery system. Among the approaches in the field of drug delivery, PEGylation has so far been the best choice for protein delivery. Here, we describe some examples of PEGylated enzymes useful in antitumoral therapies and the most recent advances in this field.     

Association between Intake of Energy and Macronutrients and Memory Impairment Severity in US Older Adults,National Health and Nutrition Examination Survey 2011–2014

Without a cure, dementia affects about 50 million people worldwide. Understanding the effects of dietary habits, a key lifestyle behavior, on memory impairment is critical to inform early behavioral modification to delay further memory loss and progression to dementia. We examined the associations of total energy intake and energy intake from macronutrients with memory impairment among older US adults using data from the nationally representative National Health and Nutrition Examination Survey study 2011–2014. A total of 3623 participants aged ≥60 years were analyzed. Comparing to those with low total energy intake, individuals with high intake were more likely to have severe memory impairment (OR: 1.52, 95% CI: 1.15 to 2.02; p_trend = 0.005). Specifically, higher energy intake from carbohydrate (OR: 1.59, 95% CI: 1.12 to 2.26) and sugar (OR: 1.54, 95% CI: 1.11 to 2.16) were both significantly associated with the presence of memory impairment. Additionally, higher energy intake from fat, carbohydrate and sugar were significantly associated with more server memory impairment (fat: p_trend = 0.04; carbohydrate: p_trend = 0.03; sugar: p_trend = 0.02). High energy intake, either total or from carbohydrates, fat or sugar, is associated with memory impairment severity in the older US population. No such association was found in energy intake from protein.     

Well-Being Among Older Gay and Bisexual Men and Women in England: A Cross-sectional Population Study

ObjectivesLesbian, gay, and bisexual (LGB) older people present an under-represented population in research, with limited research citing higher prevelance of depression, loneliness, rejection, and overall poorer health and well-being outcomes. Our study compares well-being, defined as quality of life, life satisfaction, sexual satisfaction, and depression, among LGB people with their heterosexual peers'.DesignCross-sectional population study using data from the English Longitudinal Study of Aging (ELSA), a representative panel study of older adults aged 50 and older.Setting and ParticipantsData were from ELSA wave 6, collected 2012-2013. A total of 5691 participants were included in the analysis, with 326 (5.7%) self-identifying as LGB.MeasuresWell-being was measured using CASP-19, a quality of life questionnaire; the Satisfaction with Life Scale for life satisfaction; and the Center for Epidemiologic Studies Depression Scale for depressive symptoms. Sexual satisfaction was assessed using the question “During the past three months, how satisfied have you been with your overall sex life?” In addition, t test and chi-square tests were used to test differences in sociodemographic characteristics between LGB and heterosexual participants. Bivariate logistical regression and linear regression were used to test associations between sexual orientation and well-being outcomes.ResultsIn unadjusted models, LGB participants reported significantly lower mean quality of life and life satisfaction, and had significantly lower odds of reporting satisfaction with their overall sex life and higher odds of reporting depressive symptoms above threshold. After adjustment for sociodemographic and health-related covariates, there remained significant differences between LGB and heterosexual groups in mean quality of life scores (B = ?0.96, 95% confidence interval [CI] ?1.87 to ?0.06, P = .037) and odds of sexual satisfaction (odds ratio = 0.56, 95% CI 0.38-0.82, P = .003).Conclusions/ImplicationsLGB older people report lower quality of life and lower sexual satisfaction than their heterosexual counterparts, possibly associated with a number of unwanted social experiences.     

Sequential changes in antibody levels to the ENV and GAG Antigens in human immunodeficiency virus infected subjects

Sera from 51 HTLV-III (human immunodeficiency virus, HIV)-antibody positive subjects consisting of 21 asymptomatic individuals and 15 ARC and 15 AIDS patients were analyzed for their serological profiles toward the viral antigens. One of the asymptomatic subjects only showed a p24 reactivity in the immunoblot, but antibodies to the env antigens were clearly identified by immunoprecipitation of viral antigens (RIP) followed by SDS-polyacrylamide gel electrophoresis. RIP patterns of different subjects and even different bleeds from the same subjects showed a varying reactivity to the gag antigens whereas the reactivity towards the env antigens appeared to be generally stable. RIP analysis of sequential sera of virus-infected individuals indicated a pattern consistent with an initial steady rise of antibody reactivities to the gag antigens relative to the reactivities to the envelope antigens. These reactivities reached a plateau and then slowly declined. While all sera tested had antibodies to the envelope antigens gp160, gp120 and gp4l, 86% of the asymptomatic subjects, 67% of the ARC patients and only 33% of the AIDS patients had antibodies to the gag proteins p24 and pr53gag.Corresponding author.     

Individualized quality of life of severely affected multiple sclerosis patients: practicability and value in comparison with standard inventories

Purpose

Individualized quality of life (QoL) measures differ from traditional inventories in that QoL domains/weights are not predetermined, but identified by the individual. We assessed practicability of the Schedule for the Evaluation of Individual QoL-Direct Weighting (SEIQoL-DW) interview in severely affected multiple sclerosis (MS) patients; the key QoL dimensions identified; and the correlation of the SEIQoL-DW index score with standard patient-reported outcome measures (PROMs).

Methods

Participants were people with severe MS who performed the baseline visit of the PeNSAMI trial (ISRCTN73082124). The SEIQoL-DW was administered at the patient’s home by a trained examiner. Patients then received the following PROMs: the Core-Palliative care Outcome Scale (Core-POS), the Palliative care Outcome Scale-Symptoms-MS (POS-S-MS), the European Quality of Life Five Dimensions-3L (EQ-5D-3L), and the Hospital Anxiety and Depression Scale (HADS).

Results

Of 59 enrolled patients, 11 (19 %) did not receive the SEIQoL-DW (and the other PROMs) because of severe cognitive compromise or inability to communicate. SEIQoL-DW administration was completed and deemed valid in all 48 cases (mean age 60 years, 58 % women, median Expanded Disability Status Scale score 8.5). Mean SEIQoL-DW index score was 59.1 (SD 25.5). The most commonly nominated SEIQoL-DW areas were family (94 % of the patients), relationships, and leisure activities (both 65 %). Core-POS and POS-S-MS contained 70 % of the SEIQoL-DW-nominated areas. Nevertheless, correlations between SEIQoL-DW index, Core-POS, and POS-S-MS (and the other PROMs) were negligible.

Conclusions

Individualized QoL can be assessed in severely affected MS patients, providing information that is not tracked by the standard inventories Core-POS, POS-S-MS, EQ-5D-3L, and HADS.

     

Malaria mosquito control using edible fish in western Kenya: preliminary findings of a controlled study

Background  

Biological control methods are once again being given much research focus for malaria vector control. This is largely due to the emerging threat of strong resistance to pesticides. Larvivorous fish have been used for over 100 years in mosquito control and many species have proved effective. In the western Kenyan highlands the larvivorous fish Oreochromis niloticus L. (Perciformes: Cichlidae) (formerly Tilapia nilotica) is commonly farmed and eaten but has not been previously tested in the field for malaria mosquito control.     

Proliferative activity in human urologic malignancies: a preliminary study

Cellular proliferative activity was evaluated by the determination of 3H-thymidine labeling index (LI) in 20 specimens of human urologic malignancies (13 renal cell carcinomas and 7 transitional cell bladder carcinomas). Very low LI values were found in renal cell carcinomas, with a median value of 0.28%. Slightly higher proliferative activities were observed in bladder carcinomas, with a median LI value of 1.96%. No significant correlations were found between proliferative activity and pathologic stage or histologic grading in renal cell carcinomas. Although the number of bladder carcinomas evaluated does not allow any definite conclusion, an increase in LI values was found from in situ to invasive carcinoma and from tumors at stage I to tumors at stage III.