Controlled Release of Octreotide and Assessment of Peptide Acylation from Poly(D,L-lactide-co-hydroxymethyl glycolide) Compared to PLGA Microspheres

# The Author(s) 2011. This article is published with open access at Springerlink.com Purpose To investigate the in vitro release of octreotide acetate, a somatostatin agonist, from microspheres based on a hydrophilic polyester, poly(D,L-lactide-co-hydroxymethyl glycolide) (PLHMGA). Methods Spherical and non-porous octreotide-loaded PLHMGA microspheres (12 to 16 μm) and loading efficiency of 60–70% were prepared by a solvent evaporation. Octreotide release profiles were compared with commercial PLGA formulation (Sandostatin LAR ®); possible peptide modification with lactic, glycolic and hydroxymethyl glycolic acid units was monitored. Results PLHMGA microspheres showed burst release (~20%) followed by sustained release for 20–60 days, depending on the hydrophilicity of the polymer. Percentage of released loaded peptide was high (70–90%);>60 % of released peptide was native octreotide. PLGA microspheres did not show peptide release for the first 10 days, after which it was released in a sustained manner over the next 90 days;>75 % of released peptides were acylated adducts. Conclusions PLHMGA microspheres are promising controlled systems for peptides with excellent control over release kinetics. Moreover, substantially less peptide modification occurred in PLHMGA than in PLGA microspheres. KEY WORDS acylation. aliphatic polyester. controlle

Contribution mapping: a method for mapping the contribution of research to enhance its impact.

Background: At a time of growing emphasis on both the use of research and accountability, it is important for research funders, researchers and other stakeholders to monitor and evaluate the extent to which research contributes to better action for health, and find ways to enhance the likelihood that beneficial contributions are realized. Past attempts to assess research 'impact' struggle with operationalizing 'impact', identifying the users of research and attributing impact to research projects as source. In this article we describe Contribution Mapping, a novel approach to research monitoring and evaluation that aims to assess contributions instead of impacts. The approach focuses on processes and actors and systematically assesses anticipatory efforts that aim to enhance contributions, so-called alignment efforts. The approach is designed to be useful for both accountability purposes and for assisting in better employing research to contribute to better action for health.Methods: Contribution Mapping is inspired by a perspective from social studies of science on how research and knowledge utilization processes evolve. For each research project that is assessed, a three-phase process map is developed that includes the main actors, activities and alignment efforts during research formulation, production and knowledge extension (e.g. dissemination and utilization). The approach focuses on the actors involved in, or interacting with, a research project (the linked actors) and the most likely influential users, who are referred to as potential key users. In the first stage, the investigators of the assessed project are interviewed to develop a preliminary version of the process map and first estimation of research-related contributions. In the second stage, potential key-users and other informants are interviewed to trace, explore and triangulate possible contributions. In the third stage, the presence and role of alignment efforts is analyzed and the preliminary results are shared with relevant stakeholders for feedback and validation. After inconsistencies are clarified or described, the results are shared with stakeholders for learning, improvement and accountability purposes.Conclusion: Contribution Mapping provides an interesting alternative to existing methods that aim to assess research impact. The method is expected to be useful for research monitoring, single case studies, comparing multiple cases and indicating how research can better be employed to contribute to better action for health. © 2012 Kok and Schuit; licensee BioMed Central Ltd

Non-fatal disease burden for subtypes of depressive disorder: population-based epidemiological study

Background: Major depression is the leading cause of non-fatal disease burden. Because major depression is not a homogeneous condition, this study estimated the non-fatal disease burden for mild, moderate and severe depression in both single episode and recurrent depression. All estimates were assessed from an individual and a population perspective and presented as unadjusted, raw estimates and as estimates adjusted for comorbidity. Methods: We used data from the first wave of the second Netherlands-Mental-Health-Survey-and-Incidence-Study (NEMESIS-2, n = 6646; single episode Diagnostic and Statistical Manual (DSM)-IV depression, n = 115; recurrent depression, n = 246). Disease burden from an individual perspective was assessed as 'disability weight * time spent in depression' for each person in the dataset. From a population perspective it was assessed as 'disability weight * time spent in depression *number of people affected'. The presence of mental disorders was assessed with the Composite International Diagnostic Interview (CIDI) 3.0. Results: Single depressive episodes emerged as a key driver of disease burden from an individual perspective. From a population perspective, recurrent depressions emerged as a key driver. These findings remained unaltered after adjusting for comorbidity. Conclusions: The burden of disease differs between the subtype of depression and depends much on the choice of perspective. The distinction between an individual and a population perspective may help to avoid misunderstandings between policy makers and clinicians. © 2016 Biesheuvel-Leliefeld et al

Deficient sustained attention to response task and P300 characteristics in early Huntington’s disease

Evidence for the extent and nature of attentional impairment in premanifest and manifest Huntington’s disease (HD) is inconsistent. Understanding such impairments may help to better understand early functional changes in HD and could have consequences concerning care for HD patients. We investigated attentional control in both early and premanifest HD. We studied 17 early HD subjects (mean age: 51 years), 12 premanifest HD subjects (mean age: 43 years), and 15 healthy controls (mean age: 51 years), using the sustained attention to response task (SART), a simple Go/No-go test reflecting attentional and inhibitory processes through reaction time (RT) and error rates. Simultaneously recorded EEG yielded P300 amplitudes and latencies. The early HD group made more Go errors (p < 0.001) and reacted slower (p < 0.005) than the other groups. The RT pattern during the SART was remarkably different for early HD subjects compared to the other two groups (p < 0.005), apparent as significant post-error slowing. P300 data showed that for early HD the No-go amplitude was lower than for the other two groups (p < 0.05). Subjects with early HD showed a reduced capacity to effectively control attention. They proved unable to resume the task directly after having made an error, and need more time to return to pre-error performance levels. No attentional control deficits were found for the premanifest HD group

Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in infliximab- and vedolizumab-treated patients

We report SARS-CoV-2 vaccine-induced immunity and risk of breakthrough infections in patients with inflammatory bowel disease treated with infliximab, a commonly used anti-TNF drug and those treated with vedolizumab, a gut-specific antibody targeting integrin a4b7 that does not impact systemic immunity. In infliximab-treated patients, the magnitude of anti-SARS-CoV2 antibodies was reduced 4-6-fold. One fifth of both infliximab- and vedolizumab-treated patients did not mount a T cell response. Antibody half-life was shorter in infliximab-treated patients. Breakthrough SARS-CoV-2 infections occurred more frequently in infliximab-treated patients and the risk was predicted by the level of antibody response after second vaccine dose. Overall, recipients of two doses of the BNT162b2 vaccine had higher anti-SARS-CoV-2 antibody concentrations, higher seroconversion rates, shorter antibody half-life and less breakthrough infections compared to ChAdOx1 nCoV-19 vaccine recipients. Irrespective of biologic treatment, higher, more sustained antibody levels were observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Patients treated with anti-TNF therapy should be offered third vaccine doses

Contralateral hip fractures and other osteoporosis-related fractures in hip fracture patients: Incidence and risk factors. An observational cohort study of 1,229 patients

Purpose: To report risk factors, 1-year and overall risk for a contralateral hip and other osteoporosis-related fractures in a hip fracture population. Methods: An observational study on 1,229 consecutive patients of 50 years and older, who sustained a hip fracture between January 2005 and June 2009. Fractures were scored retrospectively for 2005-2008 and prospectively for 2008-2009. Rates of a contralateral hip and other osteoporosis- related fractures were compared between patients with and without a history of a fracture. Previous fractures, gender, age and ASA classification were analysed as possible risk factors. Results: The absolute risk for a contralateral hip fracture was 13.8 %, for one or more osteoporosis-related fracture( s) 28.6 %. First-, second- and third-year risk for a second hip fracture was 2, 1 and 0 %. Median (IQR) interval between both hip fractures was 18.5 (26.6) months. One-year incidence of other fractures was 6 %. Only age was a risk factor for a contralateral hip fracture, hazard ratio (HR) 1.02 (1.006-1.042, p = 0.008). Patients with a history of a fracture (33.1 %) did not have a higher incidence of fractures during follow-up (16.7 %) than patients without fractures in their history (14 %). HR for a contralateral hip fracture for the fracture versus the non-fracture group was 1.29 (0.75-2.23, p = 0.360). Conclusion: The absolute risk of a contralateral hip fracture after a hip fracture is 13.8 %, the 1-year risk was 2 %, with a short interval between the 2 hip fractures. Age was a risk factor for sustaining a contralateral hip fracture; a fracture in history was not

The priming effect of extracellular UTP on human neutrophils: Role of calcium released from thapsigargin-sensitive intracellular stores

P2Y2 receptors, which are equally responsive to ATP and UTP, can trigger intracellular signaling events, such as intracellular calcium mobilization and mitogen-activated protein (MAP) kinase phosphorylation in polymorphonuclear leukocytes (PMN). Moreover, extracellular nucleotides have been shown to prime chemoattractant-induced superoxide production. The aim of our study was to investigate the mechanism responsible for the priming effect of extracellular nucleotides on reactive oxygen species (ROS) production induced in human neutrophils by two different chemoattractants: formyl-methionyl-leucyl-phenylalanine (fMLP) and interleukin-8 (IL-8). Nucleotide-induced priming of ROS production was concentration- and time-dependent. When UTP was added to neutrophil suspensions prior to chemoattractant, the increase of the response reached the maximum at 1 min of pre-incubation with the nucleotide. UTP potentiated the phosphorylation of p44/42 and p38 MAP kinases induced by chemoattractants, however the P2 receptor-mediated potentiation of ROS production was still detectable in the presence of a SB203580 or U0126, supporting the view that MAP kinases do not play a major role in regulating the nucleotide-induced effect. In the presence of thapsigargin, an inhibitor of the ubiquitous sarco-endoplasmic reticulum Ca2+-ATPases in mammalian cells, the effect of fMLP was not affected, but UTP-induced priming was abolished, suggesting that the release of calcium from thapsigargin-sensitive intracellular stores is essential for nucleotide-induced priming in human neutrophils

Reduction of Natural Killer but Not Effector CD8 T Lymphoyctes in Three Consecutive Cases of Severe/Lethal H1N1/09 Influenza A Virus Infection

Background: The cause of severe disease in some patients infected with pandemic influenza A virus is unclear. Methodology/Principal Findings: We present the cellular immunology profile in the blood, and detailed clinical (and postmortem) findings of three patients with rapidly progressive infection, including a pregnant patient who died. The striking finding is of reduction in natural killer (NK) cells but preservation of activated effector CD8 T lymphocytes; with viraemia in the patient who had no NK cells. Comparison with control groups suggests that the reduction of NK cells is unique to these severely ill patients. Conclusion/Significance: Our report shows markedly reduced NK cells in the three patients that we sampled and raises the hypothesis that NK may have a more significant role than T lymphocytes in controlling viral burden when the host is confronted with a new influenza A virus subtype

Exploring barriers to the use of formal maternal health services and priority areas for action in Sidama zone, southern Ethiopia.

In 2015 the maternal mortality ratio for Ethiopia was 353 per 100,000 live births. Large numbers of women do not use maternal health services. This study aimed to identify factors influencing the use of maternal health services at the primary health care unit (PHCU) level in rural communities in Sidama zone, south Ethiopia in order to design quality improvement interventions. We conducted a qualitative study in six woredas in 2013: 14 focus group discussions (FGDs) and 44 in-depth interviews with purposefully selected community members (women, male, traditional birth attendants, local kebele administrators), health professionals and health extension workers (HEWs) at PHCUs. We digitally recorded, transcribed and thematically analysed the interviews and FGDs using Nvivo. The 'three delay model' informed the analytical process and discussion of barriers to the use of maternal health services. Lack of knowledge on danger signs and benefits of maternal health services; cultural and traditional beliefs; trust in TBAs; lack of decision making power of women, previous negative experiences with health facilities; fear of going to an unfamiliar setting; lack of privacy and perceived costs of maternal health services were the main factors causing the first delay in deciding to seek care. Transport problems in inaccessible areas were the main contributing factor for the second delay on reaching care facilities. Lack of logistic supplies and equipment, insufficient knowledge and skills and unprofessional behaviour of health workers were key factors for the third delay in accessing quality care. Use of maternal health services at the PHCU level in Sidama zone is influenced by complex factors within the community and health system. PHCUs should continue to implement awareness creation activities to improve knowledge of the community on complications of pregnancy and benefits of maternal health services. The health system has to be responsive to community's cultural norms and practices. The mangers of the woreda health office and health centres should take into account the available budgets; work on ensuring the necessary logistics and supplies to be in place at PHCU