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Proteolysis is essential for the control of metabolic pathways and the cell cycle. Bacterial caseinolytic proteases (Clp) use peptidase components, such as ClpP, to degrade defective substrate proteins and to regulate cellular levels of stress-response proteins. To ensure selective degradation, access to the proteolytic chamber of the double–ring ClpP tetradecamer is controlled by a critical gating mechanism of the two axial pores. The binding of conserved loops of the Clp ATPase component of the protease or small molecules, such as acyldepsipeptide (ADEP), at peripheral ClpP ring sites, triggers axial pore opening through dramatic conformational transitions of flexible N-terminal loops between disordered conformations in the "closed" pore state and ordered hairpins in the "open" pore state. In this study, we probe the allosteric communication underlying these conformational changes by comparing residue–residue couplings in molecular dynamics simulations of each configuration. Both principal component and normal mode analyses highlight large-scale conformational changes in the N-terminal loop regions and smaller amplitude motions of the peptidase core. Community network analysis reveals a switch between intra- and inter-protomer coupling in the open–closed pore transition. Allosteric pathways that connect the ADEP binding sites to N-terminal loops are rewired in this transition, with shorter network paths in the open pore configuration supporting stronger intra- and inter-ring coupling. Structural perturbations, either through the removal of ADEP molecules or point mutations, alter the allosteric network to weaken the coupling. [ABSTRACT FROM AUTHOR]

Mitochondria are responsible for maintaining cellular energy levels, and play a major role in regulating homeostasis, which ensures physiological function from the molecular to whole animal. Sirtuin 3 (SIRT3) is the major protein deacetylase of mitochondria. SIRT3 serves as a nutrient sensor; under conditions of mild metabolic stress, SIRT3 activity is increased. Within the mitochondria, SIRT3 regulates every complex of the electron transport chain, the tricarboxylic acid (TCA) and urea cycles, as well as the mitochondria membrane potential, and other free radical scavengers. This article reviews the role of SIRT3 in regulating homeostasis, and thus physiological function. We discuss the role of SIRT3 in regulating reactive oxygen species (ROS), ATP, immunological function and mitochondria dynamics.

In Parkinson's disease (PD), post-mortem studies in affected brain regions have demonstrated a decline in mitochondrial number and function. This combined with many studies in cell and animal models suggest that mitochondrial dysfunction is central to PD pathology. We and others have shown that the mitochondrial protein deacetylase, SIRT3, has neurorestorative effects in PD models. In this study, to determine whether there is a link between PD pathology and SIRT3, we analysed SIRT3 levels in human subjects with PD, and compared to age-matched controls. In the SNc of PD subjects, SIRT3 was reduced by 56.8 ± 15.5% compared to control, regardless of age (p

Background Delivery of viral vectors as gene therapies to treat neurodegenerative diseases has been hampered by the inability to penetrate the blood brain barrier (BBB) and invasive or non-targeted delivery options prone to inducing immune responses. MR guided focused ultrasound (MR-g-FUS) and microbubbles have demonstrated safe, temporary, targeted BBB permeabilization clinically.Methods We developed clinically scalable, microbubble drug conjugates (MDCs) for the viral gene therapy, AAV.SIRT3-myc [adeno-associated virus expressing myc-tagged SIRT3], which has previously been shown to have disease modifying effects in animal models of Parkinson’s disease (PD). The lipid shells of the perfluorocarbon gas MDCs were covalently conjugated to antibodies with binding specificity to AAVs. Following systemic (iv) delivery of AAV.SIRT3-myc MDCs, MR-g-FUS was used to deliver SIRT3-myc to brain regions affected in PD. SIRT3-myc expression was determined post mortem, using immunohistochemistry.Results An in vitro, SH-SY5Y cell culture model was used to show that the localized destruction of MDCs using ultrasound exposures within biological safety limits dissociated AAV2-GFP (green fluorescent protein) from the MDCs in the targeted area while maintaining their transduction capacity. In rats, MR-g-FUS resulted in BBB permeabilization in the striatum and substantia nigra (SNc). SIRT3-myc was expressed in the striatum, but not the SNc.Conclusion These studies demonstrate that MDCs combined with MR-g-FUS are an effective method for delivery of viral vector gene therapies, such as AAV.SIRT3, to brain regions affected in PD. This technology may prove useful as a disease-modifying strategy in PD and other neurodegenerative disorders.

Parkinson's disease (PD) is a neurodegenerative movement disorder, which affects approximately 1–2% of the population over 60 years of age. Current treatments for PD are symptomatic, and the pathology of the disease continues to progresses over time until palliative care is required. Mitochondria are key players in the pathology of PD. Genetic and post mortem studies have shown a large number of mitochondrial abnormalities in the substantia nigra pars compacta (SNc) of the parkinsonian brain. Furthermore, physiologically, mitochondria of nigral neurons are constantly under unusually high levels of metabolic stress because of the excitatory properties and architecture of these neurons. The protein deacetylase, Sirtuin 3 (SIRT3) reduces the impact subcellular stresses on mitochondria, by stabilising the electron transport chain (ETC), and reducing oxidative stress. We hypothesised that viral overexpression of myc-tagged SIRT3 (SIRT3-myc) would slow the progression of PD pathology, by enhancing the functional capacity of mitochondria. For this study, SIRT3-myc was administered both before and after viral induction of parkinsonism with the AAV-expressing mutant (A53T) α-synuclein. SIRT3-myc corrected behavioural abnormalities, as well as changes in striatal dopamine turnover. SIRT3-myc also prevented degeneration of dopaminergic neurons in the SNc. These effects were apparent, even when SIRT3-myc was transduced after the induction of parkinsonism, at a time point when cell stress and behavioural abnormalities are already observed. Furthermore, in an isolated mitochondria nigral homogenate prepared from parkinsonian SIRT3–myc infected animals, SIRT3 targeted the mitochondria, to reduce protein acetylation levels. Our results demonstrate that transduction of SIRT3 has the potential to be an effective disease-modifying strategy for patients with PD. This study also provides potential mechanisms for the protective effects of SIRT3-myc.

Thomas J Dennison,1 Julian C Smith,2 Raj K Badhan,1 Afzal R Mohammed1 1Aston School of Pharmacy, Aston University, Birmingham, 2Viridian Pharma Ltd, Newport, UK Abstract: Cardiovascular disease (CVD) is the leading cause of death among men and women worldwide. In CVD, hypertension and dyslipidemia commonly coexist and are managed through coadministration of amlodipine and atorvastatin, respectively. The case for fixed-dose combination (FDC) oral dosage forms and orally disintegrating tablet (ODT) technology to enhance outcomes and compliance is strong. This work follows the development and characterization of single and FDC ODTs containing amlodipine and atorvastatin, followed by bioequivalence comparison between these single and FDC formulations, using in vitro dissolution and Caco-2 apparent permeability (Papp) and in silico physiologically based pharmacokinetic modeling approaches. ODTs containing amlodipine (5 mg) and atorvastatin (10 mg) either alone or in combination rapidly disintegrated (

Four weeks after implantation of oral endosteal metallic implants, acute inflammatory responses of the gingiva were observed. By eight weeks, the inflammation was transitional to chronic. Bony degeneration was noted eight months after implantation. No epithelial or fibrous connective tissue adherence or attachment to the blades was evident. [ABSTRACT FROM AUTHOR]

A research project that is exploring how cutting-edge technology can be used to improve social inclusion is truly inspirational, say Tony Dennison and Joanne Marshall [ABSTRACT FROM AUTHOR]

Dysregulation of the hematopoietic niche during hyperlipidemia facilitates pathologic leukocyte production, driving atherogenesis. Although definitive hematopoiesis occurs primarily in the bone marrow, during atherosclerosis this also occurs in the spleen. Cells of the bone marrow niche, particularly endothelial cells, have been studied in atherosclerosis, although little is known about how splenic endothelial cells respond to the atherogenic environment. Here we show unique dysregulated pathways in splenic compared to bone marrow endothelial cells during atherosclerosis, including perturbations of lipid metabolism and endocytic trafficking pathways. As part of this response, we identify the mixed lineage kinase domain-like (MLKL) protein as a repressor of splenic, but not bone marrow, myelopoiesis. Silencing MLKL in splenic endothelial cells results in inefficient endosomal trafficking and lipid accumulation, ultimately promoting the production of myeloid cells that participate in plaque development. These studies identify endocytic trafficking by MLKL as a key mechanism of splenic endothelial cell maintenance, splenic hematopoiesis and, subsequently, atherosclerosis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Competing Interests: Declaration of Competing Interest The author(s) have no relevant disclosures. There was no grant funding or financial support for this manuscript.

Introduction: Palbociclib is a small-molecule cyclin-dependent kinase 4/6 inhibitor used to treat hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer. Patient-specific factors impacting dose reductions or discontinuations are unknown., Methods: The primary objective was to evaluate the association of age (<60 vs. ≥60 years) with palbociclib dose reductions or discontinuations secondary to neutropenia. This single-center, retrospective chart review included hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer patients ≥18 years treated with palbociclib between April 2015 and May 2020. Patients <60 years at the time of palbociclib initiation were in the younger group and patients ≥60 years were in the older group., Results: Among the 107 patients included, younger patients were less likely than older patients to have a palbociclib starting dose <125 mg (0% vs. 11.9%, p  = 0.02). Differences in palbociclib dose reductions or treatment discontinuations secondary to neutropenia were not detected (35.4% vs. 42.4%, p  = 0.55). Neither the total number of palbociclib dose reductions (none: 54.2% vs. 49.1%, one: 33.3% vs. 42.4%, two: 12.5% vs. 8.5%, p  = 0.61), nor the final dose of palbociclib (125 mg: 54.2% vs. 40.7%, 100 mg: 29.2% vs. 27.1%, 75 mg: 16.7% vs. 32.2%, p  = 0.17) differed between younger and older patients., Conclusions: Age (<60 vs. ≥60 years) was not associated with the rate of palbociclib dose reductions or discontinuations secondary to neutropenia. Older (≥60 years) patients were more likely to start palbociclib at lower doses which may impact neutropenia and non-neutropenic intolerance.

Oncology clinical pharmacists are uniquely positioned to make interventions to impact the knowledge, attitudes, and practices of clinicians as well as patient activation and engagement. To accomplish this goal, pharmacists can target health system-related, provider-related, and patient-related factors to enhance patient-centered care and drive behavioral health changes. Interventions that pharmacists must tackle include educating team members and patients on the medication acquisition process, communicating urgency of treatment, optimizing workflows, facilitating guideline recommendations, preventing, and managing treatment toxicities, and promoting patient self-advocacy through education and shared decision-making. As crucial members of the healthcare team, oncology pharmacists can simplify highly complex treatment regimens to facilitate and optimize patients' ownership of their care. This narrative review will focus on the example of venetoclax treatment in acute myeloid leukemia to demonstrate the impact that pharmacists provide that leads to behavioral change of patients and clinicians.

Patients with chronic myeloid leukemia (CML) can be treated with oral tyrosine kinase inhibitors (TKIs). Pharmacist-led oral chemotherapy programs (POCPs) can improve TKI adherence rates, but evaluation of patient satisfaction with such programs is rare. The purpose of this analysis was to compare the satisfaction of patients with CML taking TKIs enrolled in a POCP program with that of those not enrolled. Secondary objectives were to assess adherence rates, patient-reported value, early molecular response (EMR) rates, and major molecular response (MMR) rates. This study utilized an anonymous telephone survey of patients who had taken TKIs for at least 3 months. Molecular response was determined by chart review. Of 40 patients surveyed, 50% were enrolled in the POCP, and the POCP group had more African Americans than the non-POCP group. More patients in the POCP were satisfied with their care than in the non-POCP group (100% vs. 75%, p = .047). There were no differences in high patient-reported adherence (55% vs. 60%, p = 1.000), patient-reported value for integrated services (95% vs. 90%, p = 1.000), achievement of EMR (75% vs. 75%, p = 1.000), or MMR (85% vs. 85%, p = 1.000). Patients in the POCP received more structured clinical pharmacy services; however, both groups felt the clinical pharmacist played a major role in their care (85% vs. 90%, p = 1.000). Patients in the non-POCP group reported lower satisfaction than those enrolled resulting from fragmented care that was likely due to external specialty pharmacies. Irrespective of POCP enrollment, patients reported clinical pharmacists play a major role in their therapy and value integration of their specialty pharmacy and medical team., Competing Interests: The authors have no conflict of interest to disclose., (© 2021 Harborside™.)

The extraordinarily long stigmatic silks of corn (Zea mays L.) are critical for grain production but the biology of their growth and emergence from husk leaves has remained underexplored. Accordingly, gene expression was assayed for inbreds 'B73' and 'Mo17' across five contiguous silk sections. Half of the maize genes (∼20,000) are expressed in silks, mostly in spatiotemporally dynamic patterns. In particular, emergence triggers strong differential expression of ∼1,500 genes collectively enriched for gene ontology terms associated with abiotic and biotic stress responses, hormone signaling, cell-cell communication, and defense metabolism. Further, a meta-analysis of published maize transcriptomic studies on seedling stress showed that silk emergence elicits an upregulated transcriptomic response that overlaps strongly with both abiotic and biotic stress responses. Although the two inbreds revealed similar silk transcriptomic programs overall, genotypic expression differences were observed for 5,643 B73-Mo17 syntenic gene pairs and collectively account for >50% of genome-wide expression variance. Coexpression clusters, including many based on genotypic divergence, were identified and interrogated via ontology-term enrichment analyses to generate biological hypotheses for future research. Ultimately, dissecting how gene expression changes along the length of silks and between husk-encased and emerged states offers testable models for silk development and plant response to environmental stresses., (© 2020 The Authors. The Plant Genome published by Wiley Periodicals, Inc. on behalf of Crop Science Society of America.)

As a child and adolescent neuropsychology service based within a paediatric psychology team at a large teaching hospital, we meet children and young people across the age range who experience cognitive impairment as a result of long-term health conditions or traumatic brain injury. We have a remit of providing a neuropsychological assessment and report. Typically, a neuropsychology report includes recommendations for home and for school. However, research suggests that their uptake is variable and depends on the understanding and resources of families and school systems. As a stretched service, we have very limited capacity to follow the work through to the extent that we might like. Therefore, we are always seeking effective ways to support the ongoing adaptation and implementation of the assessment recommendations in the child's various day-to-day contexts. We address both the cognitive functioning and the psychological well-being of the child as a unified whole. Drawing on systemic ideas influences our communications with children, families, schools and the medical teams in ways which help bridge the gap between hospital-based assessment and everyday life. This article describes how we are integrating our systemic and neurodevelopmental perspectives to make the assessment and the findings a meaningful intervention in themselves. We consider ways of sharing neuropsychology findings which promote the child's psychological well-being in their different contexts: hospital, home, school, community and culture.

Objectives: During the advancement of atherosclerosis, plaque cellularity is governed by the influx of monocyte-derived macrophages and their turnover via apoptotic and nonapoptotic forms of cell death. Previous reports have demonstrated that programmed necrosis, or necroptosis, of plaque macrophages contribute to necrotic core formation. Knockdown or inhibition of the necrosome components RIPK1 (receptor-interacting protein kinase 1) and RIPK3 (receptor-interacting protein kinase 3) slow atherogenesis, and activation of the terminal step of necroptosis, MLKL (mixed lineage kinase domain-like protein), has been demonstrated in advanced human atherosclerotic plaques. However, whether MLKL directly contributes to lesion development and necrotic core formation has not been investigated. Approaches and Results: MLKL expression was knocked down in atherogenic Apoe -knockout mice via the administration of antisense oligonucleotides. During atherogenesis, Mlkl knockdown decreased both programmed cell death and the necrotic core in the plaque. However, total lesion area remained unchanged. Furthermore, treatment with the MLKL antisense oligonucleotide unexpectedly reduced circulating cholesterol levels compared with control antisense oligonucleotide but increased the accumulation of lipids within the plaque and in vitro in macrophage foam cells. MLKL colocalized with the late endosome and multivesicular bodies in peritoneal macrophages incubated with atherogenic lipoproteins. Transfection with MLKL antisense oligonucleotide increased lipid localization with the multivesicular bodies, suggesting that upon Mlkl knockdown, lipid trafficking becomes defective leading to enhanced lipid accumulation in macrophages., Conclusions: These studies confirm the requirement for MLKL as the executioner of necroptosis, and as such a significant contributor to the necrotic core during atherogenesis. We also identified a previously unknown role for MLKL in regulating endosomal trafficking to facilitate lipid handling in macrophages during atherogenesis.

Background: Simple non-isoprenoid hydrocarbons accumulate in discrete regions of the biosphere, including within bacteria and algae as a carbon and/or energy store, and the cuticles of plants and insects, where they may protect against environmental stresses. The extracellular cuticular surfaces of the stigmatic silks of maize are rich in linear hydrocarbons and therefore provide a convenient system to study the biological origins and functions of these unique metabolites., Results: To test the hypotheses that genetics and environment influence the accumulation of surface hydrocarbons on silks and to examine the breadth of metabolome compositions across diverse germplasm, cuticular hydrocarbons were analyzed on husk-encased silks and silks that emerged from the husk leaves from 32 genetically diverse maize inbred lines, most of which are commonly utilized in genetics experiments. Total hydrocarbon accumulation varied ~ 10-fold among inbred lines, and up to 5-fold between emerged and husk-encased silks. Alkenes accounted for 5-60% of the total hydrocarbon metabolome, and the majority of alkenes were monoenes with a double bond at either the 7th or 9th carbon atom of the alkyl chain. Total hydrocarbon accumulation was impacted to similar degrees by genotype and husk encasement status, whereas genotype predominantly impacted alkene composition. Only minor differences in the metabolome were observed on silks that were emerged into the external environment for 3- versus 6-days. The environmental influence on the metabolome was further investigated by growing inbred lines in 2 years, one of which was warmer and wetter. Inbred lines grown in the drier year accumulated up to 2-fold more hydrocarbons and up to a 22% higher relative abundance of alkenes. In summary, the surface hydrocarbon metabolome of silks is primarily governed by genotype and husk encasement status, with smaller impacts of environment and genotype-by-environment interactions., Conclusions: This study reveals that the composition of the cuticular hydrocarbon metabolome on silks is affected significantly by genetic factors, and is therefore amenable to dissection using quantitative genetic approaches. Such studies will clarify the genetic mechanisms responsible for the accumulation of these metabolites, enabling detailed functional investigations of the diverse and complex protective roles of silk surface lipids against environmental stresses.

Meiotic crossovers (COs) play a critical role in generating genetic variation and maintaining faithful segregation of homologous chromosomes during meiosis. We develop a haplotype-specific fluorescence in situ hybridization (FISH) technique that allows visualization of COs directly on metaphase chromosomes. Oligonucleotides (oligos) specific to chromosome 10 of maize inbreds B73 and Mo17, respectively, are synthesized and labeled as FISH probes. The parental and recombinant chromosome 10 in B73 x Mo17 F 1 hybrids and F 2 progenies can be unambiguously identified by haplotype-specific FISH. Analysis of 58 F 2 plants reveals lack of COs in the entire proximal half of chromosome 10. However, we detect COs located in regions very close to the centromere in recombinant inbred lines from an intermated B73 x Mo17 population, suggesting effective accumulation of COs in recombination-suppressed chromosomal regions through intermating and the potential to generate favorable allelic combinations of genes residing in these regions.

Background: Two-stage reimplantation is the most common treatment modality considered for periprosthetic shoulder infection (PSI). Most studies to date have reported on a relatively small number of shoulders. The purpose of this study was to determine the outcome of 2-stage reimplantation for PSI in terms of both eradication of infection and restoration of function., Methods: Between 1980 and 2010, 40 shoulders (39 patients) underwent a 2-stage reimplantation for PSI; 35 shoulders (34 patients) met inclusion criteria (10 hemiarthroplasties, 24 anatomic total shoulder arthroplasties, 1 reverse total shoulder arthroplasty). Outcome data included pain, motion, Neer rating, and complications., Results: At most recent follow-up (4.1 years), 2-stage reimplantation had resulted in significant improvements in pain (from 4.4 to 2 on a 5-point scale; P < .0001), mean forward elevation (64°-118°; P < .0001), and mean external rotation (14°-41°; P < .0001). Preoperative testing showed leukocytosis in 1 patient, elevated C-reactive protein concentration in 67%, elevated erythrocyte sedimentation rate in 61%, and positive preoperative aspiration in 69%. Persistent infection, defined as positive cultures in samples obtained at the time of reimplantation, was identified in 5 shoulders (15%); 50% of persistent infections grew Propionibacterium acnes. Reoperations for infection included irrigation and débridement (1), a second 2-stage reimplantation (2), and resection arthroplasty (1); 2 additional patients were treated with chronic suppression. Reoperation for aseptic glenoid loosening was performed in 2 additional shoulders. Results were graded excellent in 10 (28%), satisfactory in 12 (33%), and unsatisfactory in 13 (39%) shoulders., Conclusion: Two-stage reimplantation eradicated PSI in 85% of the shoulders. Pain relief and good arcs of motion were achieved in many patients, but there was an overall rate of unsatisfactory results approaching 40%. Preoperative testing was not always reliable for the diagnosis of PSI., (Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background: The cost of treating infection after hip and knee arthroplasty is well documented in the literature. The purpose of this study was to determine the cost of two-stage reimplantation for deep infection after shoulder arthroplasty., Methods: Between 2003 and 2012, 57 shoulders (56 patients) underwent a two-stage reimplantation for deep periprosthetic shoulder infection; implants placed at reimplantation included anatomic total shoulder arthroplasty (a-TSA) in 58%, reverse total shoulder arthroplasty (r-TSA) in 40%, and hemiarthroplasty (HA) in 2%. During the same timeframe, 2953 primary shoulder arthroplasties (2589 patients) were performed at the same institution (a-TSA in 55%, r-TSA in 28%, and HA in 17%). Total direct medical costs were calculated by using standardized, inflation-adjusted costs for services and procedures billed during hospitalization and were adjusted to nationally representative unit costs in 2013 inflation-adjusted dollars., Results: The mean hospital cost (per shoulder) for two-stage reimplantation was $35,824 (95% CI: 33,363 to 38,285) and was significantly higher than for primary procedures (mean: $16,068; 95% CI: 15,823 to 16,314). Both Part A and Part B costs were significantly higher in two-stage reimplantation (p < 0.001). For part A (hospital services), the mean cost for two-stage reimplantation was $29,851 (95% CI: 27,741 to 31,960), compared to $13,508 (95% CI: 13,302 to 13,715) for primaries. For part B (professional costs), mean costs were $5973 (95% CI: 5493 to 6453) versus 2560 (95% CI: 2512 to 2608) respectively ., Conclusions: The hospital cost of two-stage reimplantation for the treatment of an infected shoulder arthroplasty is about two times higher than the cost of a primary shoulder arthroplasty.

Background: Irrigation and débridement (I&D) with component retention is an appealing alternative to both patients and surgeons for the management of acute or late hematogenous deep periprosthetic shoulder infection (PSI). However, the success rate and results of I&D are poorly documented. This study reports the outcomes and complications of this treatment strategy for acute and delayed-onset acute hematogenous PSI., Methods: Between 1980 and 2010, 10 shoulders (9 patients) underwent I&D with component retention for the management on an acute or delayed-onset acute hematogenous PSI at a single institution. Outcome data, including pain, range of motion, need for chronic oral antibiotic suppression therapy, eradication of infection, and need for further surgery were retrospectively collected., Results: Deep infection recurred in 3 shoulders, which were eventually treated with resection arthroplasty. Of the remaining 6 patients (7 shoulders), 5 were prescribed chronic antibiotic suppression. At the most recent follow-up, pain was graded as none in 3 shoulders, mild in 1, moderate with activity in 3, moderate in 2, and severe in 1. Among shoulders with retained components, forward elevation was greater than 110° in 6 (median, 140°; range, 30°-160°), and external rotation was greater than 40° in all shoulders (median, 50°; range, 40°-90°)., Conclusion: I&D allowed component retention in 70% of shoulders presenting with an acute or delayed-onset acute hematogenous infection. Most patients were prescribed chronic antibiotic suppression, and reasonable motion was maintained., (Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background: Brucellosis and coxiellosis are known to be endemic in ruminant populations throughout Afghanistan, but information about their prevalence and factors that affect prevalence in householders and livestock under diverse husbandry systems and pastoral settings is sparse., Methods/principal Findings: We conducted a cross-sectional survey to investigate the seroprevalence of brucellosis and Coxiella burnetii in humans and livestock in six secure districts in Herat from 26th December 2012-17th January 2013. A total of 204 households with livestock were surveyed in six Kuchi and five sedentary type villages. Blood samples from 1,017 humans, 1,143 sheep, 876 goats and 344 cattle were tested for brucellosis and Q fever. About one in six households (15.7%) had at least one Brucella seropositive person, about one in eight households (12.3%) had at least one Brucella seropositive animal and about one in four (24.5%) had either seropositive animals or humans. Ninety-seven percent of households had at least one C. burnetii seropositive person and 98.5% of households had one or more C. burnetii seropositive animals. Forty- seven householders had serological evidence of exposure to both C. burnetii and Brucella and eight animals were serologically positive for both diseases. Drinking unpasteurised milk (OR 1.6), treating animals for ticks (OR 1.4), milking sheep (OR 1.4), male gender (OR 1.4) and seropositivity to Brucella (OR 4.3) were identified as risk factors for seropositivity to C. burnetii in householders. Household factors associated with households having either Brucella seropositive animals or humans were Kuchi households (OR 2.5), having ≤ 4 rooms in the house (OR 2.9) and not owning land (OR 2.9)., Conclusions: The results from this study provide baseline information for the planning and monitoring of future interventions against these diseases. The implementation of this study greatly improved collaboration, coordination and capability of veterinary and public health professionals from government, NGOs and donor funded projects.

The successful development of compressed ODTs utilises low compression forces to create a porous structure whereby excipients are added to enhance wicking/swelling action or provide strength to the fragile tablet framework. In this work, a systematic investigation comparing materials from two different categories was employed to understand their functionality in binary mixture tablets of the most commonly used diluent mannitol. Cellulose based excipients such as HPC (SSL-SFP), L-HPC (NBD-022) and MCC (Avicel PH-102) were compared with non-cellulosic materials such as PEO (POLYOX WSR N-10) and Crospovidone (XL-10). Pure excipient properties were studied using Heckel Plot, compressibility profile, SEM and XRPD, whereas the prepared binary mixture compacts were studied for hardness, disintegration time and friability. Results from our investigation provide insight into differences encountered in product performance of ODT upon inclusion of additional materials. For example, non-cellulosic excipients Polyox and Crospovidone showed higher plasticity (Py values 588 and 450MPa) in pure form but not in binary mixtures of mannitol. Cellulosic excipients, nonetheless, offer faster disintegration (<30 sec) specifically L-HPC and MCC tablets. Disintegration time for tablets with fully substituted-HPC was prolonged (200-500 sec) upon increasing concentration between 1-10% due to gelation/ matrix formation. It can be concluded that despite the reasonably good plasticity of both cellulosic and noncellulosic excipients in pure form, the mechanical strength in binary mixtures is negatively impacted by the fragmentation/ fracture effect of mannitol.

In 2012, a dog in Afghanistan was diagnosed with trypanosomosis. We here describe the clinical picture of the animal and how the parasite was identified as Trypanosoma evansi by DNA extraction from a blood smear and molecular analysis with taxon-specific PCR assays., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Purpose: The Rural Medical Education Program (RMED) of the State University of New York (SUNY) Upstate Medical University is a 36-week clinical experience in rural communities for medical students that began in 1989. The authors sought to assess RMED's success in providing a valuable educational experience for students that assists rural communities recruit physicians., Method: In 2004, the authors used the Physician Masterfiles of the American Medical Association to compare practice locations of SUNY Upstate graduates who completed RMED with those who did not; surveyed former RMED students to assess their satisfaction with their practice location and the importance of RMED in helping them choose a location; interviewed hospital administrators in communities that have hosted RMED students to understand the impact of RMED on host communities; and compared United States Medical Licensing Examination Step 2 scores of RMED students with those of non-RMED students to evaluate educational attainment., Results: A greater percentage of former RMED students practiced in rural locations [22/86 (26%)] than did non-RMED students [95/1,307 (7%)]. Ninety-one percent (69/76) of former RMED students were satisfied with their location, and 84% (64/76) believed that RMED was important in helping them choose a location. Hospital administrators viewed the program highly because it helped them recruit physicians and benefitted their medical staff. RMED students had higher adjusted mean Step 2 scores than did non-RMED students (212.3 versus 199.1)., Conclusion: The RMED program has successfully met its goals of providing a valuable educational experience for medical students and assisting rural communities recruit physicians.