Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

Staphylococcus aureus infection dynamics

Staphylococcus aureus is a human commensal that can also cause systemic infections. This transition requires evasion of the immune response and the ability to exploit different niches within the host. However, the disease mechanisms and the dominant immune mediators against infection are poorly understood. Previously it has been shown that the infecting S. aureus population goes through a population bottleneck, from which very few bacteria escape to establish the abscesses that are characteristic of many infections. Here we examine the host factors underlying the population bottleneck and subsequent clonal expansion in S. aureus infection models, to identify underpinning principles of infection. The bottleneck is a common feature between models and is independent of S. aureus strain. Interestingly, the high doses of S. aureus required for the widely used "survival" model results in a reduced population bottleneck, suggesting that host defences have been simply overloaded. This brings into question the applicability of the survival model. Depletion of immune mediators revealed key breakpoints and the dynamics of systemic infection. Loss of macrophages, including the liver Kupffer cells, led to increased sensitivity to infection as expected but also loss of the population bottleneck and the spread to other organs still occurred. Conversely, neutrophil depletion led to greater susceptibility to disease but with a concomitant maintenance of the bottleneck and lack of systemic spread. We also used a novel microscopy approach to examine abscess architecture and distribution within organs. From these observations we developed a conceptual model for S. aureus disease from initial infection to mature abscess. This work highlights the need to understand the complexities of the infectious process to be able to assign functions for host and bacterial components, and why S. aureus disease requires a seemingly high infectious dose and how interventions such as a vaccine may be more rationally developed

Health-related quality of life after treatment for bladder cancer in England

Background Little is known about quality of life after bladder cancer treatment. This common cancer is managed using treatments that can affect urinary, sexual and bowel function. Methods To understand quality of life and inform future care, the Department of Health (England) surveyed adults surviving bladder cancer 1–5 years after diagnosis. Questions related to disease status, co-existing conditions, generic health (EQ-5D), cancer-generic (Social Difficulties Inventory) and cancer-specific outcomes (Functional Assessment of Cancer Therapy—Bladder). Results In total, 673 (54%) patients responded; including 500 (74%) men and 539 (80%) with co-existing conditions. Most respondents received endoscopic treatment (60%), while 92 (14%) and 99 (15%) received radical cystectomy or radiotherapy, respectively. Questionnaire completion rates varied (51–97%). Treatment groups reported ≥1 problem using EQ-5D generic domains (59–74%). Usual activities was the most common concern. Urinary frequency was common after endoscopy (34–37%) and radiotherapy (44–50%). Certain populations were more likely to report generic, cancer-generic and cancer-specific problems; notably those with co-existing long-term conditions and those treated with radiotherapy. Conclusion The study demonstrates the importance of assessing patient-reported outcomes in this population. There is a need for larger, more in-depth studies to fully understand the challenges patients with bladder cancer face

Health-related quality of life in lower-risk MDS patients compared with age- and sex-matched reference populations: a European LeukemiaNet study

In myelodysplastic syndromes (MDS), health-related quality of life (HRQoL) represents a relevant patient-reported outcome, which is essential in individualized therapy planning. Prospective data on HRQoL in lower-risk MDS remain rare. We assessed HRQOL by EQ-5D questionnaire at initial diagnosis in 1690 consecutive IPSS-Low/Int-1 MDS patients from the European LeukemiaNet Registry. Impairments were compared with age- and sex-matched EuroQol Group norms. A significant proportion of MDS patients reported moderate/severe problems in the dimensions pain/discomfort (49.5%), mobility (41.0%), anxiety/depression (37.9%), and usual activities (36.1%). Limitations in mobility, self-care, usual activities, pain/discomfort, and EQ-VAS were significantly more frequent in the old, in females, and in those with high co-morbidity burden, low haemoglobin levels, or red blood cells transfusion need (

Patient relevant outcomes of unicompartmental versus total knee replacement: systematic review and meta-analysis

OBJECTIVE:To present a clear and comprehensive summary of the published data on unicompartmental knee replacement (UKA) or total knee replacement (TKA), comparing domains of outcome that have been shown to be important to patients and clinicians to allow informed decision making. DESIGN:Systematic review using data from randomised controlled trials, nationwide databases or joint registries, and large cohort studies. DATA SOURCES:Medline, Embase, Cochrane Controlled Register of Trials (CENTRAL), and Clinical Trials.gov, searched between 1 January 1997 and 31 December 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES:Studies published in the past 20 years, comparing outcomes of primary UKA with TKA in adult patients. Studies were excluded if they involved fewer than 50 participants, or if translation into English was not available. RESULTS:60 eligible studies were separated into three methodological groups: seven publications from six randomised controlled trials, 17 national joint registries and national database studies, and 36 cohort studies. Results for each domain of outcome varied depending on the level of data, and findings were not always significant. Analysis of the three groups of studies showed significantly shorter hospital stays after UKA than after TKA (-1.20 days (95% confidence interval -1.67 to -0.73), -1.43 (-1.53 to -1.33), and -1.73 (-2.30 to -1.16), respectively). There was no significant difference in pain, based on patient reported outcome measures (PROMs), but significantly better functional PROM scores for UKA than for TKA in both non-trial groups (mean difference -0.58 (-0.88 to -0.27) and -0.32 (-0.48 to -0.15), respectively). Regarding major complications, trials and cohort studies had non-significant results, but mortality after TKA was significantly higher in registry and large database studies (risk ratio 0.27 (0.16 to 0.45)), as were venous thromboembolic events (0.39 (0.27 to 0.57)) and major cardiac events (0.22 (0.06 to 0.86)). Early reoperation for any reason was higher after TKA than after UKA, but revision rates at five years remained higher for UKA in all three study groups (risk ratio 5.95 (1.29 to 27.59), 2.50 (1.77 to 3.54), and 3.13 (1.89 to 5.17), respectively). CONCLUSIONS:TKA and UKA are both viable options for the treatment of isolated unicompartmental osteoarthritis. By directly comparing the two treatments, this study demonstrates better results for UKA in several outcome domains. However, the risk of revision surgery was lower for TKA. This information should be available to patients as part of the shared decision making process in choosing treatment options. SYSTEMATIC REVIEW REGISTRATION:PROSPERO number CRD42018089972

A survival analysis of 1084 knees of the Oxford unicompartmental knee arthroplasty: a comparison between consultant and trainee surgeons.

Aims The aim of this to study was to compare the previously unreported long-term survival outcome of the Oxford medial unicompartmental knee replacement (UKR) performed by trainee surgeons and Consultants. Methods We therefore identified a previously unreported cohort of 1084 knees in 947 patients who had a UKR inserted for anteromedial knee arthritis by Consultant and surgeons in training at a tertiary arthroplasty centre and performed survival analysis on the group with revision as the endpoint. Results The 10-year cumulative survival rate for revision or exchange of any part of the prosthetic components was 93.2% (95% CI 7.1, Number at risk 45). Consultant surgeons had a 9-year cumulative survival rate of 93.9% (95% CI 3.7, Number at risk 16). Trainee surgeons had a cumulative 9-year survival rate of 93.0% (95% CI 2.7, Number at risk 35). Although there was no differences in implant survival between consultants and trainees (p=0.30), there was a difference in failure pattern whereby all re-operations performed for bearing dislocation (n=7), occurred in the trainee group. This accounted for 0.6% of the entire cohort and 15% of the re-operations. Conclusions This is the largest single series of the Oxford UKR ever reported and demonstrates that good results can be achieved by a heterogeneous group of surgeons, including trainees, if performed within a high-volume centre with considerable experience with the procedure

Identification of a better Homo sapiens Class II HDAC inhibitor through binding energy calculations and descriptor analysis

Human papillomaviruses (HPVs) are the most common on sexually transmitted viruses in the world. HPVs are responsible for a large spectrum of deseases, both benign and malignant. The certain types of HPV are involved in the development of cervical cancer. In attemps to find additional drugs in the treatment of cervical cancer, inhibitors of the histone deacetylases (HDAC) have received much attention due to their low cytotoxic profiles and the E6/E7 oncogene function of human papilomavirus can be completely by passed by HDAC inhibition. The histone deacetylase inhibitors can induce growth arrest, differentiation and apoptosis of cancer cells. HDAC class I and class II are considered the main targets for cancer. Therefore, the six HDACs class II was modeled and about two inhibitors (SAHA and TSA) were docked using AutoDock4.2, to each of the inhibitor in order to identify the pharmacological properties. Based on the results of docking, SAHA and TSA were able to bind with zinc ion in HDACs models as a drug target. SAHA was satisfied almost all the properties i.e., binding affinity, the Drug-Likeness value and Drug Score with 70% oral bioavailability and the carbonyl group of these compound fits well into the active site of the target where the zinc is present. Hence, SAHA could be developed as potential inhibitors of class II HDACs and valuable cervical cancer drug candidate

High levels of untreated distress and fatigue in cancer patients

The purpose of the study was to assess a large representative sample of cancer patients on distress levels, common psychosocial problems, and awareness and use of psychosocial support services. A total of 3095 patients were assessed over a 4-week period with the Brief Symptom Inventory-18 (BSI-18), a common problems checklist, and on awareness and use of psychosocial resources. Full data was available on 2776 patients. On average, patients were 60 years old, Caucasian (78.3%), and middle class. Approximately, half were attending for follow-up care. Types of cancer varied, with the largest groups being breast (23.5%), prostate (16.9%), colorectal (7.5%), and lung (5.8%) cancer patients. Overall, 37.8% of all patients met criteria for general distress in the clinical range. A higher proportion of men met case criteria for somatisation, and more women for depression. There were no gender differences in anxiety or overall distress severity. Minority patients were more likely to be distressed, as were those with lower income, cancers other than prostate, and those currently on active treatment. Lung, pancreatic, head and neck, Hodgkin's disease, and brain cancer patients were the most distressed. Almost half of all patients who met distress criteria had not sought professional psychosocial support nor did they intend to in the future. In conclusion, distress is very common in cancer patients across diagnoses and across the disease trajectory. Many patients who report high levels of distress are not taking advantage of available supportive resources. Barriers to such use, and factors predicting distress and use of psychosocial care, require further exploration