tbuckley/cabot-search huggingface dataset:
On the specific role of the cerebellum in motor learning and cognition: Clues from PET activation and lesion studies in man
Authors: W. T. Thach
Journal: Behavioral and Brain Sciences (1996)

Brindley proposed that we initially generate movements "consciously", under higher cerebral control. As the movement is practiced, the cerebellum learns to link within itself the context in which the movement is made to the lower level movement generators. Marr and Albus proposed that the linkage is established by a special input from the inferior olive, which plays upon an input-output element within the cerebellum during the period of the learning. When the linkage is complete, the occurrence of the context (represented by a certain input to the cerebellum) will trigger (through the cerebellum) the appropriate motor response. The "learned" movement is distinguished from the "unlearned" conscious movement by its now being automatic, rapid, and stereotyped. The idea is still controversial, but has been supported by a variety of animal studies and, as reviewed here, is consistent with the results of a number of human PET and ablation studies. I have added to the idea of context-response linkage what I think is another important variable: novel combinations of downstream elements. With regard to the motor system and the muscles, this could explain how varied combinations of muscles may become active in precise time-amplitude specifications so as to produce coordinated movements appropriate to specific contexts. In this target article, I have further extended this idea to the premotor parts of the brain and their role in cognition. These areas receive influences from the cerebellum; they are active both in planning movements that are to be executed and in thinking about movements that are not to be executed. From recent evidence, the cerebellar output extends even to what has been characterized as the ultimate frontal planning area, the "prefrontal" cortex, area 46. The cerebellum thus may be involved in context-response linkage, and response combination even at these higher levels. The implication would be that, through practice, an experiential context would automatically evoke a certain mental action plan. The plan would be in the realm of thought, and could – but need not – lead to execution. The specific cerebellar contribution would be one of the context linkage and the shaping of the response, through trial and error learning. The prefrontal and premotor areas could still plan without the help of the cerebellum, but not so automatically, rapidly, stereotypically, so precisely linked to context, or so free of error. Nor would their activities improve optimally with mental practice.
Didanosine Compared with Continued Zidovudine Therapy for HIV-Infected Patients with 200 to 500 CD4 Cells/mm^3: A Double-Blind, Randomized, Controlled Trial
Authors: J S Montaner, M T Schechter, A Rachlis, J Gill, R Beaulieu, C Tsoukas, J Raboud, B Cameron, H Salomon, L Dunkle, L Smaldone, M A Wainberg
Journal: Annals of Internal Medicine (1995)

Objective: To compare the safety and efficacy of didanosine with that of continued zidovudine therapy in persons with human immunodeficiency virus (HIV) infection who had received zidovudine for at least 6 months and had CD4 cell counts of 200 to 500 CD4 cells/mm3. Design: Double-blind, randomized, controlled trial. Setting: 10 Canadian university-affiliated specialty clinics. Patients: 246 patients were assigned to receive standard doses of either zidovudine or didanosine. Outcome Measures: The primary clinical end point was the occurrence of a new, previously undiagnosed acquired immunodeficiency syndrome (AIDS)-defining illness or death. Results: 245 of 246 patients were eligible (118 receiving didanosine and 127 receiving zidovudine). Sixty-six percent were asymptomatic, 30% had AIDS-related complex, and 4% had AIDS. The median baseline CD4 count was 320 cells/mm3. The median previous duration of zidovudine therapy was 471 days. Nine new AIDS-defining illnesses developed during the study; all but one were in the zidovudine group (relative risk, 7.9 [95% CI, 1.0 to 63.3; P = 0.02]). A change to didanosine led to a statistically significant increase in CD4 counts by week 2 that persisted until the end of the study at week 48 (P < equals 0.01). Viral sensitivity studies (done in 102 patients) showed that 28% of the zidovudine group and 21% of the didanosine group had high-level in vitro resistance to zidovudine (50% inhibitory concentration greater than 0.8 µm) at baseline (P = 0.49). Only one patient in the didanosine group developed high-level resistance to zidovudine during the study. In the zidovudine group, the cumulative probability of developing high-level resistance to zidovudine was 59% at 1 year (P = 0.01). Abdominal pain, leukopenia, and neutropenia were more frequent in the zidovudine group, and hyperuricemia was more frequent in the didanosine group (P < 0.05). Conclusion: In clinically stable patients with 200 to 500 CD4 cells/mm3 who had tolerated zidovudine for at least 6 months, a change to didanosine led to a decrease in the rate of disease progression, a sustained increase in CD4 counts, and a decrease in the chances of developing high-level resistance to zidovudine. Both drugs were generally well tolerated. *For additional members of the Canadian HIV Trials Network Protocol 002 Study Group, see the Appendix.
Risk Factors for Decline in IQ in Youth With Type 1 Diabetes Over the 12 Years From Diagnosis/Illness Onset
Authors: Ashleigh Lin, Elisabeth A. Northam, George A. Werther, Fergus J. Cameron
Journal: Diabetes Care (2014)

OBJECTIVE This study examined illness-related change in intelligence quotient (IQ) in a cohort of youth with type 1 diabetes studied prospectively from disease onset in childhood to follow-up 12 years later in late adolescence/early adulthood. RESEARCH DESIGN AND METHODS Participants included type 1 diabetes patients (n = 95; mean age at follow-up 21.3 years) and healthy control participants (HCs; n = 67; mean age at follow-up 21.0 years) from a cohort followed prospectively. Measures included Wechsler Preschool and Primary Scale of Intelligence-Revised, Wechsler Intelligence Scale for Children-Revised, and Wechsler Abbreviated Scale of Intelligence and prospective collection of data on metabolic control history. RESULTS Young people with type 1 diabetes showed greater decline in verbal IQ (VIQ) and full-scale IQ (FSIQ), but not performance IQ (PIQ), than HCs. Within the diabetes group, a younger age at diabetes onset was associated with a decline in PIQ and FSIQ (P ≤ 0.001). A history of hypoglycemic seizures was associated with a decline in VIQ (P = 0.002). Long-term metabolic control was not associated with changes in IQ. Interaction terms were not significant, suggesting no moderating effect of one diabetes-related variable over another. CONCLUSIONS The presence of diabetes may negatively influence some aspects of IQ over time. Specific illness risk factors, such as an earlier age of disease onset and a history of hypoglycemic seizures, appear to put the young person at greater risk. Academic progress of children identified as at risk should be monitored and educational supports provided if necessary.
Modulation of the Nuclear Factor κb Pathway by Shp-2 Tyrosine Phosphatase in Mediating the Induction of Interleukin (Il)-6 by IL-1 or Tumor Necrosis Factor
Authors: Min You, Leah M. Flick, Dehua Yu, Gen-Sheng Feng
Journal: The Journal of Experimental Medicine (2001)

Shp-2, a src homology (SH)2-containing phosphotyrosine phosphatase, appears to be involved in cytoplasmic signaling downstream of a variety of cell surface receptors, although the mechanism is unclear. Here, we have determined a role of Shp-2 in the cytokine circuit for inflammatory and immune responses. Production of interleukin (IL)-6 in response to IL-1 alpha or tumor necrosis factor (TNF)-alpha was nearly abolished in homozygous mutant (Shp-2(-/)-) fibroblast cells. The targeted Shp-2 mutation has no significant effect on the activation of the three types of mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (Erk), c-Jun NH(2)-terminal kinase (Jnk), and p38, by IL-1/TNF, indicating that Shp-2 does not work through MAP kinase pathways in mediating IL-1/TNF-induced IL-6 synthesis. In contrast, IL-1/TNF-stimulated nuclear factor (NF)-kappa B DNA binding activity and inhibitor of kappa B (I kappa B) phosphorylation was dramatically decreased in Shp-2(-/)- cells, while the expression and activity of NF-kappa B-inducing kinase (NIK), Akt, and I kappa B kinase (IKK) were not changed. Reintroduction of a wild-type Shp-2 protein into Shp-2(-/)- cells rescued NF-kappa B activation and IL-6 production in response to IL-1/TNF stimulation. Furthermore, Shp-2 tyrosine phosphatase was detected in complexes with IKK as well as with IL-1 receptor. Thus, this SH2-containing enzyme is an important cytoplasmic factor required for efficient NF-kappa B activation. These results elucidate a novel mechanism of Shp-2 in cytokine signaling by specifically modulating the NF-kappa B pathway in a MAP kinase-independent fashion.
Calcific Aortic Valve Disease: Not Simply a Degenerative Process
Authors: Nalini M. Rajamannan, Frank J. Evans, Elena Aikawa, K. Jane Grande-Allen, Linda L. Demer, Donald D. Heistad, Craig A. Simmons, Kristyn S. Masters, Patrick Mathieu, Kevin D. O'Brien, Frederick J. Schoen, Dwight A. Towler, Ajit P. Yoganathan, Catherine M. Otto
Journal: Circulation (2011)
Share information about patients to tackle static suicide rate, doctors are told
Authors: A. O'Dowd
Journal: BMJ (2014)

Clinicians are being encouraged to share more information about patients they suspect could be considering suicide, in an attempt to tackle the static level of suicides in England.

A consensus statement on information sharing and suicide prevention, published on 17 January by the Department of Health, is signed by eight professional organisations, including the Royal College of General Practitioners, Royal College of Nursing, and Royal College of Psychiatrists.1

It is published alongside the first annual report on England’s cross government suicide prevention strategy, Preventing Suicide in England: One year On ,2 which says that better recording and sharing of information were important in helping to prevent suicide.

The report looks at progress made …
Synovial membrane cellularity and vascularity.
Authors: O FitzGerald, B Bresnihan
Journal: Annals of the Rheumatic Diseases (1995)

Studies of the synovial membrane in joint inflammation, over many years, have proven of mixed benefit: while it is rarely of diagnostic value, clues to understanding the mechanisms involved both in the initiation and maintenance of the inflammatory response have been uncovered.While the path to understanding is fraught with difficulty, progress is slowly being made and, it is hoped, will lead in turn to novel and better treatment approaches.This review of synovial membrane cellularity and vascularity will describe our current understanding of the pathways to joint damage.
The Phase III Candidate: Can We Improve the Science of Selection?
Authors: Dean Bajorin
Journal: Journal of Clinical Oncology (2003)

Oncologists making treatment recommendations for their patients and practicing evidence-based medicine rely heavily on the highest level of data from random assignment trials. Such evidence is clearly needed in advanced bladder cancer, a disease that results in more than 40,000 deaths per year in the United States and Europe. Bladder cancer is sensitive to combination chemotherapy, such as the regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), which has been studied and referenced in more than 700 publications during the last 20 years. Despite this plethora of publications, standards of care for advanced bladder cancer are derived from just several randomized trials, underscoring their importance to the field.
CD44 Regulates Arteriogenesis in Mice and Is Differentially Expressed in Patients With Poor and Good Collateralization
Authors: N. van Royen, M. Voskuil, I. Hoefer, M. Jost, S. de Graaf, F. Hedwig, J.-P. Andert, T.A.M. Wormhoudt, J. Hua, S. Hartmann, C. Bode, I. Buschmann, W. Schaper, R. van der Neut, J.J. Piek, S.T. Pals
Journal: Circulation (2004)

Arteriogenesis refers to the development of collateral conductance arteries and is orchestrated by circulating monocytes, which invade growing collateral arteries and act as suppliers of cytokines and growth factors. CD44 glycoproteins are involved in leukocyte extravasation but also in the regulation of growth factor activation, stability, and signaling. Here, we explored the role of CD44 during arteriogenesis.CD44 expression increases strongly during collateral artery growth in a murine hind-limb model of arteriogenesis. This CD44 expression is of great functional importance, because arteriogenesis is severely impaired in CD44-/- mice (wild-type, 54.5+/-14.9% versus CD44-/-, 24.1+/-9.2%, P<0.001). The defective arteriogenesis is accompanied by reduced leukocyte trafficking to sites of collateral artery growth (wild-type, 29+/-12% versus CD44-/-, 18+/-7% CD11b-positive cells/square, P<0.01) and reduced expression of fibroblast growth factor-2 and platelet-derived growth factor-B protein. Finally, in patients with single-vessel coronary artery disease, the maximal expression of CD44 on activated monocytes is reduced in case of impaired collateral artery formation (poor collateralization, 1764+/-572 versus good collateralization, 2817+/-1029 AU, P<0.05).For the first time, the pivotal role of CD44 during arteriogenesis is shown. The expression of CD44 increases during arteriogenesis, and the deficiency of CD44 severely impedes arteriogenesis. Maximal CD44 expression on isolated monocytes is decreased in patients with a poor collateralization compared with patients with a good collateralization.
Prognostic Value of Proliferation, Apoptosis, Defective DNA Mismatch Repair, and p53 Overexpression in Patients With Resected Dukes' B2 or C Colon Cancer
Authors: Megan M. Garrity, Lawrence J. Burgart, Michelle R. Mahoney, Harold E. Windschitl, Muhammad Salim, Martin Wiesenfeld, James E. Krook, John C. Michalak, Richard M. Goldberg, Michael J. O'Connell, Alfred F. Furth, Daniel J. Sargent, Linda M. Murphy, Eunice Hill, Darren L. Riehle, Cecelia H. Meyers, Thomas E. Witzig
Journal: Journal of Clinical Oncology (2004)

Purpose Molecular studies of colon cancer have provided insights into pathogenesis, yet it is unclear how important these markers are in predicting prognosis. This study investigated the prognostic significance of TUNEL, bcl-2, p53, proliferation marker Ki-67 and DNA mismatch repair (MMR) status in patients with Dukes' stage B2 and C colorectal adenocarcinomas. Patients and Methods Tumor tissue from 366 patients (75% Dukes' C, 25% Dukes' B2) from four randomized North Central Cancer Treatment Group phase III surgical adjuvant trials were used. Eighty-one percent of patients received adjuvant treatment, which was primarily fluorouracil (FU) based (90%). Tumor location was predominantly (87%) the colon. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), Ki-67, p53, bcl-2, and MMR were assayed using immunohistochemistry. Stage, grade, MMR, Ki-67, and previously determined flow cytometry markers (ploidy and S phase) were explored for associations with each other and with overall survival (OS) and disease-free survival (DFS). Results Univariately, stage B2, low grade, diploid, Ki-67 more than 27%, normal p53, and FU-based adjuvant treatment were significantly associated with improved OS and DFS (P &lt; .05). After adjusting for stage, grade, and ploidy in multivariate analysis, Ki-67 remained significantly related to both OS and DFS (P &lt; .01). Active FU-based adjuvant treatment was significant only for OS in this multivariate model. Neither bcl-2 nor TUNEL were significant. Conclusion This retrospective study indicates that Ki-67 and ploidy may have stronger prognostic impact on OS and DFS than other parameters investigated after adjusting for stage and tumor grade. Prospective studies to elucidate the mechanism and prognostic significance of these findings are necessary.
Aromatase inhibitor-induced arthralgia: a review
Authors: P. Niravath
Journal: Annals of Oncology (2013)

Though aromatase inhibitors (AIs) are an essential part of estrogen receptor-positive (ER+) breast cancer therapy, many patients discontinue the medicine before their adjuvant therapy is completed because of the arthralgia which often accompanies the medicine. Up to half of women on AI therapy experience joint pain, and up to 20% will become non-compliant with the medicine because of the joint pain. Yet, very little is known about what causes AI-induced arthralgia (AIA), and there is no established, effective treatment for this difficult problem. It compromises survivors' quality of life and leads to non-compliance. This paper will discuss AIA in depth, including potential etiologies, clinical significance, risk factors, and possible management solutions. Of note, this article presents one of the first proposed algorithms which clearly lays out a treatment plan for AIA, incorporating a variety of interventions which have been proven by the available literature.
Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial
Authors: Gerardo Priotto, Serena Kasparian, Wilfried Mutombo, Daniel Ngouama, Sara Ghorashian, Ute Arnold, Salah Ghabri, Elisabeth Baudin, Vincent Buard, Serge Kazadi-Kyanza, Médard Ilunga, Willy Mutangala, Gabriele Pohlig, Caecilia Schmid, Unni Karunakara, Els Torreele, Victor Kande
Journal: The Lancet (2009)
Hyperalgesia, synovitis and multiple biomarkers of inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty arthritis
Authors: R Torres, L Macdonald, S D Croll, J Reinhardt, A Dore, S Stevens, D M Hylton, J S Rudge, R Liu-Bryan, R A Terkeltaub, G D Yancopoulos, A J Murphy
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Background:</h3> Monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystal-induced interleukin 1 β (IL1β) release contributes to inflammation in subcutaneous air pouch and peritoneal models of acute gout and pseudogout. However, consequences of IL1 inhibition have not been explored in more clinically relevant models of crystal-induced arthritis. <h3>Objective:</h3> To develop a novel mouse model of acute gouty ankle arthritis and use it to assess the effects of genetic deletion of IL1 receptor type (IL1R1) and of exogenous mIL1 Trap (a high-affinity blocker of mouse IL1α and IL1β) on pain, synovitis and systemic inflammatory biomarkers. <h3>Methods:</h3> MSU crystals were injected into the mouse ankle joint and pain and ankle swelling were measured over 4 days. The effects of IL1 inhibition were determined in this model, and in the comparator models of crystal-induced peritonitis and subcutaneous air pouch inflammation. <h3>Results:</h3> Both IL1R1-null mice and mice pretreated with mIL1 Trap showed reduced neutrophil influx in MSU and CPPD crystal-induced peritonitis and air pouch models (p&lt;0.05). In the ankle joint model, both IL1R1 knockout mice and pretreatment with mIL1 Trap were associated with significant reductions in MSU crystal-induced elevations in hyperalgesia, inflammation, serum amyloid A and the levels of multiple inflammatory cytokines and chemokines (p&lt;0.05). Additionally, it was found that administration of mIL1 Trap after MSU crystal injection reduced established hyperalgesia and ankle swelling. <h3>Conclusions:</h3> IL1 inhibition both prevented and relieved pain and ankle joint inflammation in response to intra-articular MSU crystals in mice. Results suggested that IL1 Trap has the potential to both prevent and treat gouty arthritis.
129 MODULATION OF PHOSPHORYLATION OF HEPATITIS C VIRUS NONSTRUCTURAL PROTEIN 5A BY THE LIPID KINASE PI4KIIIα
Authors: S. Reiss, C. Harak, I. Romero-Brey, I. Rebhan, D. Radujkovic, R. Bartenschlager, V. Lohmann
Journal: Journal of Hepatology (2012)
GPs should identify and visit people at risk from cold homes, says NICE
Authors: Z. Kmietowicz
Journal: BMJ (2015)

GPs should identify people who live in cold or hard to heat homes and should visit them once a year to assess their heating needs, the National Institute for Health and Care Excellence (NICE) has recommended.1

Year round planning and action by many sectors is needed to combat problems related to cold homes and fuel poverty, NICE has said, as they can affect a range of groups including people with cardiovascular and respiratory problems, people with mental health conditions, those with disabilities, older people, and households with young children and low incomes.

People who are discharged from hospital or social care homes should also have their …
Effects of calcium supplementation on bone density in healthy children: meta-analysis of randomised controlled trials
Authors: Tania Winzenberg, Kelly Shaw, Jayne Fryer, Graeme Jones
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objectives</b> To assess the effectiveness of calcium supplementation for improving bone mineral density in healthy children and to determine if any effect is modified by other factors and persists after supplementation stops. <b>Design</b> Meta-analysis. <b>Data sources</b> Electronic bibliographic databases, hand searching of conference proceedings, and contacting authors for unpublished data. <b>Review methods</b> We included randomised placebo controlled trials of calcium supplementation in healthy children that lasted at least three months and had bone outcomes measured after at least six months of follow-up. Two reviewers independently extracted data and assessed quality. Meta-analyses predominantly used fixed effects models with outcomes given as standardised mean differences. <b>Results</b> We included 19 studies involving 2859 children. Calcium supplementation had no effect on bone mineral density at the femoral neck or lumbar spine. There was a small effect on total body bone mineral content (standardised mean difference 0.14, 95% confidence interval 0.01 to 0.27) and upper limb bone mineral density (0.14, 0.04 to 0.24). This effect persisted after the end of supplementation only at the upper limb (0.14, 0.01 to 0.28). There was no evidence that sex, baseline calcium intake, pubertal stage, ethnicity, or level of physical activity modified the effect. <b>Conclusions</b> The small effect of calcium supplementation on bone mineral density in the upper limb is unlikely to reduce the risk of fracture, either in childhood or later life, to a degree of major public health importance.
Synovial fluids facilitate small solute diffusivity.
Authors: N M Hadler
Journal: Annals of the Rheumatic Diseases (1980)

The diffusivity of water, fucose, proline, lysine, glutamic acid, glucose and sucrose was determined in a variety of inflammatory human synovial fluids. In view of the constituents of pathological synovial fluids one would predict impedence to solute movement. In several fluid diffusivity was enhanced relative to translational diffusion in water. In most fluids diffusivity was enhanced relative to diffusion in diluted serum. Diffusivity of the solutes was dependent on size and charge of the solute but independent of fluid characteristics, including glucose, protein, and complement concentrations and cellular constituents. This paper reports aberrant small solute behaviour in synovial fluids. Enhanced diffusivity relative to water was demonstrated in hyaluronate dissolved in diluted serum as well. Hyaluronate domains in the synovial fluids interact with these solutes, facilitating movement. This phenomenon affords a homoestatic mechanism as regards chondrocyte viability in spite of inflammation or a low glucose concentration.