tbuckley/cabot-search huggingface dataset:
Global and Regional Effects of Type 2 Diabetes on Brain Tissue Volumes and Cerebral Vasoreactivity
Authors: David Last, David C. Alsop, Amir M. Abduljalil, Robert P. Marquis, Cedric de Bazelaire, Kun Hu, Jerry Cavallerano, Vera Novak
Journal: Diabetes Care (2007)

The aim of this study was to evaluate the regional effects of type 2 diabetes and associated conditions on cerebral tissue volumes and cerebral blood flow (CBF) regulation.CBF was examined in 26 diabetic (aged 61.6 +/- 6.6 years) and 25 control (aged 60.4 +/- 8.6 years) subjects using continuous arterial spin labeling (CASL) imaging during baseline, hyperventilation, and CO2 rebreathing. Regional gray and white matter, cerebrospinal fluid (CSF), and white matter hyperintensity (WMH) volumes were measured on a T1-weighted inversion recovery fast-gradient echo and a fluid attenuation inversion recovery magnetic resonance imaging at 3 Tesla.The diabetic group had smaller global white (P = 0.006) and gray (P = 0.001) matter and larger CSF (36.3%, P < 0.0001) volumes than the control group. Regional differences were observed for white matter (-13.1%, P = 0.0008) and CSF (36.3%, P < 0.0001) in the frontal region, for CSF (20.9%, P = 0.0002) in the temporal region, and for gray matter (-3.0%, P = 0.04) and CSF (17.6%, P = 0.01) in the parieto-occipital region. Baseline regional CBF (P = 0.006) and CO2 reactivity (P = 0.005) were reduced in the diabetic group. Hypoperfusion in the frontal region was associated with gray matter atrophy (P < 0.0001). Higher A1C was associated with lower CBF (P < 0.0001) and greater CSF (P = 0.002) within the temporal region.Type 2 diabetes is associated with cortical and subcortical atrophy involving several brain regions and with diminished regional cerebral perfusion and vasoreactivity. Uncontrolled diabetes may further contribute to hypoperfusion and atrophy. Diabetic metabolic disturbance and blood flow dysregulation that affects preferentially frontal and temporal regions may have implications for cognition and balance in elderly subjects with diabetes.
Development and in-vitro evaluation of an optimized carvedilol transdermal therapeutic system using experimental design approach
Authors: Namrata Vora, S. Lin, P.L. Madan
Journal: Asian Journal of Pharmaceutical Sciences (2013)

The effect of formulation variables on in-vitro release and permeation properties of carvedilol from transdermal patch was studied by varying one factor at a time as preliminary study. Based on these results, design of experiments technique was applied followed by regression analysis and response surface methodology to optimize formulation variables. Central Composite IV model design was used with four formulation variables: drug loading, matrix thickness, adhesive layer thickness, and propylene glycol concentration. Nineteen formulations were prepared according to the design; and the effect of formulation variables was studied on in-vitro release and permeation profiles of these formulations. In all cases, the permeation profiles paralleled in-vitro release profiles. The drug released at 7 h and 24 h was used as release response parameters while permeation flux obtained was employed as permeation response parameter. All four formulation variables were found to be significant for release properties and three of these exhibited significant effect on permeation profile of carvedilol across artificial membrane. Constrained optimization, using 47.9% of cumulative carvedilol released at 7 h and 99.8% at 24 h as well as 25.7 μg/cm2/h of permeation flux, was applied to obtain desired release and permeation profiles. Experimentally, carvedilol was observed to release from the optimized formulation with 51.4% drug release at 7 h and 98.5% at 24 h with an observed flux value of 27.4 μg/cm2/h across artificial membrane, which showed an excellent agreement with the predicted values. The results of this investigation show that the quadratic mathematical model developed could be used to further predict formulations with desirable release and permeation properties.
Validation of N-terminal pro-brain natriuretic peptide cut-off values for risk stratification of pulmonary embolism
Authors: Mareike Lankeit, David Jiménez, Maciej Kostrubiec, Claudia Dellas, Katherina Kuhnert, Gerd Hasenfuß, Piotr Pruszczyk, Stavros Konstantinides
Journal: European Respiratory Journal (2014)

The optimal N-terminal pro-brain natriuretic peptide (NT-proBNP) cut-off value for risk stratification of pulmonary embolism remains controversial. In this study we validated and compared different proposed NT-proBNP cut-off values in 688 normotensive patients with pulmonary embolism. During the first 30 days, 28 (4.1%) patients reached the primary outcome (pulmonary embolism-related death or complications) and 29 (4.2%) patients died. Receiver operating characteristic analysis yielded an area under the curve of 0.70 (0.60–0.80) for NT-proBNP. A cut-off value of 600 pg·mL −1 was associated with the best prognostic performance (sensitivity 86% and specificity 50%) and the highest odds ratio (6.04 (95% CI 2.07–17.59), p=0.001) compared to the cut-off values of 1000, 500 or 300 pg·mL −1 . Using multivariable logistic regression analysis, NT-proBNP ≥600 pg·mL −1 had a prognostic impact on top of that of the simplified Pulmonary Embolism Severity Index and right ventricular dysfunction on echocardiography (OR 4.27 (95% CI 1.22–15.01); p=0.024, c-index 0.741). The use of a stepwise approach based on the simplified Pulmonary Embolism Severity Index, NT-proBNP ≥600 pg·mL −1 and echocardiography helped optimise risk assessment. Our findings confirm the prognostic value of NT-proBNP and suggest that a cut-off value of 600 pg·mL −1 is most appropriate for risk stratification of normotensive patients with pulmonary embolism. NT-proBNP should be used in combination with a clinical score and an imaging procedure for detecting right ventricular dysfunction.
Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study
Authors: Jun Liang, Huayong Zhang, Bingzhu Hua, Hong Wang, Liwei Lu, Songtao Shi, Yayi Hou, Xiaofeng Zeng, Gary S Gilkeson, Lingyun Sun
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objective</h3> To determine the safety and efficacy of allogeneic mesenchymal stem cell transplantation (MSCT) in refractory systemic lupus erythematosus (SLE). <h3>Methods</h3> A total of 15 patients with persistently active SLE underwent MSCT. Outcome was evaluated by changes in the SLE disease activity index (SLEDAI), serological features (anti-nuclear antibodies and anti-double-stranded DNA (anti-dsDNA)), renal function and percentage of peripheral blood regulatory T cells. <h3>Results</h3> From 11 March 2007 to 4 November 2008, 15 patients with persistently active SLE were enrolled and underwent MSCT. The mean follow-up period was 17.2±9.5 months. A total of 13 patients have been followed for more than 12 months. All patients clinically improved following treatment with mesenchymal stem cells with a marked decrease in the SLEDAI score and 24 h proteinuria. At 12-month follow-up, SLEDAI scores decreased from 12.2±3.3 to 3.2±2.8 and proteinuria decreased from 2505.0±1323.9 to 858.0±800.7 mg/24 h (all p&lt;0.05, by paired t test, n=12). At 1-year follow-up in 13 patients, 2 had a relapse of proteinuria, while the other 11 continue to have decreased disease activity on minimal treatment. Anti-dsDNA levels decreased. Improvement in glomerular filtration rate was noted in two patients in which formal testing was performed. Non-renal-related manifestations also improved significantly. No serious adverse events were reported. <h3>Conclusion</h3> Allogeneic MSCT in patients with refractory lupus resulted in amelioration of disease activity, improvement in serological markers and stabilisation of renal function. MSCT appears beneficial in treatment of patients with SLE refractory to conventional treatment options.
Requirement for Ras Guanine Nucleotide Releasing Protein 3 in Coupling Phospholipase C-γ2 to Ras in B Cell Receptor Signaling
Authors: Masatsugu Oh-hora, Sachiko Johmura, Ari Hashimoto, Masaki Hikida, Tomohiro Kurosaki
Journal: The Journal of Experimental Medicine (2003)

Two important Ras guanine nucleotide exchange factors, Son of sevenless (Sos) and Ras guanine nucleotide releasing protein (RasGRP), have been implicated in controlling Ras activation when cell surface receptors are stimulated. To address the specificity or redundancy of these exchange factors, we have generated Sos1/Sos2 double- or RasGRP3-deficient B cell lines and determined their ability to mediate Ras activation upon B cell receptor (BCR) stimulation. The BCR requires RasGRP3; in contrast, epidermal growth factor receptor is dependent on Sos1 and Sos2. Furthermore, we show that BCR-induced recruitment of RasGRP3 to the membrane and the subsequent Ras activation are significantly attenuated in phospholipase C-γ2–deficient B cells. This defective Ras activation is suppressed by the expression of RasGRP3 as a membrane-attached form, suggesting that phospholipase C-γ2 regulates RasGRP3 localization and thereby Ras activation.
Does the presence of proximal humerus growth plate changes in young baseball pitchers happen only in symptomatic athletes? An<i>x</i>ray evaluation of 21 young baseball pitchers
Authors: J Murachovsky, R Y Ikemoto, L G P Nascimento, R Serpone Bueno, E Strose, L H Almeida
Journal: British Journal of Sports Medicine (2008)

To evaluate the presence of x ray changes in the proximal humerus growth plate of 21 young pitchers.Case series.This study was conducted at the Orthopaedic and Traumatology Department of the ABC College of Medicine, Santo André, São Paulo, Brazil, tertiary institution.21 male adolescent baseball pitchers, with a mean age of 14.5 years and selected from the Brazilian National Team, were studied.The patients underwent x ray examinations of the shoulders.The x rays of the pitchers' shoulders were studied to determine any changes in the proximal humeral growth plate and correlate them with clinical findings.Fourteen athletes (66%) had radiographic changes in the humerus growth plate but only 5 (36%) had pain complaints. Nine of these 14 cases (64%) whom the observers found radiographic changes did not complain of pain. It was also observed that there was a correlation in only 11 cases between clinical and radiographic evaluations.Radiographic changes in the proximal humerus growth plate were found in 66% of the cases, but 64% were asymptomatic. These changes indicate possible evolution, in the future, to a greater degree of retroversion in pitchers' dominant shoulders.
Infant epidermal skin physiology: adaptation after birth
Authors: J.W. Fluhr, R. Darlenski, N. Lachmann, C. Baudouin, P. Msika, C. De Belilovsky, J.-P. Hachem
Journal: British Journal of Dermatology (2011)

Functional and structural skin adaptation is a dynamic process which starts immediately after birth in humans and in mammalian skin in general. This adjustment to the extrauterine dry environment is accomplished in the first year of postnatal life of humans.To assess the dynamic changes in vivo after birth in the molecular composition and skin physiology parameters compared with older children and adults.The molecular composition of the stratum corneum (SC) and the water profile were investigated noninvasively by in vivo Raman confocal microscopy as a function of depth. Functional parameters including transepidermal water loss (characterizing epidermal permeability barrier), capacitance (as an indirect parameter for SC hydration) and skin surface pH were assessed noninvasively. The measurements were performed in 108 subjects divided into six age groups: full-term newborns (1-15 days), babies aged 5-6 weeks, babies aged 6±1 months, children aged 1-2 years, children aged 4-5 years and adults aged 20-35 years.We showed that skin acidification is still under development during the first weeks of life. While the basal epidermal barrier is competent immediately after birth, the SC is less hydrated in the first 2 weeks of postnatal life. Similar continuous decreasing water content towards the surface for all age groups was observed, whereas this gradient was lower for the newborns. Dynamic changes in the amounts of the natural moisturizing factor constituents were revealed in the period of infancy.We demonstrated the relation of formation of an acidic pH as well as underlying mechanisms in the induction of a fully hydrated SC over the first weeks of human life as a dynamic functional adaptation.
Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts
Authors: Liyan Zhuang, Jayoung Kim, Rosalyn M. Adam, Keith R. Solomon, Michael R. Freeman
Journal: Journal of Clinical Investigation (2005)

Lipid rafts are cholesterol- and sphingolipid-enriched microdomains in cell membranes that regulate phosphorylation cascades originating from membrane-bound proteins. In this study, we tested whether alteration of the cholesterol content of lipid rafts in prostate cancer (PCa) cell membranes affects cell survival mechanisms in vitro and in vivo. Simvastatin, a cholesterol synthesis inhibitor, lowered raft cholesterol content, inhibited Akt1 serine-threonine kinase (protein kinase Bα)/protein kinase B (Akt/PKB) pathway signaling, and induced apoptosis in caveolin- and PTEN-negative LNCaP PCa cells. Replenishing cell membranes with cholesterol reversed these inhibitory and apoptotic effects. Cholesterol also potentiated Akt activation in normal prostate epithelial cells, which were resistant to the apoptotic effects of simvastatin. Elevation of circulating cholesterol in SCID mice increased the cholesterol content and the extent of protein tyrosine phosphorylation in lipid rafts isolated from LNCaP/sHB xenograft tumors. Cholesterol elevation also promoted tumor growth, increased phosphorylation of Akt, and reduced apoptosis in the xenografts. Our results implicate membrane cholesterol in Akt signaling in both normal and malignant cells and provide evidence that PCa cells can become dependent on a cholesterol-regulated Akt pathway for cell survival.
Navigating Between the Scylla and Charybdis of Prescribing Dietary Protein for Chronic Kidney Diseases
Authors: Harold A. Franch, William E. Mitch
Journal: Annual Review of Nutrition (2009)

A fundamental clinical problem in treating patients with chronic kidney disease (CKD) is designing their diets: an excess of protein leads to the accumulation of uremic toxins, whereas a diet insufficient in protein could lead to loss of lean body mass. The benefits of dietary protein restriction include reducing the accumulation of metabolic waste products that can suppress appetite and stimulate muscle protein wasting. There also is a potential for slowing the loss of kidney function. Unfortunately, advanced CKD is strongly associated with a protein wasting syndrome that is directly correlated with morbidity and mortality. Fortunately, the mechanisms underlying negative responses to an excess of dietary protein, including the causes of the wasting syndrome, are beginning to be understood. We have examined how dietary protein influences the mechanisms causing protein wasting, and we propose a framework for approaching the variable dietary protein requirements in patients with CKD or end-stage kidney disease.
Television entertainment and the US health-care debate
Authors: J. Turow
Journal: The Lancet (1996)

Some experts on the media say that entertainment can be more successful than news at providing insights into certain institutions, medicine being a good example. US television series that feature physicians as the central characters have been immensely popular. In the early series, dating back to the 1952 debut of City Hospital, the physician was an all-powerful hero working in a sparkling centre of healing, with medicine portrayed as a resource freely available to all. The programmes began to change in the 1970s. Plots centred more around the physicians' personal problems than on the patients, but economic and health-policy issues were still rarely discussed adequately. In the end, what viewers come away with may lead them towards false expectations, and they may increasingly blame doctors for decisions that others make and enforce.
Cholinergic Activity in Autism: Abnormalities in the Cerebral Cortex and Basal Forebrain
Authors: Elaine K. Perry, Mandy L.W. Lee, Carmen M. Martin-Ruiz, Jennifer A. Court, Stephen G. Volsen, Jenny Merrit, Elizabeth Folly, Portia E. Iversen, Margaret L. Bauman, Robert H. Perry, Gary L. Wenk
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: Measures of cholinergic transmitter activity were investigated in patients with autism because of reported neuropathological abnormalities in cholinergic nuclei in the basal forebrain. METHOD: Levels of cholinergic enzyme and receptor activity were measured in the frontal and parietal cerebral cortex of deceased autistic adults, similarly aged normal adults without mental retardation, and nonautistic mentally retarded adults. The immunoreactivity levels of brain-derived neurotrophic factor and nerve growth factor were measured in the basal forebrain. RESULTS: There were no differences between the autistic and comparison groups in choline acetyltransferase or acetylcholinesterase activity in the cerebral cortex and basal forebrain or in muscarinic M2 receptor or α-bungarotoxin binding within the cortex. Cortical M1 receptor binding was up to 30% lower than normal in the autistic subjects, and the difference reached significance in the parietal cortex. In both the parietal and frontal cortices, differences in nicotinic receptors assessed by [3H]epibatidine binding were significant and extensive (65%–73% lower in the autistic group than in the normal subjects); there were no differences in nicotine binding in the basal forebrain. Immunochemical analysis indicated lower levels of both the α4 and β2 nicotinic receptor subunits in the parietal cortex. The M1 receptor abnormality was not evident in the nonautistic group with mental retardation, although the lower [3H]epibatidine binding was apparent. In the basal forebrain, the level of brain-derived neurotrophic factor in the autistic group was three times as high as the level of the normal group. CONCLUSIONS: These neurochemical abnormalities implicate the cholinergic system in developmental disorders such as autism and suggest the potential for intervention based on cholinergic receptor modulation.
Subtleties of biomineralisation revealed by manipulation of the eggshell membrane
Authors: Nan Li, Li-na Niu, Yi-pin Qi, Cynthia K.Y. Yiu, Heonjune Ryou, Dwayne D. Arola, Ji-hua Chen, David H. Pashley, Franklin R. Tay
Journal: Biomaterials (2011)
Protein Kinase Cε Is a Predictive Biomarker of Aggressive Breast Cancer and a Validated Target for RNA Interference Anticancer Therapy
Authors: Quintin Pan, Li Wei Bao, Celina G. Kleer, Michael S. Sabel, Kent A. Griffith, Theodoros N. Teknos, Sofia D. Merajver
Journal: Cancer Research (2005)

Abstract Tumor metastasis is the major cause of morbidity and mortality in patients with breast cancer. It is critical to identify metastasis enabling genes and understand how they are responsible for inducing specific aspects of the metastatic phenotype to allow for improved clinical detection and management. Protein kinase Cε (PKCε), a member of a family of serine/threonine protein kinases, is a transforming oncogene that has been reported to be involved in cell invasion and motility. In this study, we investigated the role of PKCε in breast cancer development and progression. High-density tissue microarray analysis showed that PKCε protein was detected in 73.6% (106 of 144) of primary tumors from invasive ductal breast cancer patients. Increasing PKCε staining intensity was associated with high histologic grade (P = 0.0206), positive Her2/neu receptor status (P = 0.0419), and negative estrogen (P = 0.0026) and progesterone receptor status (P = 0.0008). Kaplan-Meier analyses showed that PKCε was significantly associated with poorer disease-free and overall survival (log-rank, P = 0.0478 and P = 0.0414, respectively). RNA interference of PKCε in MDA-MB231 cells, an aggressive breast cancer cell line with elevated PKCε levels, resulted in a cell phenotype that was significantly less proliferative, invasive, and motile than the parental or the control RNA interference transfectants. Moreover, in vivo tumor growth of small interfering RNA-PKCε MDA-MB231 clones was retarded by a striking 87% (P &amp;lt; 0.05) and incidence of lung metastases was inhibited by 83% (P &amp;lt; 0.02). PKCε-deficient clones were found to have lower RhoC GTPase protein levels and activation. Taken together, these results revealed that PKCε plays a critical and causative role in promoting an aggressive metastatic breast cancer phenotype and as a target for anticancer therapy.
Examining the exhaled levels of hydrogen peroxide in rheumatoid arthritis: a pilot study
Authors: T R Mikuls, J R O'Dell, R Ertl, D A Bergman, S I Rennard
Journal: Annals of the Rheumatic Diseases (2006)

Previous studies have assessed airway inflammation in rheumatoid arthritis by using bronchoalveolar lavage (BAL).1,2 To widen the scope of the study, a biomarker that is less invasive and less expensive is necessary. Recent studies have shown that exhaled breath condensate (EBC), a measure that is minimally invasive and substantially less expensive than BAL, can be used to assess inflammation in the lower respiratory tract.3,4 To assess the utility of this measure, we compared the levels of EBC hydrogen peroxide (H2O2) in patients with rheumatoid arthritis with values in controls.

Patients with rheumatoid arthritis (n = 22) meeting the disease classification criteria5 and controls (n = 23) were studied. As smoking influences EBC measures of inflammation,6 we assessed smoking status (current smoker v non-smoker), excluding subjects self-reporting a diagnosis of chronic …