tbuckley/cabot-search huggingface dataset:
Treatment of Hypertension in Type 2 Diabetes Mellitus: Blood Pressure Goals, Choice of Agents, and Setting Priorities in Diabetes Care
Authors: Sandeep Vijan, Rodney A. Hayward
Journal: Annals of Internal Medicine (2003)

Hypertension in patients with type 2 diabetes mellitus is a prevalent condition that leads to substantial morbidity and mortality.To evaluate the goals and optimal agents for treatment of hypertension in type 2 diabetes.Review of the medical literatureRandomized trials that evaluated the pharmacologic treatment of hypertension in patients with diabetes and reported microvascular and macrovascular outcomes.Studies were identified by using the Cochrane Library, MEDLINE, meta-analyses, review articles, and expert recommendation. The searches of the Cochrane Library and MEDLINE were performed in May 2000 and updated in April 2002. Data were abstracted to standardized forms by a single reviewer and were confirmed by a second reviewer.Treatment of hypertension in type 2 diabetes provides dramatic benefit. Target diastolic blood pressures of less than 80 mm Hg appear optimal; systolic targets have not been as rigorously evaluated, but targets of 135 mm Hg or less are reasonable. Studies that compare drug classes do not suggest obviously superior agents. However, it is reasonable to conclude that thiazide diuretics, angiotensin-II receptor blockers, and perhaps angiotensin-converting enzyme (ACE) inhibitors may be the preferred first-line agents for treatment of hypertension in diabetes. beta-Blockers and calcium-channel blockers are more effective than placebo, but they may not be as effective as diuretics, angiotensin-II receptor blockers, or ACE inhibitors; however, study results are inconsistent in this regard.Treatment of hypertension in type 2 diabetes, with blood pressure goals of 135/80 mm Hg, provides dramatic benefits. Thiazide diuretics, angiotensin II receptor blockers, and ACE inhibitors may be the best first-line treatments, although other agents are usually necessary and goals may not be achieved even with three or four agents. Aggressive blood pressure control may be the most important factor in preventing adverse outcomes in patients with type 2 diabetes.
Albuminuria in Mice after Injection of Antibodies against Aminopeptidase A
Authors: Miriam E. Gerlofs-Nijland, Karel J. M. Assmann, Henry B. P. M. Dijkman, Jürgen W.C. Dieker, Jacco P. H. F. van Son, Stef Mentzel, Jorge P. van Kats, A. H. Jan Danser, Oliver Smithies, Patricia J. T. A. Groenen, Jack F. M. Wetzels
Journal: Journal of the American Society of Nephrology (2001)

ABSTRACT. It has been shown that injection of combinations of anti-aminopeptidase A (APA) monoclonal antibodies (mAb) that inhibit the enzyme activity induces an acute albuminuria in mice. This albuminuria is not dependent on inflammatory cells, complement, or the coagulation system. APA is an important regulator of the renin-angiotensin system because it is involved in the degradation of angiotensin II (Ang II). This study examined the potential role of glomerular Ang II in the induction of albuminuria. The relation among renal Ang II, glomerular APAX enzyme activity, and albuminuria was examined first. Injection of the nephritogenic combinations ASD-3/37 and ASD-37/41 in BALB/c mice induced albuminuria, whereas the non-nephritogenic combination ASD-3/41 had no effect. There was no clear relation between the inhibition of glomerular APA activity and albuminuria, yet it was evident that intrarenal Ang II levels were significantly increased in albuminuric mice and not in nonalbuminuric mice. As a next step, anti-APA mAb were administered to angiotensinogen-deficient mice that do not produce Ang II, and kidney morphology and albuminuria were determined. Angiotensinogen-deficient mice also developed albuminuria upon ASD-37/41 administration. Altogether, these findings clearly demonstrate that Ang II is not required for the induction of albuminuria upon injection of enzyme-inhibiting anti-APA mAb.
Regulation of Ca <sup>2+</sup> Homeostasis by Atypical Na <sup>+</sup> Currents in Cultured Human Coronary Myocytes
Authors: Gilles Boccara, Cécile Choby, Jean Marc Frapier, Jean François Quignard, Joël Nargeot, Govindan Dayanithi, Sylvain Richard
Journal: Circulation Research (1999)

Primary cultured human coronary myocytes (HCMs) derived from ischemic human hearts express an atypical voltage-gated tetrodotoxin (TTX)-sensitive sodium current (I(Na)). The whole-cell patch-clamp technique was used to study the properties of I(Na) in HCMs. The variations of intracellular calcium ([Ca2+]i) and sodium ([Na+]i) were monitored in non-voltage-clamped cells loaded with Fura-2 or benzofuran isophthalate, respectively, using microspectrofluorimetry. The activation and steady-state inactivation properties of I(Na) determined a "window" current between -50 and -10 mV suggestive of a steady-state Na+ influx at the cell resting membrane potential. Consistent with this hypothesis, the resting [Na+]i was decreased by TTX (1 micromol/L). In contrast, it was increased by Na+ channel agonists that also promoted a large rise in [Ca2+]i. Veratridine (10 micromol/L), toxin V from Anemonia sulcata (0.1 micromol/L), and N-bromoacetamide (300 micromol/L) increased [Ca2+]i by 7- to 15-fold. This increase was prevented by prior application of TTX or lidocaine (10 micromol/L) and by the use of Na(+)-free or Ca(2+)-free external solutions. The Ca(2+)-channel antagonist nicardipine (5 micromol/L) blocked the effect of veratridine on [Ca2+]i only partially. The residual component disappeared when external Na+ was replaced by Li+ known to block the Na+/Ca2+ exchanger. The resting [Ca2+]i was decreased by TTX in some cells. In conclusion, I(Na) regulates [Ca2+]i in primary cultured HCMs. This regulation, effective at baseline, involves a tonic control of Ca2+ influx via depolarization-gated Ca2+ channels and, to a lesser extent, via a Na+/Ca2+ exchanger working in the reverse mode.
Treatment of chronic respiratory failure in kyphoscoliosis: oxygen or ventilation?
Authors: B. Buyse, W. Meersseman, M. Demedts
Journal: European Respiratory Journal (2003)

Patients with kyposcoliosis and chronic respiratory insufficiency are treated either with home oxygen therapy or ventilation. Kyphoscoliotic patients demonstrate impaired ventilatory mechanics, consequently ventilation seems to be the treatment of choice. Yet, no randomised controlled trials (CRT) exist to prove it. Most investigators find it difficult to ethically justify a CRT. Therefore, the current authors performed the following retrospective study: survival and pulmonary function were analysed in all consecutive kyphoscoliotic patients who started long-term oxygen therapy (LTO group; n=15, aged 62+/-11 yrs (mean+/-SD)) or LTO plus nocturnal nasal intermittent positive pressure ventilation (nNIPPV group; n=18, aged 61+/-7 yrs) in the Dept of Pulmonology (University Hospital Gasthuisberg, Leuven) between 1990-2002. Prior to treatment partial pressure of oxygen (PO2) was lower, partial pressure of carbon dioxide (PCO2) tended to be higher and vital capacity (VC) tended to be lower in the nNIPPV group than in the LTO group (PO2 5.9+/-1 versus 6.7+/-0.9 kPa (44+/-8 versus 50+/-7 mmHg), PCO2 8+/-1 versus 7.3+/-0.9 kPa (60+/-8 versus 55+/-7 mmHg), VC 32+/-12 versus 40+/-16% predicted, or 645+/-244 versus 970+/-387 mL). In the nNIPPV group the 1-yr survival was higher (100% versus 66%). nNIPPV patients demonstrated an improvement in PO2 (breathing air) +54%, PCO2 (breathing air) -21%, VC +47% and maximal static inspiratory mouth pressure +33%; these improvements were absent in the LTO group. In conclusion, nocturnal nasal intermittent positive pressure ventilation, plus long-term oxygen therapy results in more favourable survival and changes in blood gases and respiratory function than long-term oxygen therapy alone.
Integrative Genomics Identifies<i>RAB23</i>as an Invasion Mediator Gene in Diffuse-Type Gastric Cancer
Authors: Qingsong Hou, Yong Hui Wu, Heike Grabsch, Yansong Zhu, Siew Hong Leong, Kumaresan Ganesan, Debra Cross, Lay Keng Tan, Jiong Tao, Veena Gopalakrishnan, Bor Luen Tang, Oi Lian Kon, Patrick Tan
Journal: Cancer Research (2008)

Abstract Recurrent genomic amplifications and deletions are frequently observed in primary gastric cancers (GC). However, identifying specific oncogenes and tumor suppressor genes within these regions can be challenging, as they often cover tens to hundreds of genes. Here, we combined high-resolution array-based comparative genomic hybridization (aCGH) with gene expression profiling to target genes within focal high-level amplifications in GC cell lines, and identified RAB23 as an amplified and overexpressed Chr 6p11p12 gene in Hs746T cells. High RAB23 protein expression was also observed in some lines lacking RAB23 amplification, suggesting additional mechanisms for up-regulating RAB23 besides gene amplification. siRNA silencing of RAB23 significantly reduced cellular invasion and migration in Hs746T cells, whereas overexpression of RAB23 enhanced cellular invasion in AGS cells. RAB23 amplifications in primary gastric tumors were confirmed by both fluorescence in situ hybridization and genomic qPCR, and in two independent patient cohorts from Hong Kong and the United Kingdom RAB23 expression was significantly associated with diffuse-type GC (dGC) compared with intestinal-type GC (iGC). These results provide further evidence that dGC and iGC likely represent two molecularly distinct tumor types, and show that investigating focal chromosomal amplifications by combining high-resolution aCGH with expression profiling is a powerful strategy for identifying novel cancer genes in regions of recurrent chromosomal aberration. [Cancer Res 2008;68(12):4623–30]
Autoimmune Gastropathy in Type 1 Diabetic Patients With Parietal Cell Antibodies
Authors: Christophe E.M. De Block, Ivo H. De Leeuw, Johannes J.P.M. Bogers, Paul A. Pelckmans, Margareta M. Ieven, Eric A.E. Van Marck, Kristien L. Van Acker, Luc F. Van Gaal
Journal: Diabetes Care (2003)

Approximately 15-20% of type 1 diabetic patients exhibit parietal cell antibodies (PCAs) targeting gastric H+/K+ATPase. We examined whether iron deficiency anemia, pernicious anemia, and autoimmune gastritis, which may predispose to gastric tumors, were more frequent in PCA+ than in PCA- patients.Gastric biopsies from 88 consecutively recruited type 1 diabetic patients (51 men and 37 women, 47 PCA+ and 41 PCA-, aged 42 +/- 13 years) were evaluated using the updated Sydney system. Immunostaining was done for parietal cells, B- and T-cells, enterochromaffin-like (ECL) cells, and Helicobacter pylori (HP). PCAs were assayed by indirect immunofluorescence, H+/K+ATPase antibodies by enzyme immunoassay, and HP by serology, urea breath test, and histology. Pentagastrin tests were performed in 42 subjects.Autoimmune gastritis (AG) was present in 57% of PCA+ and 10% of PCA- cases (OR 12.5, P < 0.0001). PCA positivity (beta = 1.44; P = 0.04) and hypergastrinemia (beta = 0.01; P = 0.026), but not HP, age, diabetes duration, sex, and HLA-DQ type were risk factors for AG. Iron deficiency anemia (OR 3.9, P = 0.015), pernicious anemia (OR = 4.6, P = 0.022), and hypochlorhydria (OR = 20.0, P = 0.0002) were more frequent in AG+ individuals. HP infection was present in 47 patients but did not influence corpus histology or gastrinemia. (Pre)malignant lesions were found in 26% of PCA+ subjects: ECL cell hyperplasia in 7 AG+ patients, comprising 1 with a gastric carcinoid tumor, and corpus intestinal metaplasia in 11 AG+ patients, including 1 with linitis plastica.PCA+ type 1 diabetic patients should be screened for autoimmune gastritis, iron deficiency, and pernicious anemia. Particularly hypergastrinemic PCA+ patients with autoimmune gastritis are at increased risk for (pre)malignant gastric lesions.
Targeted Nanomedicine for Suppression of CD44 and Simultaneous Cell Death Induction in Ovarian Cancer: An Optimal Delivery of siRNA and Anticancer Drug
Authors: Vatsal Shah, Oleh Taratula, Olga B. Garbuzenko, Olena R. Taratula, Lorna Rodriguez-Rodriguez, Tamara Minko
Journal: Clinical Cancer Research (2013)

The proposed project is aimed at enhancing the efficiency of epithelial ovarian cancer treatment and reducing adverse side effects of chemotherapy using nanotechnology. Overexpression of the CD44 membrane receptor results in tumor initiation, growth, cancer stem cells' specific behavior, development of drug resistance, and metastases. We hypothesize that a developed cancer-targeted delivery system that combines CD44 siRNA with paclitaxel would successfully deliver its payload inside cancer cells, effectively induce cell death, and prevent metastases.We synthesized, characterized, and tested a nanoscale-based drug delivery system (DDS) containing a modified polypropylenimine (PPI) dendrimer as a carrier; anticancer drug paclitaxel as a cell death inducer; a synthetic analog of luteinizing hormone-releasing hormone (LHRH) peptide as a tumor-targeting moiety; and siRNA targeted to CD44 mRNA. The proposed DDS was tested in vitro and in vivo using metastatic ovarian cancer cells isolated from patients with malignant ascites.We found that in contrast with cells isolated from primary tumors, CD44 was highly overexpressed in metastatic cancer cells. Treatment with the proposed tumor-targeted nanoscale-based nucleic acid and DDS led to the suppression of CD44 mRNA and protein, efficient induction of cell death, effective tumor shrinkage, and prevention of adverse side effects on healthy organs.We show a high therapeutic potential for combinatorial treatment of ovarian carcinoma with a novel DDS that effectively transports siRNA targeting to CD44 mRNA simultaneously with cytotoxic agents. Clin Cancer Res; 19(22); 6193-204. ©2013 AACR.
Expression of human A53T alpha-synuclein in the rat substantia nigra using a novel AAV1/2 vector produces a rapidly evolving pathology with protein aggregation, dystrophic neurite architecture and nigrostriatal degeneration with potential to model the pathology of Parkinson's disease
Authors: James B Koprich, Tom H Johnston, M Gabriela Reyes, Xuan Sun, Jonathan M Brotchie
Journal: Molecular Neurodegeneration (2010)

The pathological hallmarks of Parkinson's disease (PD) include the presence of alpha-synuclein (α-syn) rich Lewy bodies and neurites and the loss of dopaminergic (DA) neurons of the substantia nigra (SN). Animal models of PD based on viral vector-mediated over-expression of α-syn have been developed and show evidence of DA toxicity to varying degrees depending on the type of virus used, its concentration, and the serotype of vector employed. To date these models have been variable, difficult to reproduce, and slow in their evolution to achieve a desired phenotype, hindering their use as a model for testing novel therapeutics. To address these issues we have taken a novel vector in this context, that can be prepared in high titer and which possesses an ability to produce neuronally-directed expression, with expression dynamics optimised to provide a rapid rise in gene product expression. Thus, in the current study, we have used a high titer chimeric AAV1/2 vector, to express human A53T α-syn, an empty vector control (EV), or green fluorescent protein (GFP), the latter to control for the possibility that high levels of protein in themselves might contribute to damage.We show that following a single 2 μl injection into the rat SN there is near complete coverage of the structure and expression of A53T α-syn or GFP appears throughout the striatum. Within 3 weeks of SN delivery of their respective vectors, aggregations of insoluble α-syn were observed in SN DA neurons. The numbers of DA neurons in the SN were significantly reduced by expression of A53T α-syn (52%), and to a lesser extent by GFP (24%), compared to EV controls (both P < 0.01). At the level of the striatum, AAV1/2-A53T α-syn injection produced dystrophic neurites and a significant reduction in tyrosine hydroxylase levels (by 53%, P < 0.01), this was not seen in the AAV1/2-GFP condition.In the current implementation of the model, we recapitulate the primary pathological hallmarks of PD, although a proportion of the SN damage may relate to general protein overload and may not be specific for A53T α-syn. Future studies will thus be required to optimise the dose of AAV1/2 employed before fully characterizing this model. The dynamics of the evolution of the pathology however, provide advantages over current models with respect to providing an initial screen to assess efficacy of novel treatments that might prevent/reverse α-syn aggregation.
TV: No news is bad news
Authors: T. Jackson
Journal: BMJ (2000)

AIDS: the Global Killer , Channel 4, 27 November at 11 05 pm

Horizon “The Valley of Life or Death,” BBC 2, 16 November at 9 pm

It was 14 years ago that the government urged us not to die of ignorance. Its warnings about AIDS—the tombstone and iceberg television advertisements in particular—were almost apocalyptic and came amid a wave of media hysteria about the disease. Millions were going to die, and everyone and everything—from rabbis to rabbits—were a potential source of infection, the press screamed.

Now millions around the world either have died or are infected by HIV, but no one, certainly not the British press, is holding the front page any more. Despite the enormous global death toll, AIDS has been too slow in its onset to sustain mainstream media interest.

AIDS: The Global Challenge , by photojournalist Nick Danziger, was billed …
Matrix metalloproteinases in destructive pulmonary pathology
Authors: P T G Elkington
Journal: Thorax (2005)

Pain, irritability and feeding intolerance are common symptoms affecting quality of life in children with severe neurological impairment (SNI). We performed a retrospective study to explore the use of gabapentinoid medications for symptom control in children with SNI. Patients attending the palliative care or gastroenterology department being treated with gabapentin for irritability, vomiting or pain of unknown origin were included. Information was gathered retrospectively from medical documentation. Irritability was reduced in 30 of the 42 patients included. Gabapentin was discontinued in 15 children, 12 of whom then received pregabalin. Three children had a good response to pregabalin, six a minimal improvement and three no improvement. These results support the use of gabapentinoids in this patient cohort.
Impact of Quality of Life on Patient Expectations Regarding Phase I Clinical Trials
Authors: Jonathan D. Cheng, James Hitt, Bogda Koczwara, Kevin A. Schulman, Caroline B. Burnett, Darrell J. Gaskin, Julia H. Rowland, Neal J. Meropol
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Quality of life (QOL) is increasingly recognized as a critical cancer-treatment outcome measure, but little is known about the impact of QOL on the patient decision-making process. A pilot study was conducted in an effort to (1) measure the expectations of patients, physicians, and research nurses regarding the potential benefits and toxicities from experimental and standard therapies, and (2) determine the relationship of QOL to patient perceptions regarding treatment options. METHODS: Thirty cancer patients enrolling in phase I clinical trials, their physicians, and their research nurses were administered questionnaires that assessed demographics, QOL, and treatment expectations. RESULTS: Compared with their physicians, patients overestimated potential benefits and toxicities from experimental therapy (mean expected benefit, 59.8% v 23.8%, P &lt; .01; mean expected toxicity, 29.8% v 16.0%, P &lt; .01). Patients estimated a greater potential for benefit (59.8% v 36.8%, P &lt; .01) and less potential for toxicity (29.8% v 45.6%, P = .01) for experimental therapy, compared with standard therapy. Short Form- 36 general health perception correlated with patient perception of potential benefit from experimental therapy (r = .48, P = .01). CONCLUSION: Participants in phase I clinical trial have high expectations regarding the success of experimental therapy and discount potential toxicity. Patient QOL may affect the expectation of benefit from experimental therapy and, ultimately, treatment choice. Understanding the interactions between QOL and patient expectations may guide the development of improved strategies to present appropriate information to patients considering early-phase clinical trials.
Long-term effects of xamoterol on left ventricular diastolic function and late remodeling: a study in patients with anterior myocardial infarction and single-vessel disease.
Authors: H Pouleur, C van Eyll, C Hanet, P Cheron, A A Charlier, M F Rousseau
Journal: Circulation (1988)

The purpose of the study was to examine whether the prolonged administration of the beta 1-adrenoceptor partial agonist xamoterol could improve left ventricular diastolic function and affect the global remodeling process of the left ventricle after anterior myocardial infarction. In 22 patients with anterior myocardial infarction and single-vessel disease, left ventricular angiography (+ Millar) was performed under basal conditions 1 to 2 months after the acute myocardial infarction. Eight patients were then treated for 3 months with placebo and 14 were treated with xamoterol (200 mg bid) and a second left ventricular angiographic study was performed. Angiograms were digitized frame by frame to derive the diastolic pressure-volume relationship and to compute wall stress. An index of elastic myocardial stiffness was computed at a constant stress of 30 kdynes/cm2 before and after treatment. To evaluate changes in left ventricular shape, segmental areas in anterior and inferior segments were computed and compared at end-diastole and end-systole. After xamoterol, left ventricular end-diastolic pressure and mean diastolic wall stress decreased (from 24 +/- 5 to 15 +/- 5 mm Hg and from 57 +/- 32 to 38 +/- 22 kdynes/cm2, respectively; both p less than .01 vs baseline and vs placebo). These changes were accompanied by a downward shift in the diastolic pressure-volume relationship and by a decrease in the index of myocardial stiffness from 526 +/- 270 to 371 +/- 194 kdynes/cm2 (p less than .02).(ABSTRACT TRUNCATED AT 250 WORDS)
Increased capillary permeability to albumin in diabetic rat myocardium.
Authors: T Yamaji, T Fukuhara, M Kinoshita
Journal: Circulation Research (1993)

To clarify the mechanism for the well-known increase in microvascular permeability that occurs with diabetes mellitus, we investigated capillary permeability to albumin in diabetic rat myocardium by electron microscopy using albumin-gold (Alb-Au) complexes as a tracer. Diabetes was induced by an intravenous injection of streptozotocin. After 24-32 weeks, hearts from diabetic rats and age-matched control rats were perfused with Krebs-Henseleit bicarbonate buffer containing Alb-Au for 5 or 20 minutes and then fixed and processed for electron microscopy. The binding and transport of Alb-Au by capillary endothelium was quantitatively evaluated. In control rats, Alb-Au particles were found preferentially bound to the luminal plasmalemmal vesicles. In diabetic rats, the labeling of luminal vesicles was more extensive and more pronounced after 5 minutes of perfusion when compared with control vesicles. The plasma membrane proper was also heavily labeled in diabetic rats. After 20 minutes, Alb-Au particles were transported across the capillary endothelium via plasmalemmal vesicles, but they did not penetrate the intercellular junctions in either control or diabetic rats. The vesicular transport of Alb-Au across the capillary endothelium was significantly increased in the diabetic myocardium when compared with control myocardium (percentage of abluminal labeled vesicles, 25.9 +/- 5.5% versus 1.3 +/- 0.5%; p < 0.01). The study on food-restricted rats with body weights close to those of diabetic rats suggested that caloric deficiency alone did not have much effect on capillary permeability. The data indicate that capillary permeability to albumin is markedly increased in diabetic myocardium because of enhanced vesicular transport. This may play an important role in the pathogenesis of diabetic cardiomyopathy.