tbuckley/cabot-search huggingface dataset:
The Highs and Lows of Cannabinoid Receptor Expression in Disease: Mechanisms and Their Therapeutic Implications
Authors: Lydia K. Miller, Lakshmi A. Devi
Journal: Pharmacological Reviews (2011)

Alterations in the endogenous cannabinoid system have been described in almost every category of disease. These changes can alternatively be protective or maladaptive, such as producing antinociception in neuropathic pain or fibrogenesis in liver disease, making the system an attractive therapeutic target. However, the challenge remains to selectively target the site of disease while sparing other areas, particularly mood and cognitive centers of the brain. Identifying regional changes in cannabinoid receptor-1 and -2 (CB(1)R and CB(2)R) expression is particularly important when considering endocannabinoid system-based therapies, because regional increases in cannabinoid receptor expression have been shown to increase potency and efficacy of exogenous agonists at sites of disease. Although there have been extensive descriptive studies of cannabinoid receptor expression changes in disease, the underlying mechanisms are only just beginning to unfold. Understanding these mechanisms is important and potentially relevant to therapeutics. In diseases for which cannabinoid receptors are protective, knowledge of the mechanisms of receptor up-regulation could be used to design therapies to regionally increase receptor expression and thus increase efficacy of an agonist. Alternatively, inhibition of harmful cannabinoid up-regulation could be an attractive alternative to global antagonism of the system. Here we review current findings on the mechanisms of cannabinoid receptor regulation in disease and discuss their therapeutic implications.
A Sphingosine-1–Phosphate-Activated Calcium Channel Controlling Vascular Smooth Muscle Cell Motility
Authors: Shang-Zhong Xu, Katsuhiko Muraki, Fanning Zeng, Jing Li, Piruthivi Sukumar, Samir Shah, Alexandra M. Dedman, Philippa K. Flemming, Damian McHugh, Jacqueline Naylor, Alex Cheong, Alan N. Bateson, Christopher M. Munsch, Karen E. Porter, David J. Beech
Journal: Circulation Research (2006)

In a screen of potential lipid regulators of transient receptor potential (TRP) channels, we identified sphingosine-1-phosphate (S1P) as an activator of TRPC5. We explored the relevance to vascular biology because S1P is a key cardiovascular signaling molecule. TRPC5 is expressed in smooth muscle cells of human vein along with TRPC1, which forms a complex with TRPC5. Importantly, S1P also activates the TRPC5-TRPC1 heteromultimeric channel. Because TRPC channels are linked to neuronal growth cone extension, we considered a related concept for smooth muscle. We find S1P stimulates smooth muscle cell motility, and that this is inhibited by E3-targeted anti-TRPC5 antibody. Ion permeation involving TRPC5 is crucial because S1P-evoked motility is also suppressed by the channel blocker 2-aminoethoxydiphenyl borate or a TRPC5 ion-pore mutant. S1P acts on TRPC5 via two mechanisms, one extracellular and one intracellular, consistent with its bipolar signaling functions. The extracellular effect appears to have a primary role in S1P-evoked cell motility. The data suggest S1P sensing by TRPC5 calcium channel is a mechanism contributing to vascular smooth muscle adaptation.
Laboratory contamination of Mycobacterium tuberculosis cultures.
Authors: N E Dunlap, R H Harris, W H Benjamin, J W Harden, D Hafner
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

The purpose of this study was to investigate possible laboratory contamination of Mycobacterium tuberculosis cultures which resulted in the misdiagnosis of tuberculosis. We have investigated three cases in which a patient's culture was positive for M. tuberculosis but there was not a high clinical suspicion for disease. In each instance, another patient with clinically obvious pulmonary tuberculosis had specimens cultured concurrently within the same clinical laboratory. The isolates from both the obvious cases of tuberculosis and the suspect cases were obtained through the State of Alabama TB Laboratory, but these isolates originated at a commercial laboratory, a community hospital laboratory, and at a university hospital. MTB isolates were fingerprinted by probing for the insertion sequence IS6110. With each of the three pairs of isolates (case and suspicious case), identical IS6110 banding patterns were found suggesting identical MTB strains. Because the patients were geographically separated, it is strongly suspected that laboratory contamination of M. tuberculosis cultures resulted in the three suspect cases being diagnosed with tuberculosis. These findings indicate that positive M. tuberculosis cultures resulting from laboratory contamination can occur.
Repaglinide Administration Improves Brachial Reactivity in Type 2 Diabetic Patients
Authors: Daniela Manzella, Rodolfo Grella, Angela Marie Abbatecola, Giuseppe Paolisso
Journal: Diabetes Care (2005)

Several studies have demonstrated that endothelial dysfunction plays a central role in diabetic mortality and that the prooxidative effect of postprandial hyperglycemia may actively contribute to atherogenesis. Thus, we investigated the possible effect of short-acting (repaglinide) and long-acting (glibenclamide) insulin secretagogues on endothelial function in type 2 diabetic patients.Sixteen type 2 diabetic patients undergoing diet treatment and with poor glucose control volunteered for the study. The study was designed as a 4-month, randomized, cross-over, parallel-group trial of repaglinide (1 mg twice a day) versus glibenclamide (5 mg twice a day). All patients underwent the following investigations: 1) anthropometrics determinations, 2) blood sampling for routine laboratory analyses and for assessment of oxidative stress indexes, and 3) a brachial reactivity test to evaluate the endothelial function through the study of arterial diameter and flow changes with and without intraarterial infusion of N(G)-monomethyl-l-arginine, an inhibitor of nitric oxide synthase and tetraethylammonium chloride (TEA), a Ca(2+)-activated K(+) (K(Ca)) channel blocker. All patients were randomly assigned to receive repaglinide or glibenclamide for a period of 4 weeks.Repaglinide administration was associated with a significant reduction in 2-h plasma glucose levels (P < 0.001) and in plasma thiobarbituric acid-reactive substances (TBARS) concentrations (P < 0.001) and with a significant increase in plasma antioxidant power, assessed as Trolox equivalent antioxidant capacity (TEAC) (P < 0.001), effects not observed after glibenclamide administration. With regard to brachial reactivity parameters, repaglinide but not glibenclamide was associated with a significant improvement in brachial reactivity parameters (P < 0.003 for all parameters). In contrast, intra-arterial infusion of L-NMMA and TEA reduced the beneficial effect of repaglinide.Repaglinide administration, through good control of postprandial glucose levels, improves brachial reactivity and declines oxidative stress indexes.
Noninvasive and invasive evaluation of pulmonary arterial pressure in highlanders
Authors: B. K. Kojonazarov, B. Z. Imanov, T. A. Amatov, M. M. Mirrakhimov, R. Naeije, M. R. Wilkins, A. A. Aldashev
Journal: European Respiratory Journal (2006)

The purpose of the present study was to evaluate Doppler echocardiography for the detection of pulmonary hypertension in high-altitude inhabitants. In total, 60 (55 male) patients aged 18–71 yrs were recruited from an ECG screening programme applied to 1,430 inhabitants living at an altitude of 2,500–3,600 m in Kyrgyzstan. Of these, 44 met ECG criteria for right ventricular hypertrophy. All underwent Doppler echocardiography followed by a cardiac catheterisation within 7 days of arrival in Bishkek (Kyrgyzstan; altitude 760 m). Pulmonary flow acceleration time and the maximum velocity of tricuspid regurgitation were measured. Sufficient quality tricuspid regurgitant jets were recovered in only 28% of the patients. Therefore, pulmonary artery pressure was estimated from the pulmonary flow acceleration time, which was recovered in 100% of the patients. It was found that 37 (62%) of the patients had pulmonary hypertension on echocardiography. Pulmonary hypertension was confirmed in 29 patients on catheterisation. Pulmonary hypertension was detected with 70% sensitivity and 88% specificity by echocardiography, as compared to 59% sensitivity and 81 % specificity by ECG. The correlation coefficient between echocardiography and catheterisation studies was r<sup>2</sup> = 0.78. It is concluded that a combination of ECG and echocardiography may be useful for screening high-altitude pulmonary hypertension.
Changes in A1C Levels Are Significantly Associated With Changes in Levels of the Cardiovascular Risk Biomarker hs-CRP
Authors: Oliver Schnell, Ildiko Amann-Zalan, Zhihong Jelsovsky, Annette Moritz, Justo L. Bermejo, Christopher G. Parkin, Matthias A. Schweitzer, Lawrence Fisher, William H. Polonsky
Journal: Diabetes Care (2013)

The effect of therapeutic strategies on cardiovascular (CV) disease can be evaluated by monitoring changes in CV risk biomarkers. This study investigated the effect of a structured self-monitoring of blood glucose (SMBG) protocol and the resulting improvements in glycemic control on changes in high-sensitivity C-reactive protein (hs-CRP) in insulin-naïve patients with type 2 diabetes.The Structured Testing Program (STeP) study was a prospective, cluster-randomized, multicenter trial in which 483 poorly controlled, insulin-naïve patients with type 2 diabetes were randomized to active control (ACG) or structured testing (STG) that included quarterly structured SMBG. Changes in A1C, hs-CRP, and glycemic variability (STG subjects only) were measured at baseline and quarterly.Reductions in geometric mean hs-CRP values were significantly greater in the STG group at months 3 (P = 0.005), 6 (P = 0.0003), and 12 (P = 0.04) than in the ACG group. STG patients at high CV risk (>3 mg/L) showed significantly greater reductions in hs-CRP levels than ACG patients at high CV risk: -3.64 mg/dL (95% CI -4.21 to -3.06) versus -2.18 mg/dL (-2.93 to -1.43), respectively (P = 0.002). There was a strong correlation between reductions in hs-CRP and A1C in both groups: standardized coefficient (β) was 0.25 for the entire cohort (P < 0.0001), 0.31 for STG (P < 0.0001), and 0.16 for ACG (P = 0.02).Reductions in hs-CRP level are associated with reductions in A1C but not reductions in lipids or glycemic variability. Comprehensive structured SMBG-based interventions that lower A1C may translate into improvements in CV risk, as evidenced by levels of the biomarker hs-CRP.
Notes of an Easter Holiday Trip to Madeira
Authors: T. S. Wells
Journal: BMJ (1880)

Lastly, the wound was thoroughly cleansed of blood and seen to be dry; then the flap was laid down and accurately closed with wire sutures.A pad of lint and oil silk covering were used, and bandaged round the joint to exclude the air, and prevent any collection of blood beneath the flap.I never haze recourse to antiseptic precautions in the operation or in dressing the wound; and in after-dressings, I trust entirely and with confidence to the pre-septicism of cleanliness and general hygienic arrangements.Under this system, I have never yet known py;emia or septicaemia to follow any joint-excision in now an unusually large number of cases.In the present case, the ordinary amount of swelling followed the operation, but which gradually subsided; and the joint was not un- covered for some days.Then primary union had taken place throughout the whole length of the incision, although generally the angles re- main open and ooze for some time.Two or three of the sutures were picked out, the others remaining until the adhesion had become firm- in the course of another week or two.Three sinuses, existing before the operation, afterwards served to drain away a small quantity of adhesive serous fluid.Two months after operation, on July 4th, the splints were removed for the first time, when the bones were found to have firmly united, and the patient could raise the limb a little from the bed.The splints were reapplied.The man's general health had much improved ; and, instead of presenting a withered and prematurely old appearance, his rejuvenescence was a matter of general comment in the hospital.
Evolution of Escherichia coli to 42 °C and Subsequent Genetic Engineering Reveals Adaptive Mechanisms and Novel Mutations
Authors: Troy E. Sandberg, Margit Pedersen, Ryan A. LaCroix, Ali Ebrahim, Mads Bonde, Markus J. Herrgard, Bernhard O. Palsson, Morten Sommer, Adam M. Feist
Journal: Molecular Biology and Evolution (2014)

Adaptive laboratory evolution (ALE) has emerged as a valuable method by which to investigate microbial adaptation to a desired environment. Here, we performed ALE to 42 °C of ten parallel populations of Escherichia coli K-12 MG1655 grown in glucose minimal media. Tightly controlled experimental conditions allowed selection based on exponential-phase growth rate, yielding strains that uniformly converged toward a similar phenotype along distinct genetic paths. Adapted strains possessed as few as 6 and as many as 55 mutations, and of the 144 genes that mutated in total, 14 arose independently across two or more strains. This mutational recurrence pointed to the key genetic targets underlying the evolved fitness increase. Genome engineering was used to introduce the novel ALE-acquired alleles in random combinations into the ancestral strain, and competition between these engineered strains reaffirmed the impact of the key mutations on the growth rate at 42 °C. Interestingly, most of the identified key gene targets differed significantly from those found in similar temperature adaptation studies, highlighting the sensitivity of genetic evolution to experimental conditions and ancestral genotype. Additionally, transcriptomic analysis of the ancestral and evolved strains revealed a general trend for restoration of the global expression state back toward preheat stressed levels. This restorative effect was previously documented following evolution to metabolic perturbations, and thus may represent a general feature of ALE experiments. The widespread evolved expression shifts were enabled by a comparatively scant number of regulatory mutations, providing a net fitness benefit but causing suboptimal expression levels for certain genes, such as those governing flagellar formation, which then became targets for additional ameliorating mutations. Overall, the results of this study provide insight into the adaptation process and yield lessons important for the future implementation of ALE as a tool for scientific research and engineering.
Maternal metabolism and obesity: modifiable determinants of pregnancy outcome
Authors: S. M. Nelson, P. Matthews, L. Poston
Journal: Human Reproduction Update (2009)

Obesity among pregnant women is highly prevalent worldwide and is associated in a linear manner with markedly increased risk of adverse outcome for mother and infant. Obesity in the mother may also independently confer risk of obesity to her child. The role of maternal metabolism in determining these outcomes and the potential for lifestyle modification are largely unknown.Relevant studies were identified by searching PubMed, the metaRegister of clinical trials and Google Scholar without limitations. Sensitive search strategies were combined with relevant medical subject headings and text words.Maternal obesity and gestational weight gain have a significant impact on maternal metabolism and offspring development. Insulin resistance, glucose homeostasis, fat oxidation and amino acid synthesis are all disrupted by maternal obesity and contribute to adverse outcomes. Modification of lifestyle is an effective intervention strategy for improvement of maternal metabolism and the prevention of type 2 diabetes and, potentially, gestational diabetes.Maternal obesity requires the development of effective interventions to improve pregnancy outcome. Strategies that incorporate a detailed understanding of the maternal metabolic environment and its consequences for the health of the mother and the growth of the child are likely to identify the best approach.
Prostaglandin E<sub>2</sub> Enhances Chemical and Mechanical Sensitivities of Pulmonary C Fibers in the Rat
Authors: CHING-YIN HO, QIHAI GU, JU-LUN HONG, LU-YUAN LEE
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

It has been recently reported that pulmonary reflex responses to injection or inhalation challenge of capsaicin are enhanced by exogenous Prostaglandin E2 (PGE2). The present study was carried out to determine whether PGE2 enhances the stimulatory effects of chemical stimulants and lung inflation on vagal pulmonary C fibers, and if so, whether the excitabilities of other types of lung afferents are also augmented by PGE2. In anesthetized, open-chest rats, administration of PGE2 (1.5 μ g/kg/min for 2 min) did not significantly change the baseline activity of vagal pulmonary C fibers, but it markedly enhanced the stimulatory effects of both low (0.25 μ g/kg) and high doses (0.5 μ g/kg) of capsaicin on these fibers. Similarly, potentiating effects of PGE2 were found on the pulmonary C-fiber responses to injections of lactic acid and adenosine, although considerable variability existed in the degrees of potentiation between the different stimulants. Furthermore, PGE2 infusion also significantly enhanced the C-fiber response to constant-pressure lung inflation (tracheal pressure [Pt] = 30 cm H2O). In contrast, PGE2 did not alter the responses of either slowly adapting pulmonary receptors or rapidly adapting pulmonary receptors to lung inflation. In summary, these results show that the sensitivity of pulmonary C-fiber afferents to both mechanical and chemical stimuli is enhanced by PGE2, suggesting that endogenous release of this autocoid may play a part in the airway irritation and dyspneic sensation associated with airway inflammation.
Bias in Assessment of Health-Related Quality of Life in a Hemodialysis Population
Authors: Mark Unruh, Guofen Yan, Milena Radeva, Ron D. Hays, Robert Benz, Nicolaos V. Athienites, John Kusek, Andrew S. Levey, Klemens B. Meyer
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Examined is the relationship of patient-reported health-related quality of life (HRQOL) to the mode of survey administration in the Hemodialysis Study. In addition to self-administered surveys to assess HRQOL, interviewer-administered surveys were made available to include patients with poor vision, decreased manual dexterity, or strong preference. For examining the predictors of participation by self-administration of the survey, multiple logistic regression was performed. For examining the relationship of HRQOL results to mode of survey administration, adjusted differences between the self-administered and interviewer-administered groups were obtained from multiple linear regression models accounting for sociodemographic and case-mix factors. A total of 978 of the first 1000 subjects in the Hemodialysis Study completed the survey by interview (n = 427) or by self-administration (n = 551). The interviewer-administered group was older, was more likely black, had longer duration of ESRD, had a higher prevalence of diabetes, and had more severe comorbidity (all P < 0.01). After adjustment for these differences, patients in the interviewer-administered group had higher scores on scales that measured Role-Physical, Role-Emotional, and Effects of Kidney Disease (all P < 0.001). Dialysis studies that restrict HRQOL measurement to patients who are able to complete surveys without assistance will not accurately represent the health of the overall hemodialysis population. Clinical studies and clinical practices using HRQOL as an outcome should include interviewer administration or risk a selection bias against subjects with older age, minority status, and higher level of comorbidity. Future investigation should include research of survey modalities with a low response burden such as telephone interview, computer-assisted interview, and proxy administration. E-mail: [email protected]
Effect of a Clinical Pathway to Reduce Hospitalizations in Nursing Home Residents With Pneumonia
Authors: Mark Loeb, Soo Chan Carusone, Ron Goeree, Stephen D Walter, Kevin Brazil, Paul Krueger, Andrew Simor, Lorraine Moss, Thomas Marrie
Journal: JAMA (2006)

ContextNursing home residents with pneumonia are frequently hospitalized. Such transfers may be associated with multiple hazards of hospitalization as well as economic costs.ObjectiveTo assess whether using a clinical pathway for on-site treatment of pneumonia and other lower respiratory tract infections in nursing homes could reduce hospital admissions, related complications, and costs.Design, Setting, and ParticipantsA cluster randomized controlled trial of 680 residents aged 65 years or older in 22 nursing homes in Hamilton, Ontario, Canada. Nursing homes began enrollment between January 2, 2001, and April 18, 2002, with the last resident follow-up occurring July 4, 2005. Residents were eligible if they met a standardized definition of lower respiratory tract infection.InterventionsTreatment in nursing homes according to a clinical pathway, which included use of oral antimicrobials, portable chest radiographs, oxygen saturation monitoring, rehydration, and close monitoring by a research nurse, or usual care.Main Outcome MeasuresHospital admissions, length of hospital stay, mortality, health-related quality of life, functional status, and cost.ResultsThirty-four (10%) of 327 residents in the clinical pathway group were hospitalized compared with 76 (22%) of 353 residents in the usual care group. Adjusting for clustering of residents in nursing homes, the weighted mean reduction in hospitalizations was 12% (95% confidence interval [CI], 5%-18%; P = .001). The mean number of hospital days per resident was 0.79 in the clinical pathway group vs 1.74 in the usual care group, with a weighted mean difference of 0.95 days per resident (95% CI, 0.34-1.55 days; P = .004). The mortality rate was 8% (24 deaths) in the clinical pathway group vs 9% (32 deaths) in the usual care group, with a weighted mean difference of 2.9% (95% CI, –2.0% to 7.9%; P = .23). There were no significant differences between the groups in health-related quality of life or functional status. The clinical pathway resulted in an overall cost savings of US $1016 per resident (95% CI, $207-$1824) treated.ConclusionTreating residents of nursing homes with pneumonia and other lower respiratory tract infections with a clinical pathway can result in comparable clinical outcomes, while reducing hospitalizations and health care costs.Trial Registrationclinicaltrials.gov Identifier: NCT00157612
Heterogeneity among human collagenases demonstrated by monoclonal antibody that selectively recognizes and inhibits human neutrophil collagenase.
Authors: K A Hasty, M S Hibbs, A H Kang, C L Mainardi
Journal: The Journal of Experimental Medicine (1984)

The heterogeneity of human collagenases has been examined using a monoclonal antibody to neutrophil collagenase. This antibody inhibited collagenase activity and, when covalently coupled to Sepharose, bound both latent and active enzyme. Although human neutrophil collagenase was inhibited by the antibody, the activity of human skin and rheumatoid synovial collagenase was not significantly diminished in the presence of the antibody. Competitive inhibition studies also differentiated between these collagenases. Only human neutrophil collagenase effectively blocked the antibody in a competitive enzyme-linked immunosorbent assay while skin and rheumatoid synovial collagenase again failed to interact with the antibody. The unequivocal recognition of neutrophil collagenase as an immunologically distinct entity from other collagenases supports the hypothesis that neutrophil collagenase is a separate gene product from fibroblast or synovial collagenase.