tbuckley/cabot-search huggingface dataset:
α-Latrotoxin and Its Receptors: Neurexins and CIRL/Latrophilins
Authors: Thomas C Südhof
Journal: Annual Review of Neuroscience (2001)

▪ Abstract α-Latrotoxin, a potent neurotoxin from black widow spider venom, triggers synaptic vesicle exocytosis from presynaptic nerve terminals. α-Latrotoxin is a large protein toxin (120 kDa) that contains 22 ankyrin repeats. In stimulating exocytosis, α-latrotoxin binds to two distinct families of neuronal cell-surface receptors, neurexins and CLs (Cirl/latrophilins), which probably have a physiological function in synaptic cell adhesion. Binding of α-latrotoxin to these receptors does not in itself trigger exocytosis but serves to recruit the toxin to the synapse. Receptor-bound α-latrotoxin then inserts into the presynaptic plasma membrane to stimulate exocytosis by two distinct transmitter-specific mechanisms. Exocytosis of classical neurotransmitters (glutamate, GABA, acetylcholine) is induced in a calcium-independent manner by a direct intracellular action of α-latrotoxin, while exocytosis of catecholamines requires extracellular calcium. Elucidation of precisely how α-latrotoxin works is likely to provide major insight into how synaptic vesicle exocytosis is regulated, and how the release machineries of classical and catecholaminergic neurotransmitters differ.
A 35-Year-Old Pregnant Woman Considering Maternal Serum Screening and Amniocentesis
Authors: Michael Mennuti
Journal: JAMA (1996)

<h3>Dr Daley</h3> : Mrs J, a 35-year-old married attorney and mother of 2 preschool-aged children, is in her first trimester of pregnancy. She is considering maternal serum screening and/or amniocentesis for the detection of neural tube defects and chromosomal abnormalities. She is insured with a managed care organization through her husband's medical insurance. Mrs J is healthy and has had 3 previous pregnancies. Her first pregnancy was uncomplicated during gestation, with a 40-hour labor, ending in a cesarean delivery of a healthy boy at term. Her second pregnancy ended in a spontaneous miscarriage during the first trimester. In the first trimester of her third pregnancy, Mrs J's obstetrician, Dr O, offered her serum screening and/or amniocentesis. She and her husband declined both, feeling that the risks of neural tube defects and chromosomal abnormalities were low and that they would not be willing to terminate a pregnancy in the second trimester if
Geographical Variation in the Penetrance of CDKN2A Mutations for Melanoma
Authors: D. T. Bishop
Journal: JNCI Journal of the National Cancer Institute (2002)

Germline mutations in the CDKN2A gene, which encodes two proteins (p16INK4A and p14ARF), are the most common cause of inherited susceptibility to melanoma. We examined the penetrance of such mutations using data from eight groups from Europe, Australia and the United States that are part of The Melanoma Genetics Consortium.We analyzed 80 families with documented CDKN2A mutations and multiple cases of cutaneous melanoma. We modeled penetrance for melanoma using a logistic regression model incorporating survival analysis. Hypothesis testing was based on likelihood ratio tests. Covariates included gender, alterations in p14ARF protein, and population melanoma incidence rates. All statistical tests were two-sided.The 80 analyzed families contained 402 melanoma patients, 320 of whom were tested for mutations and 291 were mutation carriers. We also tested 713 unaffected family members for mutations and 194 were carriers. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval (CI) = 0.12 to 0.62) by age 50 years and 0.67 (95% CI = 0.31 to 0.96) by age 80 years. Penetrance was not statistically significantly modified by gender or by whether the CDKN2A mutation altered p14ARF protein. However, there was a statistically significant effect of residing in a location with a high population incidence rate of melanoma (P =.003). By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia.This study, which gives the most informed estimates of CDKN2A mutation penetrance available, indicates that the penetrance varies with melanoma population incidence rates. Thus, the same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance.
Clinical spectrum associated with positive ANCA titres in 94 consecutive patients: is there a relation with PR-3 negative c-ANCA and hypergammaglobulinaemia ?
Authors: D Blockmans, E Stevens, G Marien, H Bobbaers
Journal: Annals of the Rheumatic Diseases (1998)

<h3>OBJECTIVE</h3> To calculate the positive predictive value (ppv) of cytoplasmic anti-neutrophil cytoplasmic antibodies (c-ANCAs) and anti-proteinase 3 (PR 3) antibodies for Wegener’s granulomatosis (WG) and to evaluate their association with other diseases. <h3>METHODS</h3> The clinical files of all 94 patients who had a positive c- or perinuclear (p)-ANCA test, or both, in the laboratory of the University Hospital, Leuven between April 1995 and March 1996 and who attended the Internal Medicine Department of the hospital were retrospectively studied. <h3>RESULTS</h3> Of the 94 patients with ANCAs (fluorescence titre ⩾ 1/40), 57 were c-ANCA positive and 45 p-ANCA positive (eight were simultaneously c- and p-ANCA positive). Of the 57 c-ANCA positive patients, 23 had WG. The ppv for WG thus was 40%. This value did not increase by defining a higher threshold for a positive ANCA. There was not a good relation between ANCA titres and disease activity in the WG patients, nor was there a relation between anti-PR 3 antibody levels and WG disease activity. The ppv of anti-PR 3 antibodies for WG however was very high (85%). There was a positive correlation between the level of (hyper) gammaglobulinaemia and c-ANCA titres in those patients with final diagnoses not known to be associated with c-ANCA. Forty five patients had positive p-ANCAs. The largest group were those with inflammatory bowel disease (n = 20, of whom the majority had colitis ulcerosa or primary sclerosing cholangitis, or both); the great majority of these patients had no anti-myeloperoxidase antibodies. Vasculitis was present in eight patients, of whom two had WG (both were also c-ANCA positive). <h3>CONCLUSION</h3> There is a low ppv of c-ANCAs for WG, caused by a high percentage of PR 3 negative, positive c-ANCA determinations, possibly related to hypergammaglobulinaemia. Anti-PR 3 antibodies have a high ppv for WG. However, neither c-ANCA titre, nor the level of anti-PR 3 antibodies correlated with the activity of the disease.
Rising Incidence of Small Renal Masses: A Need to Reassess Treatment Effect
Authors: John M. Hollingsworth, David C. Miller, Stephanie Daignault, Brent K. Hollenbeck
Journal: JNCI Journal of the National Cancer Institute (2006)

The incidence of kidney cancer has been rising over the last two decades, especially in cases where the disease is localized. Although rates of renal surgery parallel this trend, mortality rates have continued to rise. To investigate the basis of this "treatment disconnect" (i.e., increased rates of treatment accompanied by increased mortality rates), we analyzed patient data from nine registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. We assembled a cohort of 34 503 kidney cancer patients and derived incidence, treatment, and mortality trends for kidney cancer, overall and as a function of tumor size. From 1983 to 2002, the overall age-adjusted incidence rate for kidney cancer rose from 7.1 to 10.8 cases per 100 000 US population; tumors ≤4 cm in size accounted for most of the increase. Adjusted rates of renal surgery increased concurrently, most notably for tumors ≤4 cm (0.9–3.6 surgeries per 100 000 US population). However, among kidney cancer patients, all-cause mortality per 100 000 US population increased from 1.5 deaths in 1983 to 6.5 deaths in 2002, with the greatest absolute increase noted for patients with lesions >7 cm. Our results demonstrate that the rising incidence of kidney cancer is largely attributable to an increase in small renal masses that are presumably curable. The fact that increased detection and treatment of small tumors is not reducing mortality argues for a reassessment of the current treatment paradigm.
LI-cadherin: a marker of gastric metaplasia and neoplasia
Authors: C Grötzinger, J Kneifel, D Patschan, N Schnoy, I Anagnostopoulos, S Faiss, R Tauber, B Wiedenmann, R Gessner
Journal: Gut (2001)

<h3>BACKGROUND</h3> Intestinal metaplasia is considered a risk factor for the development of gastric adenocarcinomas of the intestinal type and is found in approximately 20% of gastric biopsies. Conventional histology only detects advanced stages of intestinal metaplasia. <h3>AIMS</h3> To study expression of the enterocyte specific adhesion molecule liver-intestinal (LI)-cadherin in intestinal metaplasia as well as in gastric cancer, and to evaluate its use as a diagnostic marker molecule. <h3>PATIENTS</h3> Gastric biopsies (n=77) from 30 consecutive patients (n=30; aged 28–90 years) as well as surgically resected tissue samples (n=24) of all types of gastric carcinomas were analysed. <h3>METHODS</h3> Single and double label immunofluorescence detection on cryosections of gastric biopsies; alkaline phosphatase antialkaline phosphatase method on paraffin embedded carcinoma tissue sections. <h3>RESULTS</h3> Of 77 biopsies (from 30 patients), 12 (from 10 patients) stained positive for LI-cadherin. LI-cadherin staining correlated with the presence of intestinal metaplasia. Conventional histological diagnosis however failed to detect subtle gastric intestinal metaplasia (three of 10 patients). In contrast, only LI-cadherin and villin were positive in these cases whereas sucrase-isomaltase also failed to detect intestinal metaplasia in four of 10 patients. Well differentiated gastric carcinomas showed intense staining for LI-cadherin while undifferentiated carcinomas showed only weak diffuse cytoplasmic staining. <h3>CONCLUSIONS</h3> To detect early metaplastic changes in the gastric mucosa, LI-cadherin has a sensitivity superior to sucrase-isomaltase and conventional histology and comparable with that of villin. Its specificity exceeds that of villin. Thus LI-cadherin represents a new, reliable, and powerful marker molecule for early detection of gastric intestinal metaplasia and well differentiated adenocarcinomas.
The Effect of Pendelluft and Dead Space on Nitrogen Clearance: Mathematical and Experimental Models and their Application to the Study of the Distribution of Ventilation*
Authors: Ivan Safonoff, George E. Emmanuel
Journal: Journal of Clinical Investigation (1967)

Reinspired mixed dead space gas and Pendelluft may be considered to be part of a single process of interalveolar gas transfer. The effect of interalveolar gas transfer on nitrogen clearance from a two chamber lung model can be described by a single set of equations which hold for synchronous, and series ventilation. Interalveolar gas transfer may theoretically be either bidirectional or unidirectional. Bidirectional transfer results in an underestimation of the effective ventilation and volume of the well-ventilated compartment when nitrogen washout is analyzed by available methods. The volume of the poorly ventilated compartment is overestimated and its effective ventilation is usually overestimated but may be correctly or underestimated as distribution becomes more uneven. Unidirectional transfer has the same qualitative effect except that the ventilation of the poorly ventilated space is always overestimated. The distortions produced by both types of gas transfer become less marked as ventilation becomes more uneven.Nitrogen washout data from a model consisting of two rubber balloons connected with a Y tube agree well with the mathematical predictions. Application of the theory to data obtained from patients with advanced chronic obstructive lung disease suggests that estimates of the functional residual capacity and of the volume and ventilation of the poorly ventilated spaces are not greatly affected by interalveolar gas transfer when nitrogen washout is analyzed by usual methods.
Biomechanical Forces in Atherosclerosis-Resistant Vascular Regions Regulate Endothelial Redox Balance via Phosphoinositol 3-Kinase/Akt-Dependent Activation of Nrf2
Authors: Guohao Dai, Saran Vaughn, Yuzhi Zhang, Eric T. Wang, Guillermo Garcia-Cardena, Michael A. Gimbrone
Journal: Circulation Research (2007)

Local patterns of biomechanical forces experienced by endothelial cells (ECs) in different vascular geometries appear to play an essential role in regulating EC function and determining the regional susceptibility to atherosclerosis, even in the face of systemic risk factors. To study how biomechanical forces regulate EC redox homeostasis, an important pathogenic factor in atherogenesis, we have cultured human ECs under 2 prototypic arterial shear stress waveforms, “atheroprone” and “atheroprotective,” which were derived from 2 distinct vascular regions in vivo that are typically “susceptible” or “resistant” to atherosclerosis. We demonstrate that atheroprotective flow decreases EC intracellular redox level and protects ECs against oxidative stress–induced injury. To identify the molecular mechanisms that control this cellular response, we examined several major oxidative/antioxidative pathways and found that atheroprotective flow upregulated certain antioxidant genes and strongly activated the transcription factor Nrf2. Using a strategy of small interfering RNA inhibition of Nrf2 expression combined with genome-wide transcriptional profiling, we determined the downstream targets of Nrf2 activation and identified Nrf2 as a critical determinant for the changes in endothelial redox balance exerted by atheroprotective flow. In addition, we showed that atheroprotective flow activates Nrf2 via the phosphoinositol 3-kinase/Akt pathway, and this activation occurs differentially in atherosclerosis-resistant and atherosclerosis-susceptible regions of the mouse aorta. Taken together, our data demonstrate that hemodynamic forces present in atherosclerosis-resistant and -susceptible regions of the vasculature differentially regulate EC redox state and antioxidant potential. These alterations in redox homeostasis are primarily the result of the phosphoinositol 3-kinase/Akt-dependent activation of Nrf2 and its downstream transcriptional targets.
The differential effects of three forms of interferon alfa on hepatic regeneration after partial hepatectomy in the rat
Authors: Stephen Wong, Tony Gauthier, Kelly D. E. Kaita, Gerald Y. Minuk
Journal: Hepatology (1995)

The purpose of this study was to determine whether all commercially available forms of interferon alfa (INF alpha) have the same inhibitory effect on hepatic regeneration and whether this inhibitory effect can be prevented by putrescine, a hepatic growth promotor. Adult male Sprague-Dawley rats (n = 92) received either IFN alpha-2a, 2b, n1, or saline, 0 and 18 hours after partial hepatectomy (PHx) or 16 hours before PHx. A subgroup of 29 rats being treated with IFn alpha-2a or saline also received putrescine (5, 50, or 500 mg/kg) 16 hours before PHx. Hepatic regeneration was documented by determining [3H]-thymidine incorporation into hepatic DNA (DNA synthesis), hepatic putrescine levels, and, in selected cases, ornithine decarboxylase (ODC) activity at 24 hours after PHx. The results of the study showed that hepatic regeneration was unaffected when IFN alpha was administered 0 and 18 hours after PHx. When administered at -16 hours, only IFN alpha-2a significantly inhibited DNA synthesis and was associated with decreased hepatic putrescine levels. Inhibition was dose-dependent in that a 10-fold increase in IFN alpha-2a caused a further decrease in both DNA synthesis and hepatic putrescine levels. At the higher dose, IFN alpha-2b and n1 also inhibited DNA synthesis and lowered hepatic putrescine levels and ODC activity. Exogenous putrescine (5 and 50 mg/kg) restored hepatic regenerative activity to normal but was toxic at high concentrations (500 mg/kg). These data indicate that not all commercially available forms of IFN alpha inhibit hepatic regeneration in the rat to the same extent.
Mesangial cell, glomerular and renal vascular responses to endothelin in the rat kidney. Elucidation of signal transduction pathways.
Authors: K F Badr, J J Murray, M D Breyer, K Takahashi, T Inagami, R C Harris
Journal: Journal of Clinical Investigation (1989)

We investigated the actions of endothelin in anesthetized rats and cultured mesangial cells. Intravenous infusion of endothelin (10 pmol/min) decreased renal blood flow by 44% at 20 min without changing arterial pressure, which subsequently rose significantly from 124 +/- 3 to 133 +/- 4 mmHg over 60 min. Micropuncture during the nonhypertensive period revealed increases in afferent (65%) and efferent (82%) arteriolar resistances, thereby reducing nephron plasma flow rate. The glomerular ultrafiltration coefficient (Kf) fell from 0.097 +/- 0.035 to 0.031 +/- 0.011 nl/(s.mmHg) as did single nephron filtration rate (41 +/- 3 to 19 +/- 3 nl/min). Addition of 5 nM endothelin to mesangial cells plated on a silicone rubber substrate increased the intensity and number of tension-generated wrinkles, and caused their reappearance in forskolin prerelaxed cells. 20-30 s following exposure of fura-2 loaded mesangial cells to 10 nM endothelin, single cell intracellular calcium concentration ([Ca]i) increased from a mean baseline value of 66 +/- 11 (SE) to a peak of 684 +/- 250 nM (P less than 0.05) followed by a sustained elevation at 145 +/- 42 nM. Anion exchange HPLC revealed rapid (15 s) and dose-dependent stimulation of inositol 1,4,5-trisphosphate (IP3) generation following exposure of [3H]myoinositol preloaded mesangial cells to 10-100 nM endothelin. Endothelin also led to intracellular alkalinization of 2'7'-bis(2-carboxy-ethyl)-5(and-6)carboxyfluorescein (BCECF)-loaded mesangial cells and its addition was associated with dramatic augmentation of mitogenic activity. Thus, endothelin exerts potent constrictor effects on renal arterioles which precede its systemic hypertensive action. It lowers Kf and contracts mesangial cells, likely through stimulation of IP3 generation and elevation of [Ca]i. It is a potent mesangial cell mitogen. These studies define functional responses and signal transduction pathways for endothelin in the rat kidney and propose a potential role for this peptide in the control of mesangial cell function, glomerular filtration rate, and renal vascular tone.
Disruption of negative feedback loop between vasohibin-1 and vascular endothelial growth factor decreases portal pressure, angiogenesis, and fibrosis in cirrhotic rats
Authors: Laura Coch, Marc Mejias, Annalisa Berzigotti, Ester Garcia-Pras, Javier Gallego, Jaime Bosch, Raul Mendez, Mercedes Fernandez
Journal: Hepatology (2014)

Pathological angiogenesis represents a critical hallmark for chronic liver diseases. Understanding the mechanisms regulating angiogenesis is essential to develop new therapeutic strategies that specifically target pathological angiogenesis without affecting physiological angiogenesis. Here we investigated the contribution and therapeutic impact of the endogenous angioinhibitor vasohibin-1 in portal hypertension and cirrhosis. The spatiotemporal expression profiling of vasohibin-1 and its relationship with vascular endothelial growth factor (VEGF), angiogenesis, and fibrogenesis was determined through the analysis of human cirrhotic liver specimens, widely accepted in vivo animal models of portal hypertension and cirrhosis, and in vitro angiogenesis assays. Effects of vasohibin-1 overexpression by adenoviral-mediated gene transfer on angiogenesis, fibrogenesis, and portal hypertension-associated hemodynamic alterations were also studied in rats. We found that vasohibin-1 and VEGF are up-regulated, in mesentery and liver, in cirrhotic and precirrhotic portal hypertensive rats and cirrhosis patients. Our results are consistent with vasohibin-1/VEGF cascades being spatially and temporally coordinated through a negative-feedback loop driving pathological angiogenesis. Paradoxically, further overexpression of vasohibin-1 by adenoviral gene transfer exerts multifold beneficial effects in portal hypertension and cirrhosis: reduction of pathologic angiogenesis, attenuation of liver fibrogenesis partly mediated through inhibition of hepatic stellate cell activation, and significant decreases in portocollateralization, splanchnic blood flow, portohepatic resistance, and portal pressure. The explanation for this apparent contradiction is that, unlike endogenous vasohibin-1, the ectopic overexpression is not regulated by VEGF and therefore disrupts the negative-feedback loop, thus generating constant, but lower levels of VEGF synthesis sufficient to maintain vascular homeostasis but not pathological angiogenesis. Conclusion : Our study provides evidence that vasohibin-1 regulates portal hypertension-associated pathological angiogenesis and highlights that increasing vasohibin-1 might be a promising novel therapeutic strategy for portal hypertension and cirrhosis. (Hepatology 2014;60:633–647)
Are the DTI results positive evidence for George Bernard Shaw's view?
Authors: Rolf Verleger, Rebekka Lencer
Journal: Behavioral and Brain Sciences (2004)

We discuss how Burns' conception may be further extended to integrate research on eye movement abnormalities, but then point to a contradiction between Burns' conception of schizophrenia as the genetic price for human social life and the diffusion tensor imaging (DTI) data, which constitute his central piece of evidence.
Role of Th2-molecules in OVA-Induced Intestinal Anaphylaxis
Authors: E.E. Forbes, K.R. Groschwitz, R. Ahrens, E.B. Brandt, M.E. Rothenberg, P.S. Foster, K.I. Matthaei, S.P. Hogan
Journal: Journal of Allergy and Clinical Immunology (2007)
Only 3% of US citizens follow good health advice
Authors: Janice Hopkins Tanne
Journal: BMJ (2005)

Obesity in children in England continues to rise 334 More than one in four children in England are overweight or obese, said a government report published last week which showed that obesity in young people is continuing to rise.The report said that the prevalence of obesity in children aged 2 to 10 increased from 9.9% in 1995 to 13.7% in 2003.The total number of overweight and obese children rose from 22.7% to 27.7% in this period.Obesity increased most in older children aged 8 to 10, rising from 11.2% in 1995 to 16.5% in 2003.Levels of obesity were similar for both sexes, increasing from 9.6% in 1995 to 14.9% in 2003 for boys and from 10.3% to 12.5% for girls.Children living in households with the lowest incomes had higher rates of obesity than those from households with the highest incomes (15.8% v 13.3%).