tbuckley/cabot-search huggingface dataset:
Mitochondrial Dysfunction in Autism
Authors: Cecilia Giulivi, Yi-Fan Zhang, Alicja Omanska-Klusek, Catherine Ross-Inta, Sarah Wong, Irva Hertz-Picciotto, Flora Tassone, Isaac N. Pessah
Journal: JAMA (2010)

Impaired mitochondrial function may influence processes highly dependent on energy, such as neurodevelopment, and contribute to autism. No studies have evaluated mitochondrial dysfunction and mitochondrial DNA (mtDNA) abnormalities in a well-defined population of children with autism.To evaluate mitochondrial defects in children with autism.Observational study using data collected from patients aged 2 to 5 years who were a subset of children participating in the Childhood Autism Risk From Genes and Environment study in California, which is a population-based, case-control investigation with confirmed autism cases and age-matched, genetically unrelated, typically developing controls, that was launched in 2003 and is still ongoing. Mitochondrial dysfunction and mtDNA abnormalities were evaluated in lymphocytes from 10 children with autism and 10 controls.Oxidative phosphorylation capacity, mtDNA copy number and deletions, mitochondrial rate of hydrogen peroxide production, and plasma lactate and pyruvate.The reduced nicotinamide adenine dinucleotide (NADH) oxidase activity (normalized to citrate synthase activity) in lymphocytic mitochondria from children with autism was significantly lower compared with controls (mean, 4.4 [95% confidence interval {CI}, 2.8-6.0] vs 12 [95% CI, 8-16], respectively; P = .001). The majority of children with autism (6 of 10) had complex I activity below control range values. Higher plasma pyruvate levels were found in children with autism compared with controls (0.23 mM [95% CI, 0.15-0.31 mM] vs 0.08 mM [95% CI, 0.04-0.12 mM], respectively; P = .02). Eight of 10 cases had higher pyruvate levels but only 2 cases had higher lactate levels compared with controls. These results were consistent with the lower pyruvate dehydrogenase activity observed in children with autism compared with controls (1.0 [95% CI, 0.6-1.4] nmol × [min × mg protein](-1) vs 2.3 [95% CI, 1.7-2.9] nmol × [min × mg protein](-1), respectively; P = .01). Children with autism had higher mitochondrial rates of hydrogen peroxide production compared with controls (0.34 [95% CI, 0.26-0.42] nmol × [min × mg of protein](-1) vs 0.16 [95% CI, 0.12-0.20] nmol × [min × mg protein](-1) by complex III; P = .02). Mitochondrial DNA overreplication was found in 5 cases (mean ratio of mtDNA to nuclear DNA: 239 [95% CI, 217-239] vs 179 [95% CI, 165-193] in controls; P = 10(-4)). Deletions at the segment of cytochrome b were observed in 2 cases (ratio of cytochrome b to ND1: 0.80 [95% CI, 0.68-0.92] vs 0.99 [95% CI, 0.93-1.05] for controls; P = .01).In this exploratory study, children with autism were more likely to have mitochondrial dysfunction, mtDNA overreplication, and mtDNA deletions than typically developing children.
Endoscopic Treatment of Anastomotic Biliary Strictures After Living Donor Liver Transplantation: Outcomes After Maximal Stent Therapy
Authors: Ting-Hui Hsieh, M. Edwyn Harrison, Michael D. Crowell, Kristin L. Mekeel, Bashar A. Aqel, Elizabeth J. Carey, Thomas J. Byrne, Hugo E. Vargas, David D. Douglas, Jorge Rakela, Kunam S. Reddy, Adyr A. Moss, David C. Mulligan
Journal: Clinical Gastroenterology and Hepatology (2011)
Apolipoprotein L1 Risk Variants Associate with Systemic Lupus Erythematosus-Associated Collapsing Glomerulopathy
Authors: Christopher P. Larsen, Marjorie L. Beggs, Mohammad Saeed, Patrick D. Walker
Journal: Journal of the American Society of Nephrology (2013)

Collapsing glomerulopathy is a devastating renal disease that primarily affects African Americans and associates with numerous etiologies, such as HIV and autoimmune disease. The presence of APOL1 risk alleles associates with HIV-associated collapsing glomerulopathy, but it is unknown whether these risk alleles also associate with systemic lupus erythematosus (SLE) -associated collapsing glomerulopathy. Here, re-examination of 546 renal biopsies from African-American patients with SLE identified 26 cases of collapsing glomerulopathy, which we genotyped for APOL1 risk alleles using DNA extracted from archived biopsy tissue. APOL1 strongly associated with SLE-associated collapsing glomerulopathy (P<0.001). In a recessive model, two APOL1 risk alleles conferred 5.4-fold (95% CI=2.4 to 12.1) higher odds of developing SLE-associated collapsing glomerulopathy (P<0.001). In conclusion, APOL1 genotyping of African-American patients with SLE might help identify patients at risk for collapsing glomerulopathy, an entity with a poor prognosis that is often resistant to treatment.
Sensitivity of leukemic T-cell lines to arsenic trioxide cytotoxicity is dependent on the induction of phosphatase B220/CD45R expression at the cell surface
Authors: Mohcine Benbijja, Amine Mellouk, Pierre Bobé
Journal: Molecular Cancer (2014)

Arsenic trioxide (As2O3) is highly effective in treating acute promyelocytic leukemia (APL), but shows more variable therapeutic efficacy for other types of hematological malignancies. Previously, we reported that As2O3 selectively eliminates pathogenic B220-expressing T cells in autoimmune MRL/lpr mice. We investigated herein the relationship between As2O3 sensitivity of leukemic T-cell lines and the expression levels of the B220 isoform of transmembrane tyrosine phosphatase CD45. GSH content, O2- production, and B220, HSP70, Fas and FasL membrane expression was measured by flow cytometry. Subcellular localization of B220 was determined by imaging flow cytometry. Cell death was analyzed by morphological changes, annexin V and propidium iodide staining, and caspase 8 and 9 activation. B220 mRNA expression was analyzed by RT-PCR. Activated NF-κB p50 was quantified by a DNA binding ELISA. We selected human (Jurkat, Jurkat variant J45.01, HPB-ALL) and mouse (EL-4, BW5147, L1210) T-cell lines for their marked differences in As2O3 sensitivity over a large range of doses (1 to 20 μM). Differences in redox status cannot explain the dramatic differences in As2O3 sensitivity observed among the T-cell lines. Unexpectedly, we found that B220 is differentially induced on As2O3-treated T-cell lines. As2O3 treatment for 24 h induced low (HPB-ALL), intermediate (Jurkat) and high (EL-4, BW5147) levels of B220 membrane expression, membrane-bound HSP70 and cell death, but inhibited NF-κB p50 nuclear translocation. When high levels of B220 expression were achieved with low doses of As2O3, the T-cell lines died by apoptosis only. When high doses of As2O3 were required to induce B220 expression, leukemic T cells died by both apoptosis and necrosis. Cellular redox status is not essential for As2O3 sensitivity of leukemic T cells, suggesting the existence of additional factors determining their sensitivity to As2O3 cytotoxicity. Phosphatase B220 could be such a factor of sensitivity. As2O3 treatment inhibits NF-κB p50 nuclear translocation, and induces B220 expression and cell death in a dose and time dependent manner. The levels of B220 induction on leukemic T cells strictly correlate with both the extent and form of cell death, B220 might therefore play a checkpoint role in death pathways.
The Impact of Outpatient Diabetes Management on Serum Lipids in Urban African-Americans With Type 2 Diabetes
Authors: Diane M. Erdman, Curtiss B. Cook, Kurt J. Greenlund, Wayne H. Giles, Imad El-Kebbi, Gina J. Ryan, Daniel L. Gallina, David C. Ziemer, Virginia G. Dunbar, Lawrence S. Phillips
Journal: Diabetes Care (2002)

OBJECTIVE—Treating dyslipidemia in diabetic patients is essential, particularly among minority populations with increased risk of complications. Because little is known about the impact of outpatient diabetes management on lipid outcomes, we examined changes in lipid profiles in urban African-Americans who attended a structured diabetes care program. RESEARCH DESIGN AND METHODS—A retrospective analysis of initial and 1-year follow-up lipid values was conducted among patients selected from a computerized registry of an urban outpatient diabetes clinic. The independent effects of lipid-specific medications, glycemic control, and weight loss on serum total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels were evaluated by analysis of covariance and multiple linear regression. RESULTS—In 345 patients (91% African-American and 95% with type 2 diabetes), HbA1c decreased from 9.3% at the initial visit to 8.2% at 1 year (P &amp;lt; 0.001); total and LDL cholesterol and triglyceride levels were significantly lower, and HDL cholesterol was higher. After stratifying based on use of lipid-specific therapy, different outcomes were observed. In 243 patients not taking dyslipidemia medications, average total cholesterol, LDL cholesterol, and triglyceride concentrations at 1 year were similar to initial values, whereas in 102 patients receiving pharmacotherapy, these lipid levels were all lower at 1 year relative to baseline (P &amp;lt; 0.001). Mean HDL cholesterol increased regardless of lipid treatment status (P &amp;lt; 0.001). After adjusting for other variables, changes in LDL cholesterol concentration were associated only with use of lipid-specific agents (P = 0.003), whereas improved HbA1c and weight loss had no independent effect. Lipid therapy, improved glycemic control, and weight loss were not independently related to changes in HDL cholesterol and therefore could not account for the positive changes observed. Use of lipid-directed medications, improvement in glycemic control, and weight loss all resulted in significant declines in triglyceride levels but only improved HbA1c and weight loss had an independent effect. CONCLUSIONS—Among urban African-Americans, diabetes management led to favorable changes in HDL cholesterol and triglyceride levels, but improved glycemic control and weight loss had no independent effect on LDL cholesterol concentration. Initiation of pharmacologic therapy to treat high LDL cholesterol levels should be considered early in the course of diabetes management to reach recommended targets and reduce the risk of cardiovascular complications in this patient population.
The ambitious '95-95 by 2025' roadmap for the diagnosis and management of fungal diseases
Authors: D. W. Denning
Journal: Thorax (2015)

Fungal lung disease affects tens of millions worldwide and leads to over a million deaths annually. After skin disease (1 billion affected) and mucosal candidiasis (most women at some time and oral and oesophageal candidiasis), pulmonary fungal disease is the third most common fungal disease group, and the most serious.

On 5 May 2015, the Global Action Fund for Fungal Infections (GAFFI) launched a 10-year ambitious target to enable 95% of the world's population to have access to fungal diagnostics and 95% to have access to antifungal therapy by 2025.1 The key pulmonary fungal diseases and the necessary diagnostics are shown in table 1.

View this table:

Table 1 
Common fungal lung diseases, their estimated burden and required diagnostic tests



The current deficiencies in diagnostic provision across the world are stark. No Aspergillus IgG or precipitins testing for chronic pulmonary aspergillosis and aspergilloma in Africa, and many other countries. No low cost PCR for Pneumocystis pneumonia (PCP) diagnosis anywhere, and currently PCP is diagnosable before death in children in only the most sophisticated hospitals. Skin prick testing and/or fungal-specific IgE testing for allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitisation is barely used in the assessment of severe asthma outside a few centres with a special interest. The diagnosis of invasive aspergillosis is difficult …
Degradation of Promoter-bound p65/RelA Is Essential for the Prompt Termination of the Nuclear Factor κB Response
Authors: Simona Saccani, Ivan Marazzi, Amer A. Beg, Gioacchino Natoli
Journal: The Journal of Experimental Medicine (2004)

Transcription factors of the nuclear factor (NF)-κB/Rel family translocate into the nucleus upon degradation of the IκBs. Postinduction repression of NF-κB activity depends on NF-κB–regulated resynthesis of IκBα, which dissociates NF-κB from DNA and exports it to the cytosol. We found that after activation, p65/RelA is degraded by the proteasome in the nucleus and in a DNA binding–dependent manner. If proteasome activity is blocked, NF-κB is not promptly removed from some target genes in spite of IκBα resynthesis and sustained transcription occurs. These results indicate that proteasomal degradation of p65/RelA does not merely regulate its stability and abundance, but also actively promotes transcriptional termination.
Cancer morbidity in rheumatoid arthritis.
Authors: P Prior, D P Symmons, C F Hawkins, D L Scott, R Brown
Journal: Annals of the Rheumatic Diseases (1984)

A consecutive series of 489 patients with rheumatoid arthritis seen at the centre was studied to determine their cancer morbidity. Overall the 36 cancers diagnosed in the series between 1964 and 1981 were not significantly in excess of the expected number, but there was a highly significant excess of tumours of the reticuloendothelial system. The excess was mainly due to 6 observed cases of lymphoma. We conclude that there is a highly significant association between rheumatoid arthritis and the subsequent development of lymphoproliferative malignancy in this series.
Sex differences in the incidence of colorectal cancer: an exploration of oestrogen and progesterone receptors.
Authors: S Singh, M C Sheppard, M J Langman
Journal: Gut (1993)

Sex differences exist in the site specific incidences of colorectal cancer. The increased incidence of colonic cancer in women with breast cancer and the protective effect of increasing parity suggest a role for sex hormones. To explore the molecular basis, the expression of messenger RNA for oestrogen and progesterone receptors in the large bowel has been studied. With northern and dot blot analyses mRNA coding for oestrogen receptor and progesterone receptor in large bowel cancers and corresponding normal mucosa and in adenomatous polyps has been identified. There were no significant differences in receptor mRNA concentrations between males and females or between cancers, normal mucosae, and polyps, except for rectal cancers, which had higher progesterone receptor concentrations than corresponding normal tissue. Oestrogen and progesterone receptor mRNA concentrations were strongly correlated in both cancers and normal tissues. Enzyme immunoassay for oestrogen receptor gave values of 1.2-7.4 fmol/mg total protein, an amount similar to that seen in normal breast tissue. Oestrogen receptor protein and mRNA for oestrogen receptor and progesterone receptor are present in the large bowel.
Spontaneous sarcomeric oscillations at intermediate activation levels in single isolated cardiac myofibrils.
Authors: W A Linke, M L Bartoo, G H Pollack
Journal: Circulation Research (1993)

Spontaneous oscillations observed in various heart muscle preparations are widely thought to be triggered by spontaneous release of Ca2+ from the sarcoplasmic reticulum (SR). Here, we report undamped propagated oscillations that occur in the absence of SR. In single cardiac myofibrils treated with Triton X-100 to remove SR and held isometrically, partial activation initiated periodic fluctuations of sarcomere length persisting up to 1 hour. Oscillation characteristics could be readily quantitated by virtue of the small size of the preparation. In an individual sarcomere, the oscillation cycle generally consisted of a slow shortening phase, followed by a phase of rapid lengthening. Oscillations usually propagated along the myofibril--frequently along the entire specimen--in a wavelike fashion (average velocity, 12.3 microns/s at 10 degrees C; Q10, approximately 1.3). The oscillation period was 2.30 and 1.72 seconds at 10 degrees and 20 degrees C, respectively, and was insensitive to stretch. The average oscillation amplitude, which was temperature independent, decreased with stretch from more than 20% of the mean sarcomere length at lengths below 2 microns to zero beyond a sarcomere length of 3 microns. Stiffening of the Z line by labeling with anti-alpha-actinin resulted in a dose-dependent decrease of oscillation amplitude, while the period was not affected. Tension oscillations could not be detected in single myofibrils but were frequently detectable in myofibril doublets, where the oscillation magnitude (approximately 1 microgram) was above the noise floor. Addition of 10 mumol/L ryanodine to the activating solution did not alter oscillation characteristics, as expected, since the oscillations are unrelated to SR calcium release. On the basis of our results, we consider a mechanism for the oscillations in which a length dependence of myofibrillar Ca2+ sensitivity and a dynamic Z-line structure are essential.
The effect of portacaval anastomosis on oral carbohydrate tolerance and on plasma insulin levels
Authors: C. D. Holdsworth, L. Nye, E. King
Journal: Gut (1972)

In patients with portal hypertension, plasma insulin levels were raised both fasting and after oral glucose or intravenous tolbutamide. This supports previous suggestions that resistance to endogenous insulin plays a major role in producing the impaired glucose tolerance found in chronic hepatic dysfunction. The operation of portacaval anastomosis was followed by impaired oral fructose tolerance, but did not significantly change oral glucose tolerance. Plasma insulin levels were unchanged by the operation, either fasting or following the stimulus of an oral glucose load or intravenous tolbutamide. The insulin response after operation was only higher after intensive pancreatic β cell stimulation by a combination of glucose, tolbutamide, and glucagon. These results indicate that, in patients with hepatic dysfunction, little insulin is being removed by the liver from the portal blood except when the insulin secretory rate is unusually high.
Overexpression of 5-Lipoxygenase and Cyclooxygenase 2 in Hamster and Human Oral Cancer and Chemopreventive Effects of Zileuton and Celecoxib
Authors: Ning Li, Sandeep Sood, Su Wang, Mingzhu Fang, Peng Wang, Zheng Sun, Chung S. Yang, Xiaoxin Chen
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Previous studies have suggested an important role of aberrant arachidonic acid metabolism, especially the cyclooxygenase (Cox) pathway, in oral carcinogenesis. However, it is unknown whether the 5-lipoxygenase (5-Lox) pathway contributes to oral carcinogenesis, and whether combination of inhibitors of both pathways may have synergistic or additive effects of chemoprevention. Experimental Design: 5-Lox expression was examined in 7,12-dimethylbenz[a]anthracene (DMBA)–induced hamster and human oral cancer tissues by immunohistochemistry, and Cox2 expression was investigated in hamster oral tissues using in situ hybridization. Zileuton (a specific 5-Lox inhibitor) and celecoxib (a specific Cox2 inhibitor), either alone or in combination, were investigated for their chemopreventive effects on the DMBA-induced hamster model at the post-initiation stage through topical application. Results: 5-Lox was overexpressed during oral carcinogenesis in hamsters and humans, as well as Cox2 in the hamster tissues. In a chemoprevention study using the post-initiation DMBA model, incidence of hamster oral squamous cell carcinoma was reduced from 76.9% (20 of 26) to 45.8% (11 of 24, P &amp;lt; 0.05) and 32.1% (9 of 28, P &amp;lt; 0.01) by 3% and 6% topical zileuton, respectively; and to 57.6% (15 of 26, P &amp;gt; 0.05) and 50% (12 of 24, P &amp;lt; 0.05) by 3% and 6% topical celecoxib, respectively. When used in combination, celecoxib and zileuton (3% of each) had an additive inhibitory effect on the incidence of squamous cell carcinoma (36%, 9 of 25, P &amp;lt; 0.01). Other pathologic variables and the levels of leukotriene B4 and prostaglandin E2 of the hamster tissues were reduced as well. Conclusions: The results clearly showed that both 5-Lox and Cox2 played important roles in oral carcinogenesis. Zileuton and celecoxib prevented oral carcinogenesis at the post-initiation stage through their inhibitory effects on arachidonic acid metabolism.
Categorisation of Complications and Validation of the Clavien Score for Percutaneous Nephrolithotomy
Authors: Jean J.M.C.H. de la Rosette, Dedan Opondo, Francisco P.J. Daels, Guido Giusti, Álvaro Serrano, Sangam V. Kandasami, J. Stuart Wolf, Magnus Grabe, Stavros Gravas
Journal: European Urology (2012)
Autonomic Neurotransmission: 60 Years Since Sir Henry Dale
Authors: Geoffrey Burnstock
Journal: The Annual Review of Pharmacology and Toxicology (2008)

In the early twentieth century, Sir Henry Dale and others described brilliant studies of autonomic neurotransmission utilizing acetylcholine and noradrenaline. However, within the past 60 years, new discoveries have changed our understanding of the organization of the autonomic nervous system, including the structure and function of the nonsynaptic autonomic neuroeffector junction, the multiplicity of neurotransmitters, cotransmission, neuromodulation, dual control of vascular tone by perivascular nerves and endothelial cells, the molecular biology of receptors, and trophic signaling. Further, it is now recognized that an outstanding feature of autonomic neurotransmission is the inherent plasticity afforded by its structural and neurochemical organization and the interaction between expression of neural mediators and environmental factors. In this way, autonomic neurotransmission is matched to ongoing changes in demands and can sometimes be compensatory in pathophysiological situations.
Specific adherence of Escherichia coli (strain RDEC-1) to membranous (M) cells of the Peyer's patch in Escherichia coli diarrhea in the rabbit.
Authors: L R Inman, J R Cantey
Journal: Journal of Clinical Investigation (1983)

The RDEC-1 strain Escherichia coli is an enteroadherent bacterium that produces diarrhea in the rabbit. A histopathologically similar disease has been described in humans. The RDEC-1 bacterium adheres to the epithelium of lymphoid follicles in rabbit ileal Peyer's patches by 4 h postinoculation, 3-4 d before its adherence to absorptive epithelium. The purpose of this study was to determine whether the RDEC-1 bacterium adheres to a specific cell type in the lymphoid follicle epithelium. RDEC-1 bacteria were given in a dose of 2 X 10(6) by the orogastric route to postweanling rabbits. The distal ileal Peyer's patch, taken from 5 control rabbits and 43 rabbits at intervals in the first 24 h postinoculation, was examined by routine and high-voltage electron microscopy. The RDEC-1 bacterium adhered specifically to M (membranous) rather than absorptive epithelial cells of the lymphoid follicle epithelium. Further understanding of how the bacterium attaches to M cells, which transport antigens to intraepithelial lymphocytes, could be useful in designing vaccines to protect mucosal surfaces.