tbuckley/cabot-search huggingface dataset:
Genomic Organization of the Mammalian<i>Mhc</i>
Authors: Attila Kumánovics, Toyoyuki Takada, Kirsten Fischer Lindahl
Journal: Annual Review of Immunology (2003)

The Human Genome Project transformed the quest of more than 50 years to understand the major histocompatibility complex (Mhc). The sequence of the Mhc from human and mouse, together with a large amount of sequence and mapping information from several other species, allows us to draw general conclusions about the organization and origin of this crucial part of the immune system. The Mhc is a mosaic of stretches formed by conserved and nonconserved genes. Surprisingly, of the ∼3.6-Mb Mhc, the stretches that encode the class I and class II genes, which epitomize the Mhc, are the least conserved part, whereas the ∼1.7-Mb stretches that encode at least 115 other genes are highly conserved. We summarize the available data to answer the questions (a) What is the Mhc? and (b) How can we define it in a general, not species-specific, way? Knowing what is essential and what is incidental helps us understand the fundamentals of the Mhc, and defining the species differences makes the model organisms more useful.
Ultrasound guided dry needling and autologous blood injection for patellar tendinosis
Authors: Steven L J James, Kaline Ali, Chris Pocock, Claire Robertson, Joy Walter, Jonathan Bell, David Connell
Journal: British Journal of Sports Medicine (2007)

To evaluate the efficacy of ultrasound guided dry needling and autologous blood injection for the treatment of patellar tendinosis.Prospective cohort study.Hospital/clinic based.47 knees in 44 patients (40 men, 7 women, mean age 34.5 years, age range 17 to 54 years) with refractory tendinosis underwent sonographic examination of the patellar tendon following referral with a clinical diagnosis of patellar tendinosis (mean symptom duration 12.9 months).Ultrasound guided dry needling and injection of autologous blood into the site of patellar tendinosis was performed on two occasions four weeks apart.Pre- and post-procedure Victorian Institute of Sport Assessment scores (VISA) were collected to assess patient response to treatment. Follow up ultrasound examination was done in 21 patients (22 knees).Therapeutic intervention led to a significant improvement in VISA score: mean pre-procedure score = 39.8 (range 8 to 72) v mean post procedure score = 74.3 (range 29 to 100), p<0.001; mean follow up 14.8 months (range 6 to 22 months). Patients were able to return to their sporting interests. Follow up sonographic assessment showed a reduction in overall tendon thickness and in the size of the area of tendinosis (hypoechoic/anechoic areas within the proximal patellar tendon). A reduction was identified in interstitial tears within the tendon substance. Neovascularity did not reduce significantly or even increased.Dry needling and autologous blood injection under ultrasound guidance shows promise as a treatment for patients with patellar tendinosis.
An investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma
Authors: Mina Sarah Ally, Sumaira Aasi, Ashley Wysong, Claudia Teng, Eric Anderson, Irene Bailey-Healy, Anthony Oro, Jinah Kim, Anne Lynn Chang, Jean Yuh Tang
Journal: Journal of the American Academy of Dermatology (2014)
Contribution of Abcc4-Mediated Gastric Transport to the Absorption and Efficacy of Dasatinib
Authors: Brian D. Furmanski, Shuiying Hu, Ken-ichi Fujita, Lie Li, Alice A. Gibson, Laura J. Janke, Richard T. Williams, John D. Schuetz, Alex Sparreboom, Sharyn D. Baker
Journal: Clinical Cancer Research (2013)

Several oral multikinase inhibitors are known to interact in vitro with the human ATP-binding cassette transporter ABCC4 (MRP4), but the in vivo relevance of this interaction remains poorly understood. We hypothesized that host ABCC4 activity may influence the pharmacokinetic profile of dasatinib and subsequently affect its antitumor properties.Transport of dasatinib was studied in cells transfected with human ABCC4 or the ortholog mouse transporter, Abcc4. Pharmacokinetic studies were done in wild-type and Abcc4-null mice. The influence of Abcc4 deficiency on dasatinib efficacy was evaluated in a model of Ph(+) acute lymphoblastic leukemia by injection of luciferase-positive, p185(BCR-ABL)-expressing Arf(-/-) pre-B cells.Dasatinib accumulation was significantly changed in cells overexpressing ABCC4 or Abcc4 compared with control cells (P < 0.001). Deficiency of Abcc4 in vivo was associated with a 1.75-fold decrease in systemic exposure to oral dasatinib, but had no influence on the pharmacokinetics of intravenous dasatinib. Abcc4 was found to be highly expressed in the stomach, and dasatinib efflux from isolated mouse stomachs ex vivo was impaired by Abcc4 deficiency (P < 0.01), without any detectable changes in gastric pH. Abcc4-null mice receiving dasatinib had an increase in leukemic burden, based on bioluminescence imaging, and decreased overall survival compared with wild-type mice (P = 0.048).This study suggests that Abcc4 in the stomach facilitates the oral absorption of dasatinib, and it possibly plays a similar role for other orally administered substrates, such as acetylsalicylic acid. This phenomenon also provides a mechanistic explanation for the malabsorption of certain drugs following gastric resection.
Effects of Continuous Positive Airway Pressure on Early Signs of Atherosclerosis in Obstructive Sleep Apnea
Authors: Luciano F. Drager, Luiz A. Bortolotto, Adelaide C. Figueiredo, Eduardo M. Krieger, Geraldo Lorenzi-Filho
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: Obstructive sleep apnea (OSA) is associated with adverse cardiovascular outcomes, including myocardial infarction and stroke. Atherosclerosis is a key mechanism for these cardiovascular events. Recent cross-sectional studies showed the presence of early signs of atherosclerosis in patients with OSA who were free of comorbidities.Objectives: To determine the impact of treatment with continuous positive airway pressure (CPAP) on atherosclerosis.Methods: We randomly assigned 24 patients with severe OSA (age, 46 ± 6 yr) who were free of comorbidities to receive no treatment (control, n = 12) or CPAP (n = 12) for 4 months. Carotid intima-media thickness, arterial stiffness (evaluated by pulse-wave velocity), carotid diameter, 24-hour blood pressure monitoring, C-reactive protein, and catecholamines were determined at baseline and after 4 months.Measurements and Main Results: At baseline, all measurements were similar in both groups and did not change in the control group after 4 months. In contrast, a significant decrease occurred in carotid intima-media thickness (707 ± 105 vs. 645 ± 95 μm, P = 0.04), pulse-wave velocity (10.4 ± 1.0 vs. 9.3 ± 0.9 m/s, P < 0.001), C-reactive protein (3.7 ± 1.8 vs. 2.0 ± 1.2 mg/L, P = 0.001), and catecholamines (365 ± 125 vs. 205 ± 51 ng/ml, P < 0.001) after 4 months of CPAP. Carotid diameter did not change significantly. Regarding the whole group, changes in carotid intima-media thickness were correlated with changes in catecholamines (r = 0.41, P < 0.05). Changes in pulse-wave velocity were correlated with changes in C-reactive protein (r = 0.58, P < 0.01) and catecholamines (r = 0.54, P < 0.01).Conclusions: The treatment of OSA significantly improves early signs of atherosclerosis, supporting the concept that OSA is an independent risk factor for atherosclerosis.Clinical trial registered with www.clinicaltrials.gov (NCT 00400543).
Laparoscopic myomectomy: a current view
Authors: J.-B. Dubuisson
Journal: Human Reproduction Update (2000)

Since 1990 laparoscopic myomectomy (LM) has provided an alternative to laparotomy when intramural and subserous myomata are to be managed surgically. However, this technique is still the subject of debate. Based on their own experience together with data from the literature, the authors report on the situation today regarding the operative technique for LM and the risks and benefits of the technique as compared with myomectomy by laparotomy. The operative technique comprises four main phases: hysterotomy; enucleation; suture of the myomectomy site and extraction of the myoma. LM offers the possibility of a minimally invasive approach to treat medium-sized (<9 cm) subserous and intramural myomata by surgery when there are only two or three of them. When conducted by experienced surgeons, the risk of peri-operative complications is no higher using this technique. Use of the laparoscopic route could reduce the haemorrhagic risk associated with myomectomy. LM could reduce also the risk of post-operative adhesions as compared with laparotomy. Spontaneous uterine rupture seems to be rare after LM but further studies are needed before it can be said whether the strength of the hysterotomy scars after LM is equivalent to that obtained after laparotomy. The risk of recurrence seems to be higher after LM than after myomectomy performed by laparotomy.
Missed outpatient appointments
Authors: T. Fysh
Journal: Journal of the Royal Society of Medicine (2002)

Dr Murdock and his colleagues (June 2002 JRSM1) think that an important reason for the 14% non-attendance rate in their clinics was patient apathy. I found a similar rate in an inner-city general practice, audited as part of my final year studies. Of 7282 patients given appointments in the year to March 2001, 1032 (16%) were either late or did not attend. The average appointment was ten minutes; and, if there was no other useful activity when an appointment was missed, the time lost to the practice in a year would have been 172 hours. The running cost of the practice, excluding prescriptions, was about £20 per appointment. If there are 38 000 general practitioners in the UK and each sees 8000 patients a year, and if we take a conservative non-attendance rate of 10%, the annual loss to the National Health Service comes to over £600 million—to be added to the £300 million wasted on missed hospital outpatient appointments.

The solution proposed by Murdock and colleagues is overbooking—as used by many airline companies and hotels to make up for anticipated non-attendance. The difference is that they are dealing with customers who have already paid for their service directly. I feel a more fruitful way to encourage attendance would be to instigate a system of fines for non-attendance. The fine, which might be £10, could be avoided by cancelling within 24 hours, thereby giving the practice time to find a replacement patient. It is impossible to say how much extra revenue would be generated nationally by the system, since we cannot predict how many people would cancel appointments and how many would pay the penalty. Some other questions would arise—for example, should fines be means-tested? Is £10 too much or too little? How should any such payment be made? Who exactly should coordinate penalty fines? Where should the proceeds go? Should the outpatient department or general practice make ‘reminder’ phone calls if possible? Should any group of people be exempt (e.g. the homeless)? Should the penalty be increased if not paid promptly (as happens with parking fines)? What form should an appeals system take?

This system of fines would not compromise the ethos of free healthcare at the point of delivery, nor could it be condemned as a ‘stealth tax’ since the fine is entirely avoidable. Many other institutions impose fines for rule-breaking—for speeding, for late return of library books—and these seem to work. The general public might support the scheme since most people do keep their appointments and are paying through their taxes for those who do not.
Electrolyte disturbances in elderly patients with severe diarrhea due to cholera.
Authors: J Cieza, Y Sovero, L Estremadoyro, F Dumler
Journal: Journal of the American Society of Nephrology (1995)

The purpose of this clinical study was to evaluate prospectively electrolyte disturbances in elderly patients with severe diarrhea due to cholera. A total of 20 adult (Group I; < 60 yr) and 22 elderly (Group II; > or = 60 yr) patients were studied. In all patients, extracellular fluid (ECF) volume reexpansion was achieved with normal saline at 50 mL/kg per hour. Once a diuresis of 40 mL/h was achieved, intravenous therapy was discontinued and patients' ECF volumes were reexpanded orally with a polyelectrolyte solution. Blood and urine samples were obtained on admission, at the time when adequate diuresis ensued, and after 12 h of oral ECF volume reexpansion. On admission, both groups had severe ECF volume contraction but only mild increases in osmolality (308 +/- 12 and 310 +/- 13 mosmol/kg for Groups I and II respectively; P = NS). Acidemia (pH) was equally severe in both (Group I: 7.13 +/- 0.11; Group II: 7.11 +/- 0.09; P = NS), and the anion gap was comparably increased in both groups (30 +/- 8 and 26 +/- 7 mmol/L for Groups I and II, respectively; P = NS). None of the patients was hypokalemic at the time of admission (Group I: 4.3 +/- 0.5 mmol/L; Group II: 4.5 +/- 0.5 mmol/L; P = NS). Adequate diuresis was achieved at 2.0 +/- 0.7 h in both groups. At the end of the rapid ECF volume reexpansion phase, the anion gap normalized in both groups (Group I: 15.6 +/- 3.7 mmol/L; Group II: 14.4 +/- 2.8 mmol/L; P = NS), and serum potassium concentrations remained normal (Group I: 4.4 +/- 0.4 mmol/L; Group II: 4.1 +/- 0.4 mmol/L; P = NS). We conclude that use of aggressive intravenous hydration with normal saline followed by oral ECF volume reexpansion allows prompt correction of electrolyte abnormalities in adult and elderly patients with severe diarrhea as a result of cholera.
An anti-human ICAM-1 antibody inhibits human rhinovirus infection in the mouse model of human major group rhinovirus infection
Authors: Stephanie Traub, Alan Carruthers, Rebecca Dunmore, Leila Gogsadze, Nathan W. Bartlett, Weidong Hao, Qing Zhu, Katie Bernard, Michael Dymond, Andrew Leishman, Alison Humbles, Ian K. Anderson, Roland Kolbeck, Matthew Sleeman, Ted Wells, Sebastian L. Johnston
Journal: European Respiratory Journal (2011)

Introduction:  Human rhinoviruses (HRV) cause the common cold and the majority of acute exacerbations of asthma and COPD. 90% of HRV belong to the major group and use human ICAM-1 (intercellular adhesion molecule 1) for cell attachment and entry. We previously established a human/mouse chimeric ICAM-1 transgenic mouse model of human major group rhinovirus infection. However, antiviral approaches have not yet been studied in this model.   Aim:  To evaluate the inhibition of HRV-induced airway inflammation by a mouse anti-human ICAM-1 antibody.   Methods:  Transgenic mice were treated i.n. or i.v. with an ICAM-1 antibody before HRV16 or HRV14 challenge. To exclude possible effects of an ICAM-1 antibody on cell trafficking we evaluated an ICAM-1 antibody in the transgenic mice by infecting them with minor group HRV1B or in an LPS challenge model.   Results:  Both i.n. and i.v. dosed ICAM-1 antibody inhibited HRV16 induced bronchoalveolar lavage (BAL) cells (p   Conclusion:  We have shown for the first time that an anti-human ICAM-1 specific antibody can be used to prevent human rhinovirus entry and replication and induction of airway inflammation in vivo.
Biallelic Mutations in <i>BRCA1</i> Cause a New Fanconi Anemia Subtype
Authors: Sarah L. Sawyer, Lei Tian, Marketta Kähkönen, Jeremy Schwartzentruber, Martin Kircher, Jacek Majewski, David A. Dyment, A. Micheil Innes, Kym M. Boycott, Lisa A. Moreau, Jukka S. Moilanen, Roger A. Greenberg
Journal: Cancer Discovery (2014)

Deficiency in BRCA-dependent DNA interstrand crosslink (ICL) repair is intimately connected to breast cancer susceptibility and to the rare developmental syndrome Fanconi anemia. Bona fide Fanconi anemia proteins, BRCA2 (FANCD1), PALB2 (FANCN), and BRIP1 (FANCJ), interact with BRCA1 during ICL repair. However, the lack of detailed phenotypic and cellular characterization of a patient with biallelic BRCA1 mutations has precluded assignment of BRCA1 as a definitive Fanconi anemia susceptibility gene. Here, we report the presence of biallelic BRCA1 mutations in a woman with multiple congenital anomalies consistent with a Fanconi anemia-like disorder and breast cancer at age 23. Patient cells exhibited deficiency in BRCA1 and RAD51 localization to DNA-damage sites, combined with radial chromosome formation and hypersensitivity to ICL-inducing agents. Restoration of these functions was achieved by ectopic introduction of a BRCA1 transgene. These observations provide evidence in support of BRCA1 as a new Fanconi anemia gene (FANCS).We establish that biallelic BRCA1 mutations cause a distinct FA-S, which has implications for risk counselling in families where both parents harbor BRCA1 mutations. The genetic basis of hereditary cancer susceptibility syndromes provides diagnostic information, insights into treatment strategies, and more accurate recurrence risk counseling to families.
New role for the (pro)renin receptor in T-cell development
Authors: Sabrina Geisberger, Ulrike Maschke, Matthias Gebhardt, Markus Kleinewietfeld, Arndt Manzel, Ralf A. Linker, Ann Chidgey, Ralf Dechend, Genevieve Nguyen, Oliver Daumke, Dominik N. Muller, Mark D. Wright, Katrina J. Binger
Journal: Blood (2015)
Invasion of Liver Tissue by Blood-Borne Mammary Carcinoma Cells
Authors: K. P. Dingemans
Journal: JNCI Journal of the National Cancer Institute (1974)

The mode of invasion of liver tissue by mammary carcinoma cells was studied after the injection of such cells into the portal system of intact, isologous mice. The initial invasion was investigated during the first hours after the injection, before most tumor cells were eliminated. Later stages of invasion were examined in the border areas of tumor nodules developing after 8–12 days. The tumor, maintained by subcutaneous transplantations, was characterized by acinus-like structures in which most cells were connected by junctions. A suspension, prepared mechanically, contained not only monodispersed cells, but also tiny, compact clumps of cells with junctions at the tumor-fluid interface. Immediately after the injections, large emboli with essentially the same structure as these tiny clumps formed in the hepatic portal branches. In the adjacent sinusoids, these emboli had thin extensions in which the tumor cells had no junctions. Only tumor cells in sinusoids invaded the liver parenchyma. Discontinuities in the endothelial cells probably developed first, and subsequently tumor-cell pseudopods were extended into the underlying hepatocytes. In the border areas of the tumor nodules developing later, tumor cells protruded deeply into surrounding hepatocytes. Junctions between hepatocytes and tumor cells were common, especially associated with intercellular lumina surrounded by both tumor cells and hepatocytes. With time, hepatocytes were excessively deformed by the tumor cells. However, no active destruction of hepatocytes by tumor cells was recorded.
Nitric Oxide–Independent Dilation of Conductance Coronary Arteries to Acetylcholine in Conscious Dogs
Authors: Zhi Ming, Robert Parent, Michel Lavallée
Journal: Circulation Research (1997)

Abstract NO and prostacyclin formation cannot entirely account for receptor-operated endothelium-dependent dilation of coronary vessels, since vasodilator responses are not completely suppressed by inhibitors of these agents. Therefore, we considered that another factor, such as an endothelium-derived hyperpolarizing factor described in vitro, may participate in NO- and prostacyclin-independent coronary dilator responses. In conscious instrumented dogs, intracoronary acetylcholine (ACh, 30.0 ng · kg −1 · min −1 ) increased the external epicardial coronary diameter (CD) by 0.18±0.03 mm (from 3.44±0.11 mm) when increases in coronary blood flow (CBF) were prevented and increased the CD by 0.20±0.05 when CBF was allowed to increase. After the administration of intracoronary N ω -nitro- l -arginine methyl ester (L-NAME), CBF responses to ACh were abolished, but CD responses (0.23±0.05 from 3.22±0.09 mm) were maintained. Blockade of NO formation was confirmed by reduced CD baselines and blunted flow-dependent CD responses caused by adenosine and transient coronary artery occlusions after L-NAME administration. ACh-induced CD increases resistant to L-NAME and indomethacin were reduced after the administration of intracoronary quinacrine, an inhibitor of phospholipase A 2 , or proadifen, an inhibitor of cytochrome P-450. Quinacrine or proadifen alone (without L-NAME) did not alter CD responses to ACh, but L-NAME given after proadifen blunted ACh-induced increases in CD. The increases in CD caused by arachidonic acid given after L-NAME+indomethacin were antagonized by proadifen but not altered by quinacrine. Thus, a cytochrome P-450 metabolite of arachidonic acid accounts for L-NAME–resistant and indomethacin-resistant dilation of large epicardial coronary arteries to ACh. Conversely, NO formation is the dominant mechanism of ACh-induced dilation after blockade of the cytochrome P-450 pathway.
Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation
Authors: Kiichi Nakahira, Sun-Young Kyung, Angela J. Rogers, Lee Gazourian, Sojung Youn, Anthony F. Massaro, Carolina Quintana, Juan C. Osorio, Zhaoxi Wang, Yang Zhao, Laurie A. Lawler, Jason D. Christie, Nuala J. Meyer, Finnian R. Mc. Causland, Sushrut S. Waikar, Aaron B. Waxman, Raymond T. Chung, Raphael Bueno, Ivan O. Rosas, Laura E. Fredenburgh, Rebecca M. Baron, David C. Christiani, Gary M. Hunninghake, Augustine M. K. Choi
Journal: PLoS Medicine (2013)

Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients.Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers.Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.