tbuckley/cabot-search huggingface dataset:
Quantitative Relation Between Interstitial Adenosine Concentration and Coronary Blood Flow
Authors: David W. Stepp, Richard Van Bibber, Keith Kroll, Eric O. Feigl
Journal: Circulation Research (1996)

The effect of exogenous and endogenous adenosine in controlling coronary flow was determined using an axially distributed mathematical model of the myocardium to estimate interstitial adenosine concentration from coronary arterial and venous adenosine values. The left main coronary artery was perfused at constant pressure in closed-chest, anesthetized dogs, and exogenous adenosine was infused intracoronary to increase coronary flow. Basal interstitial adenosine was 92 nmol/L, just at the threshold for increasing coronary flow. An increase in interstitial adenosine concentration of only 62% was sufficient to increase coronary flow from 5% to 50% of maximal flow. The possible contribution of an endothelial dilator secondary to activation of adenosine receptors on endothelial cells was tested by comparing the response to exogenous intracoronary adenosine infusion with increases in endogenous adenosine produced by inhibition of adenosine kinase and adenosine deaminase. If adenosine increases coronary flow by an endothelial mechanism, then the interstitial ED50 of exogenous adenosine would be lower than that for endogenous adenosine due to the postulated additional endothelial dilator. The interstitial ED50 for exogenous adenosine was 156 nmol/L, not different from the endogenous ED50 of 150 nmol/L. In conclusion, basal interstitial adenosine concentration is at the threshold of a remarkably steep dose-response curve for increasing coronary blood flow. No evidence was found for an endothelium-mediated vasodilator mechanism secondary to adenosine receptor activation of endothelial cells in vivo. The steep adenosine dose-response curve indicates that measurements of adenosine concentration should be interpreted with caution, because small changes in adenosine concentration cause large changes in coronary flow.
Israel's ban on use of Ethiopians' blood: how many infectious donations were prevented?
Authors: Edward H Kaplan
Journal: The Lancet (1998)

Many countries exclude blood donations thought to be associated with unacceptably high risks of HIV-1 or other infection. Blood donations from Ethiopian immigrants to Israel were taken and then discarded, without informing the donors, owing to the high prevalence of HIV-1 infection in this community relative to other Israelis. 1 Schmemann S Ethiopians in Israel riot over dumping of donated blood. New York Times. 1996; January 29; Google Scholar , 2 Vikhanski L Israel's blood policy causes furor. Nat Med. 1996; 2: 260 Crossref Scopus (3) Google Scholar This policy became known via a newspaper exposé in January, 1996. One consequence was a violent protest by 10000 Ethiopian immigrants that led to injuries to roughly 70 demonstrators and police officers; 2 Vikhanski L Israel's blood policy causes furor. Nat Med. 1996; 2: 260 Crossref Scopus (3) Google Scholar a second was the establishment of a commission of inquiry chaired by former Israeli president Yitzhak Navon. 3 Navon Y Winograd E Hillel N Nagan L Rachmilevich E Zakai Y Summoning to Clarify the Blood Donation Affair of Ethiopian Immigrants (in Hebrew). Government of Israel, Jerusalem1996 Google Scholar
Effects of Fluid Resuscitation With Colloids vs Crystalloids on Mortality in Critically Ill Patients Presenting With Hypovolemic Shock
Authors: Djillali Annane
Journal: JAMA (2013)

Evidence supporting the choice of intravenous colloid vs crystalloid solutions for management of hypovolemic shock remains unclear.To test whether use of colloids compared with crystalloids for fluid resuscitation alters mortality in patients admitted to the intensive care unit (ICU) with hypovolemic shock.A multicenter, randomized clinical trial stratified by case mix (sepsis, trauma, or hypovolemic shock without sepsis or trauma). Therapy in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was open label but outcome assessment was blinded to treatment assignment. Recruitment began in February 2003 and ended in August 2012 of 2857 sequential ICU patients treated at 57 ICUs in France, Belgium, North Africa, and Canada; follow-up ended in November 2012.Colloids (n = 1414; gelatins, dextrans, hydroxyethyl starches, or 4% or 20% of albumin) or crystalloids (n = 1443; isotonic or hypertonic saline or Ringer lactate solution) for all fluid interventions other than fluid maintenance throughout the ICU stay.The primary outcome was death within 28 days. Secondary outcomes included 90-day mortality; and days alive and not receiving renal replacement therapy, mechanical ventilation, or vasopressor therapy.Within 28 days, there were 359 deaths (25.4%) in colloids group vs 390 deaths (27.0%) in crystalloids group (relative risk [RR], 0.96 [95% CI, 0.88 to 1.04]; P = .26). Within 90 days, there were 434 deaths (30.7%) in colloids group vs 493 deaths (34.2%) in crystalloids group (RR, 0.92 [95% CI, 0.86 to 0.99]; P = .03). Renal replacement therapy was used in 156 (11.0%) in colloids group vs 181 (12.5%) in crystalloids group (RR, 0.93 [95% CI, 0.83 to 1.03]; P = .19). There were more days alive without mechanical ventilation in the colloids group vs the crystalloids group by 7 days (mean: 2.1 vs 1.8 days, respectively; mean difference, 0.30 [95% CI, 0.09 to 0.48] days; P = .01) and by 28 days (mean: 14.6 vs 13.5 days; mean difference, 1.10 [95% CI, 0.14 to 2.06] days; P = .01) and alive without vasopressor therapy by 7 days (mean: 5.0 vs 4.7 days; mean difference, 0.30 [95% CI, -0.03 to 0.50] days; P = .04) and by 28 days (mean: 16.2 vs 15.2 days; mean difference, 1.04 [95% CI, -0.04 to 2.10] days; P = .03).Among ICU patients with hypovolemia, the use of colloids vs crystalloids did not result in a significant difference in 28-day mortality. Although 90-day mortality was lower among patients receiving colloids, this finding should be considered exploratory and requires further study before reaching conclusions about efficacy.clinicaltrials.gov Identifier: NCT00318942.
Neurotrophins: Roles in Neuronal Development and Function
Authors: Eric J Huang, Louis F Reichardt
Journal: Annual Review of Neuroscience (2001)

Neurotrophins regulate development, maintenance, and function of vertebrate nervous systems. Neurotrophins activate two different classes of receptors, the Trk family of receptor tyrosine kinases and p75NTR, a member of the TNF receptor superfamily. Through these, neurotrophins activate many signaling pathways, including those mediated by ras and members of the cdc-42/ras/rho G protein families, and the MAP kinase, PI-3 kinase, and Jun kinase cascades. During development, limiting amounts of neurotrophins function as survival factors to ensure a match between the number of surviving neurons and the requirement for appropriate target innervation. They also regulate cell fate decisions, axon growth, dendrite pruning, the patterning of innervation and the expression of proteins crucial for normal neuronal function, such as neurotransmitters and ion channels. These proteins also regulate many aspects of neural function. In the mature nervous system, they control synaptic function and synaptic plasticity, while continuing to modulate neuronal survival.
T follicular helper cells differentiate from Th2 cells in response to helminth antigens
Authors: Arielle Glatman Zaretsky, Justin J. Taylor, Irah L. King, Fraser A. Marshall, Markus Mohrs, Edward J. Pearce
Journal: The Journal of Experimental Medicine (2009)

The relationship of T follicular helper (TFH) cells to other T helper (Th) subsets is controversial. We find that after helminth infection, or immunization with helminth antigens, reactive lymphoid organs of 4get IL-4/GFP reporter mice contain populations of IL-4/GFP-expressing CD4+ T cells that display the TFH markers CXCR5, PD-1, and ICOS. These TFH cells express the canonical TFH markers BCL6 and IL-21, but also GATA3, the master regulator of Th2 cell differentiation. Consistent with a relationship between Th2 and TFH cells, IL-4 protein production, reported by expression of huCD2 in IL-4 dual reporter (4get/KN2) mice, was a robust marker of TFH cells in LNs responding to helminth antigens. Moreover, the majority of huCD2/IL-4–producing Th cells were found within B cell follicles, consistent with their definition as TFH cells. TFH cell development after immunization failed to occur in mice lacking B cells or CD154. The relationship of TFH cells to the Th2 lineage was confirmed when TFH cells were found to develop from CXCR5− PD-1− IL-4/GFP+ CD4+ T cells after their transfer into naive mice and antigen challenge in vivo.
Troponin and Tropomyosin
Authors: R. John Solaro, Helen M. Rarick
Journal: Circulation Research (1998)

Abstract —We present a current perception of the regulation of activation of cardiac myofilaments with emphasis on troponin (Tn) and tropomyosin (Tm). Activation involves both a Ca 2+ -regulated molecular switch and a potentiated state, dependent on feedback effects of force-generating crossbridges. Recent developments in the elucidation of the structure and arrangement of the myofilament proteins offer insights into the molecular interactions that constitute the switching and potentiating mechanisms. Transgenic mice overexpressing myofilament proteins, in vitro studies of mutant myofilament proteins, multidimensional multinuclear nuclear magnetic resonance, and fluorescence resonance energy transfer offer important approaches to understanding the molecular signaling processes. These studies reveal special features of the cardiac myofilament proteins that appear specialized for the unique functions of the heart. An important aspect of these special features is their role in mechanical, chemical, and neurohumoral coupling processes that tune myofilament activation to hemodynamics and beating frequency. Understanding these processes has become essential to understanding cardiac pathologies such as heart failure, ischemia and reperfusion injury, stunning, and familial hypertrophic cardiac myopathies.
Gender differences in COPD: are women more susceptible to smoking effects than men?
Authors: I.-C. Sorheim, A. Johannessen, A. Gulsvik, P. S. Bakke, E. K. Silverman, D. L. DeMeo
Journal: Thorax (2010)

The number of female smokers developing chronic obstructive pulmonary disease (COPD) is rapidly increasing, but whether or not there exists a differential susceptibility by gender remains controversial.How smoking behaviour and subsequent lung function reduction differed by gender was examined in a study including 954 subjects with COPD and 955 subjects without COPD. The study focused on two subgroups: subjects with COPD <60 years of age (early-onset group, n=316) and subjects with COPD with <20 pack-years of smoking (low exposure group, n=241).In the low exposure group, female subjects with COPD had lower forced expiratory volume in 1 s (FEV(1)) % predicted (48.7% vs 55.8%, p=0.001) and more severe disease (50.4% vs 35.6%, p=0.020, in GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage 3 and 4) than male subjects with COPD. Females also had lower FEV(1)% predicted (50.6% vs 56.0%, p=0.006) and more severe COPD (41.7% vs 31.1% in GOLD stage 3 and 4, p=0.050) in the early-onset group. Using multivariate regression, female gender was associated with 5.7% lower FEV(1)% predicted in the low exposure group (p=0.012) and a similar trend was observed in the early-onset group (p=0.057). The number of pack-years was not significantly associated with lung function in female subjects with COPD in this study, and the dose-response relationship between smoking and lung function differed by gender at lower levels of smoking exposure. Interaction analysis suggested that the effect of smoking on lung function might be different by gender (p=0.027 in all subjects with COPD).Female gender was associated with lung function reduction and more severe disease in subjects with COPD with early onset of disease or low smoking exposure. The findings may suggest a gender difference in susceptibility to the lung-damaging effects of cigarette smoking, but alternative explanations should be considered.
Abstract IA18: Molecular mechanisms regulating synergistic effect of immunotherapy and chemotherapy of cancer
Authors: Dmitry Gabrilovich, Rupal Ramakrishnan, Chun Huang
Journal: Clinical Cancer Research (2012)

Abstract Despite recent advances in the development of new chemotherapeutic drugs and improvements in radiation therapy, conventional cancer therapy often falls short of the goal of controlling tumor progression. Therapeutic cancer vaccines and adoptive T-cell transfer are long considered as very attractive therapeutic options in the treatment of cancer. However, clinical trials of different cancer vaccines performed in recent years demonstrated rather weak clinical efficacy. It has become apparent that therapeutic cancer vaccines given as a single agent may not produce substantial clinical benefits and combination with conventional methods of treatment will be necessary. The use of conventional cancer chemotherapy in combination with cancer vaccines was previously not considered as very attractive due to the potent immunosuppressive effect usually associated with chemotherapy. This paradigm was challenged in recent years by serendipitous observations made in a number of phase I/II clinical trials that reported high rates of objective clinical responses when cancer vaccines were combined with chemotherapy. The paradox is that the types of chemotherapy that are used in lung cancer are known to suppress the immune system. We have recently demonstrated that chemotherapy and cytotoxic T cells (CTL) have a synergistic cytotoxic effect that may be mediated by mannose-6-phosphate receptor (MPR). We have shown that when cancer vaccines or adoptive T-cell transfer are used as a single modality, only limited numbers of T cells are able to penetrate the tumor parenchyma. CTLs exert their cytotoxic effect only against tumor cells that express specific antigen, since it requires a direct cell-cell contact, and release of perforin and granzymes (GrzB). If chemotherapy is administered immediately after immunotherapy, it causes disruption of tumor stroma that allows for better penetration of antigen-specific T cells. Chemotherapy via autophagy causes substantial increase in MPR expression on tumor cells. Small number of activated CTLs interacting with tumor cells expressing tumor antigen can release GrzB that can penetrate into neighboring tumor cells without requirement for cell-cell contact. Therefore large number of tumor cells including those that do not express specific antigen would be susceptible to the effect of CTLs. This may explain substantial enhancement of antitumor effect of combined treatment. It is likely that this effect would not be long-lasting since CTL activity will be eliminated by chemotherapy and the immune suppressive tumor microenvironment. However, it may provide a sufficient window to achieve a significant antitumor effect. Since memory T cells are more resistant to chemotherapy than effector T cells, it is possible that subsequent immunization would be able to boost antitumor immunity and thus provide a longer lasting effect of combined therapy.
Age factors potentiating drug toxicity in the reproductive axis.
Authors: R F Walker
Journal: Environmental Health Perspectives (1986)

Traditionally, drug toxicity in the reproductive system has been a concern only as it affects fertility and fecundity in young individuals. The purpose of this report is to address the potential problem of synergy between drug actions and abnormal secretion of reproductive hormones that together produce disease in older individuals. Thus, reproductive toxicity has different, but no less serious implications in aging individuals. During aging, the coordinated function of elements within the reproductive neuroendocrine axis degrades. This change promotes atypical secretion of hormones producing abnormal responses in target organs and thus creates a condition with pathogenic potential. Certain drugs may contribute to reproductive toxicity in aging individuals either by accelerating the process of dysregulation and/or by synergizing with hormones to stimulate pathologic changes in target tissues. The geriatric population of the world is increasing, and since it consumes a proportionately larger percentage of drugs than younger groups, this novel form of reproductive toxicity may represent a problem in drug safety that warrants serious consideration.
THE MECHANISM OF THE ABDERHALDEN REACTION
Authors: J. Bronfenbrenner
Journal: The Journal of Experimental Medicine (1915)

1. The Abderhalden reaction is specific. 2. The properties of serum on which it depends develop in experimental animals simultaneously with antibodies during the process of immunization. 3. It is impossible to observe by direct methods the presence of digesting ferments in the blood of immune animals. 4. The Abderhalden test may be resolved into two phases. A dialyzable substance appears in the second phase and is the result of the autodigestion of serum. 5. The autodigestion of serum in the Abderhalden test is due to the removal of antitrypsin from the serum by the sensitized substratum.
Serotonergic modulation of visceral sensation: lower gut
Authors: M Camilleri
Journal: Gut (2002)

The role of 5-HT agents in the modulation of lower gastrointestinal function is discussed. Selective serotonin reuptake inhibitors are of potential benefit in functional gastrointestinal diseases although formal evidence is lacking. Novel pharmacological approaches include 5-HT(3) antagonists and 5-HT(4) agonists. These pharmacological classes have shown beneficial effects on a global efficacy end point, and ameliorated more than one symptom of lower gut function in clinical trials. They offer promise for the development of novel therapies for the treatment and control of irritable bowel syndrome.
QL-11 * HEALTH-RELATED QUALITY OF LIFE, COGNITIVE FUNCTIONING AND SURVIVAL IN PATIENTS TREATED WITH STEREOTACTIC RADIOTHERAPY FOR BRAIN METASTASES: A PROSPECTIVE STUDY
Authors: Esther Habets, Linda Dirven, Ruud Wiggenraad, Hanneke Zwinkels, Geert Lycklama á Nijeholt, Martin Taphoorn
Journal: Neuro-Oncology (2014)

BACKGROUND: Although stereotactic radiotherapy (SRT) for brain metastases is expected to have a less detrimental effect on cognition and health-related quality of life (HRQoL) than whole-brain radiotherapy (WBRT), the precise effect is largely unknown. METHODS: Cognition and HRQoL were measured prior to SRT, 3 and 6 months follow-up. Four cognitive domains and seven preselected scales of the EORTC-QLQC30 and BN20 were analysed. Survival analysis was performed and effect of total volume of brain metastases and Karnofsky Performance Status (KPS) (both categorized) on overall survival (OS) was examined. Linear mixed models were used to analyse cognition and HRQoL over time, also separately for KPS and tumor volume. RESULTS: Mean age of the 97 patients was 63 years, median OS was 7.7 months. Median OS was significantly shorter for KPS < 90 compared to KPS ≥ 90 and for large compared to smaller tumor volume. Prior to SRT, memory and attention were worse compared to matched healthy controls, and all HRQoL scores were lower than of the general population. On group level, patients worsened in physical functioning after 6 months follow-up. Cognitive domain scores did not change over 6 months. Mean HRQoL scores over 6 months time were significantly lower for patients with baseline KPS < 90 compared to KPS ≥ 90 for physical, cognitive and role functioning, and motor dysfunction. Mean physical and cognitive functioning over time were lower for large than for smaller tumors. Information processing speed over time was worse for patients with KPS < 90 than KPS ≥ 90, and for large tumor volume compared to small volumes. CONCLUSION: Before SRT, cognitive functioning and HRQoL are moderately impaired in patients with brain metastases. Low KPS and large tumor volume are associated with shorter survival and worse cognition and HRQoL. Over time, SRT does not have a detrimental effect on cognition and HRQoL, suggesting that SRT should be preferred over WBRT.
TEMPORARY INSANITY AS A DEFENSE
Authors: LEO L. ORENSTEIN, ALFRED WEISSTEIN
Journal: American Journal of Psychiatry (1958)

It is not necessary to argue the point that transitory psychoses occur, and are seen frequently by the clinician. Occasionally a crime is committed during such a state— sometimes referred to as an acute psychotic episode. We must establish a set of criteria for the clinical diagnosis of the condition when it exists or is alleged to have existed, and these, we feel, will suffice for purposes of defense. We here quote Overholser (4) who quotes Isaac Ray, Insanity (the word was used then by medical men as equivalent with "psychosis"), is a disease, and as is the case with all other diseases, the fact of its existence is never established by a single diagnostic symptom, but by the whole body of symptoms, no particular one of which is present in every case. The Ray awards of the A.P.A. have in recent years resulted in a growing body of knowledge, most helpful to forensic psychiatry. We have already alluded to Overholser's award book "The Psychiatrist and the Law." Another of these miniature classics is the one by Zilboorg(5). The second winner of the Ray award, frequently humorous, at times bitterly critical, is none the less clinical in his observations. Concerning the M'Naghten rule, he says, "It is the monster of the earnest psychiatrist which prevents him from introducing into the courtroom true understanding of human psychology and of the criminal act." In the Brannen case in Queens County, State of New York, a psychiatrist was asked the question, "What is psychosis ?" and instead of being limited to a brief answer was permitted to go up in front of the jury box and with pencil and paper explain schematically the relationship between quantity of ego functioning and psychosis. This was made possible by a team of competent defense lawyers, and even more important, an alert, curious and tolerant judge. One wonders whether Judge Farrell was even interested in adding to medico-legal history when he agreed that the psychiatrist may use diagrams in clarifying his clinical points. Later, the same lawyers and in the same case, further attacked the status quo when they were successful in a habeas corpus writ and obtained Brannen's release from Matteawan without referral to the court of orginal jurisdiction. The Brannen case alone could have been an interesting presentation. We chose to include other clinical material because we desire a discussion of the broader aspects of temporary insanity as a defense. Acute psychotic episodes, or transitory psychotic states, or temporary insanity are terms depicting the same clinical entity. A person in such state manifests in behavior and expresses n words evidence of marked diminution of ego functioning. This may result in disturbance of thinking, perception, and judgment to such severe degree as to make it impossible for the affected person to distinguish reality from unreality.