tbuckley/cabot-search huggingface dataset:
Metabolic compensation for profound erythrocyte adenylate kinase deficiency. A hereditary enzyme defect without hemolytic anemia.
Authors: E Beutler, D Carson, H Dannawi, L Forman, W Kuhl, C West, B Westwood
Journal: Journal of Clinical Investigation (1983)

A child with hemolytic anemia was found to have severe erythrocyte adenylate kinase (AK) deficiency, but an equally enzyme-deficient sibling had no evidence of hemolysis. No residual enzyme activity was found in erythrocytes by spectrophotometric methods that could easily have detected 0.1% of normal activity. However, concentrated hemolysates were shown to have the capacity to generate small amounts of ATP and AMP from ADP after prolonged incubation. Hemolysates could also catalyze the transfer of labeled gamma-phosphate from ATP to ADP. Intact erythrocytes were able to transfer phosphate from the gamma-position of ATP to the beta-position, albeit at a rate substantially slower than normal. They could also incorporate 14C-labeled adenine into ADP and ATP. Thus, a small amount of residual AK-like activity representing about 1/2,000 of the activity normally present could be documented in the deficient erythrocytes. The residual activity was not inhibited by N-ethylmaleimide, which completely abolishes the activity of the normal AK1 isozyme of erythrocytes. The minute amount of residual activity in erythrocytes could represent a small amount of the AK2 isozyme, which has not been thought to be present in erythrocytes, or the activity of erythrocyte guanylate kinase with AMP substituting as substrate for GMP. Peripheral blood leukocytes, cultured skin fibroblasts, and transformed lymphoblasts from the deficient subject manifested about 17, 24, and 74%, respectively, of the activity of the concurrent controls. This residual activity is consistent with the existence of genetically independent AK isozyme, AK2, which is known to exist in these tissues. The cause of hemolysis in the proband was not identified. Possibilities include an unrelated enzyme deficiency or other erythrocyte enzyme defect and intraction of another unidentified defect with AK deficiency.
Frequency and correlates of malaria overdiagnosis and treatment in western Kenya
Authors: F M Onchiri, P Pavlinac, B O Singa, J N Mulongo, C Farquhar, G C John-Stewart, J Walson
Journal: The Lancet Global Health (2014)

BackgroundDespite decreasing malaria burden in sub-Saharan Africa, fever in children is frequently attributed to malaria and empirically treated with antimalarial drugs. The 2010 WHO guidelines recommend laboratory confirmation of malaria before initiating therapy, but the uptake of these guidelines is slow. We determined frequency and predictors of malaria overtreatment in febrile children at two western Kenya rural hospitals in regions with varied malaria endemicity.MethodsWe enrolled consecutive febrile children aged 6 months to 15 years presenting to Kisii Provincial (malaria endemicity: hypoendemic) or Homa Bay District (malaria endemicity: holoendemic) hospitals between March, 2012, and November, 2013. Detailed demographic, clinical, and laboratory data were collected, including physician diagnosis at admission and corresponding treatments. All children were screened for HIV with antibody or PCR testing, for malaria using smear microscopy and Paracheck Pf rapid diagnostic tests, and for invasive bacterial infections using blood culture. We determined the frequency of clinician-prescribed antimalarial treatment among those with negative smear and rapid diagnostic test results and evaluated independent predictors of overtreatment using multivariate logistic regression. Because the sites had marked differences in underlying malaria endemicities that might impact clinician suspicion of parasitaemia, analyses were stratified and compared by site.FindingsAmong the 1362 children enrolled (685 in Kisii and 677 in Homa Bay), 46 (6·7%) and 310 (45·8%) had laboratory-confirmed malaria in Kisii and Homa Bay, respectively (p<0·001). Among children without malaria, 7·0% and 57·2% were empirically prescribed antimalarials at Kisii and Homa Bay, respectively (p<0·001). Significant predictors of malaria overtreatment in Homa Bay included presence of more than one danger sign according to Integrated Management of Childhood Illness guidelines (adjusted odds ratio 8·47, 95% CI 4·81–14·89), fever lasting more than 7 days (4·94, 1·90–12·86), and fever greater than 390C (3·07, 1·58–5·96). The sensitivity of clinical malaria diagnosis (vs gold-standard laboratory-based diagnosis) was lower in Kisii than in Homa Bay (73·0% vs 95·3%, p<0·001), whereas specificity was higher in Kisii than in Homa Bay (93·2% vs 33·7%, p<0·001).InterpretationMalaria was treated, despite negative laboratory testing, more frequently in Homa Bay than in Kisii, probably owing to underlying higher malaria prevalence. Despite availability of diagnostic testing, malaria prevalence appears to influence the clinical management of children in Kenya and may result in missed opportunities to accurately diagnose alternative causes of fever. Strengthening health system use and adherence to existing treatment guidelines appears necessary, particularly in areas of high malaria endemicity.FundingUS National Institutes of Health.
Chikungunya disease in nonhuman primates involves long-term viral persistence in macrophages
Authors: Karine Labadie, Thibaut Larcher, Christophe Joubert, Abdelkrim Mannioui, Benoit Delache, Patricia Brochard, Lydie Guigand, Laurence Dubreil, Pierre Lebon, Bernard Verrier, Xavier de Lamballerie, Andreas Suhrbier, Yan Cherel, Roger Le Grand, Pierre Roques
Journal: Journal of Clinical Investigation (2010)

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that induces in humans a disease characterized by fever, rash, and pain in muscles and joints. The recent emergence or reemergence of CHIKV in the Indian Ocean Islands and India has stressed the need to better understand the pathogenesis of this disease. Previous CHIKV disease models have used young or immunodeficient mice, but these do not recapitulate human disease patterns and are unsuitable for testing immune-based therapies. Herein, we describe what we believe to be a new model for CHIKV infection in adult, immunocompetent cynomolgus macaques. CHIKV infection in these animals recapitulated the viral, clinical, and pathological features observed in human disease. In the macaques, long-term CHIKV infection was observed in joints, muscles, lymphoid organs, and liver, which could explain the long-lasting CHIKV disease symptoms observed in humans. In addition, the study identified macrophages as the main cellular reservoirs during the late stages of CHIKV infection in vivo. This model of CHIKV physiopathology should allow the development of new therapeutic and/or prophylactic strategies.
[432] FAVORABLE CROSS-RESISTANCE PROFILE OF TWO NOVEL HEPATITIS C VIRUS INHIBITORS, SCH-503034 AND HCV-796, AND ENHANCED ANTI-REPLICON ACTIVITY MEDIATED BY THE COMBINED USE OF BOTH COMPOUNDS
Authors: A.Y. Howe, R. Ralston, R. Chase, X. Tong, A. Skelton, M. Flint, S. Mullen, C. Broom, E.A. Emini
Journal: Journal of Hepatology (2007)
Synergistic effects of ultrasound-targeted microbubble destruction and TAT peptide on gene transfection: An experimental study in vitro and in vivo
Authors: Zhiyi Zhou, Ping Zhang, Jianli Ren, Haitao Ran, Yuanyi Zheng, Pan Li, Qunxia Zhang, Maohui Zhang, Zhigang Wang
Journal: Journal of Controlled Release (2013)
Endocardial mapping in humans in sinus rhythm with normal left ventricles: activation patterns and characteristics of electrograms.
Authors: D M Cassidy, J A Vassallo, F E Marchlinski, A E Buxton, W J Untereker, M E Josephson
Journal: Circulation (1984)

Endocardial catheter mapping was performed in 15 patients in sinus rhythm who had no evidence of structural heart disease and normal left ventricles. Mapping was performed with the use of 10 mm interelectrode distance from various left ventricular endocardial sites. In 10 patients a quantitative analysis of electrographic amplitude, duration, and amplitude/duration ratio was performed. The normal left ventricular bipolar electrograms had an amplitude of greater than 3 mV, a duration of less than 70 msec, and an amplitude/duration ratio of greater than 0.045. Local activation times were also assessed in the 15 patients. This analysis revealed two endocardial breakthrough sites, one on the midinferior septum and a second on the anterior wall near the insertion of the anterior papillary muscle. We therefore have defined normal quantitative characteristics of left ventricular bipolar electrograms and the normal left ventricular activation sequence in the intact normal human left ventricle.
Obesity and Calorie Bookkeeping
Authors: Max A. Goldzieher
Journal: JAMA (1961)

<h3>To the Editor:—</h3> My letter of Sept. 10 did not state that I was "banishing emotions or at least excommunicating them"; nor did I disagree with "the well-accepted fact that there are different obesities and differences in patients." In fact, in previous publications I have stated that obesity is merely a symptom and not a disease entity. I am aware that some obese people are emotionally unstable or outright neurotic; many of these patients seem to be far better balanced after losing their excess weight and regaining a less unsightly appearance. Would it be possible that in these cases the obesity is the cause and not the consequence of their emotional turmoil? Nevertheless, I recognize that emotional difficulties may lead to unwise eating habits and thus to a gain in weight, but I object to the overemphasis of the psychological explanation—a recurrent phenomenon or fad not unknown to the student
Putting the brakes on arthritis: can suppressors of cytokine signaling (SOCS) suppress rheumatoid arthritis?
Authors: Robert Rottapel
Journal: Journal of Clinical Investigation (2001)

During the immune response, as in a great symphony, timing is everything. Imagine the disastrous night of November 3, 1822, when Beethoven conducted a revival of his popular opera Fidelio. The musicians played their parts from the score perfectly but missed every cue of the great master, who was deaf to everything but his own imagination. The evening ended in chaos. The critical role for molecular cues firing at the right time is also true for the cellular players of the immune network, a system stitched together by the interplay of multiple cytokines. These peptide signals coordinate cell survival, migration, proliferation, and activation of cellular effector function. Not only do the right cytokine signals have to be initiated at the right time, but the duration of each signal must be perfectly controlled. Otherwise, disasters like autoimmunity or malignancies of the hematopoietic system can result.

The longevity of cytokine signals transduced by the JAK/STAT pathway is regulated, in part, by a family of endogenous JAK kinase inhibitor proteins referred to as suppressors of cytokine signaling (SOCS) (1, 2). The SOCS family contains eight members of related proteins that share a common modular organization of an SH2 domain followed by a SOCS-box (reviewed in ref. 3). Two members of this family, SOCS-1 and SOCS-3, are potent inhibitors of JAK kinase family members. Both SOCS-1 and SOCS-3 bind to the positive regulatory tyrosine in the activation loop of JAK kinases through their respective SH2 domains, thereby occluding the accessibility of the active site to substrates (4). The tissue expression patterns of SOCS proteins are complex and distinct for each family member.

Several SOCS members are early-response genes for a variety of cytokines and growth factors. For example, IL-6 induces SOCS-1, erythropoietin induces SOCS-2, and TNF-α induces SOCS-3, while IFN-γ potently induces all three family members. The transcriptional regulation of these SOCS family members appears to be under the exquisite control of the STAT transcription factors. Since SOCS-1 and SOCS-3 expression is tightly coupled to upstream cytokine signaling events it appears that they function as components of a negative feedback loop to dynamically terminate cytokine-mediated signals. Support for this model has been borne out by analysis of mice lacking SOCS proteins. SOCS-1–deficient mice die 3 weeks after birth as a result of unbridled IFN-γ signaling leading to widespread myelomonocytic infiltration of visceral organs and skin (5, 6). Socs1–/–/IFN-γ+/– mice develop an autoimmune polymyositis about 160 days after birth (7). Deficiency in SOCS-3 in mice results in embryonic lethality at day 12–16 and fetal liver erythrocytosis (8). For more on the central role of SOCS-3 in neuro-endocrine cross-regulation, see the Perspective by Auernhammer and Melmed in this issue (9).
The “Poison Chair” Treatment for Multiple Sclerosis
Authors: Allan H. Ropper
Journal: New England Journal of Medicine (2012)

In the very curious incident of the “poison chair,” hundreds of people in several European cities appeared at clinics with eczematous burns that had no apparent cause. The source was found to be dimethyl fumarate (fumarate), which was used as a fungicide and desiccant in the shipping of sofas. A Finnish physician uncovered the toxin by doggedly pursuing a local outbreak.1 Fumarate and its esters have had a much better safety record as medicinal than as industrial agents. A German biochemist administered fumaric acid to himself in 1959, believing his psoriasis was due to a deficiency of fumarate,2 and a . . .
Cost of Obstetric Services
Authors: Thomas M. Tierney
Journal: JAMA (1979)

To the Editor.—  A COMMENTARY by Hein and Ferguson,  Cost of Maternity Care in Rural Hospitals (240:2051,1978), is being widely circulated in the rural counties of western Oregon as a conclusive argument against the local Health Systems Agency's concern for small-hospital obstetric cost efficiency. The Hein-Ferguson article is unpersuasive, and a response seems necessary.  Focusing on room charges for mother and infant and delivery room fees, the authors conclude that obstetric services are less expensive in small hospitals. But that argument completely ignores the fundamental difference between hospital costs and patient charges.  If institutional health service prices consistently reflected the cost of providing each service, then the facile assumption that low patient fees mean cost efficiency would be justified. However, for a number of reasons hospitals often price certain services independently of costs, and patient prices therefore may not be a good measure of the cost of those services
Reporting Clinical Outcomes of Breast Reconstruction: A Systematic Review
Authors: S. Potter, A. Brigic, P. F. Whiting, S. J. Cawthorn, K. N. L. Avery, J. L. Donovan, J. M. Blazeby
Journal: JNCI Journal of the National Cancer Institute (2010)

Breast reconstruction after mastectomy for cancer requires accurate evaluation to inform evidence-based participatory decision making, but the standards of outcome reporting after breast reconstruction have not previously been considered.We used extensive searches to identify articles reporting surgical outcomes of breast reconstruction. We extracted data using published criteria for complication reporting modified to reflect reconstructive practice. Study designs included randomized controlled trials, cohort studies, and case series. The Cochrane Risk of Bias tool was used to critically appraise all study designs. Other criteria used to assess the studies were selection and funding bias, statistical power calculations, and institutional review board approval. Wilcoxon signed rank tests were used to compare the breadth and frequency of study outcomes, and χ² tests were used to compare the number of studies in each group reporting each of the published criteria. All statistical tests were two-sided.Surgical complications following breast reconstruction in 42,146 women were evaluated in 134 studies. These included 11 (8.2%) randomized trials, 74 (55.2%) cohort studies, and 49 (36.6%) case series. Fifty-three percent of studies demonstrated a disparity between methods and results in the numbers of complications reported. Complications were defined by 87 (64.9%) studies and graded by 78 (58.2%). Details such as the duration of follow-up and risk factors for adverse outcomes were omitted from 47 (35.1%) and 58 (43.3%) studies, respectively. Overall, the studies defined fewer than 20% of the complications they reported, and the definitions were largely inconsistent.The results of this systematic review suggest that outcome reporting in breast reconstruction is inconsistent and lacks methodological rigor. The development of a standardized core outcome set is recommended to improve outcome reporting in breast reconstruction.
Sleep problems and work injuries: A systematic review and meta-analysis
Authors: Katrin Uehli, Amar J. Mehta, David Miedinger, Kerstin Hug, Christian Schindler, Edith Holsboer-Trachsler, Jörg D. Leuppi, Nino Künzli
Journal: Sleep Medicine Reviews (2013)

Sleep problems are a potential risk factor for work injuries but the extent of the risk is unclear. We conducted a systematic review and meta-analysis to quantify the effect of sleep problems on work injuries.A systematic literature search using several databases was performed. Sleep problems of any duration or frequency as well as work injuries of any severity were of interest. The effect estimates of the individual studies were pooled and relative risks (RR) and 95% confidence intervals (CI) were calculated through random effects models. Additionally, the population attributable risk was estimated.In total, 27 observational studies (n = 268,332 participants) that provided 54 relative risk estimates were included. The findings of the meta-analysis suggested that workers with sleep problems had a 1.62 times higher risk of being injured than workers without sleep problems (RR: 1.62, 95% CI: 1.43-1.84). Approximately 13% of work injuries could be attributed to sleep problems.This systematic review confirmed the association between sleep problems and work injuries and, for the first time, quantified its magnitude. As sleep problems are of growing concern in the population, these findings are of interest for both sleep researchers and occupational physicians.
Cytoplasmic dynein colocalizes with melanosomes in normal human melanocytes
Authors: G. Vancoillie, J. Lambert, A. Mulder, H.K. Koerten, A.M. Mommaas, P. Van Oostveldt, J.-M. Naeyaert
Journal: British Journal of Dermatology (2000)

Background Melanocytic dendrites consist of a central core of microtubules and a subcortical actin network. Several studies provide arguments supporting the hypothesis that actin‐based and microtubule‐based motor proteins co‐operate in melanosome transport towards the dendrite tips. Melanosomes can move bidirectionally along microtubules in vitro, and in murine melanocytes, they move towards the cell periphery and back again. Microtubules have a fast‐growing plus end and a slow‐growing minus end . Microtubule‐associated motor proteins move unidirectionally either towards the plus or towards the minus end. However, it is not known which motor protein is responsible for minus end‐directed movement of melanosomes. Objectives We aimed to investigate the in vitro expression of the minus end‐directed motor protein cytoplasmic dynein in normal human epidermal melanocytes, keratinocytes and dermal fibroblasts. Methods Reverse transcription–polymerase chain reaction and Northern blot analysis were used. In addition, an attempt to obtain insight into the subcellular localization of cytoplasmic dynein, immunofluorescence studies and immunogold electron microscopic studies were performed. Results The three different forms of cytoplasmic dynein heavy chain were expressed in all studied skin cells. Immunofluorescence staining showed similar punctate distributions for dynein heavy chain 1 and dynein heavy chain 2 in melanocytes, with accentuation in the perinuclear area and dendrite tips. Double labelling with a melanosome marker showed apparent co‐localization of both dynein heavy chains 1 and 2 with melanosomes in the perinuclear area and dendrite tips. For the dynein intermediate chain of 74 kDa, again a punctate staining pattern was seen with intense centrosomal staining. A close association of dynein intermediate chain 74 and α‐tubulin with the melanosome surface was detected using immunogold electron microscopy. Conclusions The colocalization of different subunits of the cytoplasmic dynein complex with melanosomes is consistent with the hypothesis that this motor protein supports minus end‐directed melanosome movement along microtubules.
Computer diagnosis of supraventricular and ventricular arrhythmias. A new esophageal technique.
Authors: J M Jenkins, D Wu, R C Arzbaecher
Journal: Circulation (1979)

Computerized arrhythmia monitors recognize only a few of the significant arrhythmias and generally fail to detect arrhythmias of supraventricular origin. This is because conventional surface leads, which are sufficient for QRS recognition, are highly inadequate for automated P-wave detection. A new two-lead system, which includes a swallowable capsule-electrode for esophageal monitoring of atrial activity, is used in an on-line arrhythmia monitor. Three interval measurements (AA, AR and RR) and a QRS shape measurement provide the foundation for a detailed interpretation of each beat. Building on the single-beat analysis, a contextual diagnostic algorithm then recognizes and reports on-line the following arrhythmias: couplets, bigeminy, trigeminy, ventricular tachycardia, supraventricular tachycardia, atrial flutter, atrial fibrillation, ventricular tachycardia with retrograde conduction to the atria, first-degree block, second-degree block, Wenckebach periodicity, advanced block, third-degree block and sinus bradycardia.
Sudden cardiac death in sport.
Authors: R J Northcote, D Ballantyne
Journal: BMJ (1983)

After running to Athens from Marathon in 490 BC, bringing the news of victory over the Persians, Pheidippides, who was a trained runner, is reported to have collapsed and died.'The number of case reports of similar events during strenuous physical activity has increased, particularly over the past 10 years, and has paralleled a boom in sporting activity.In 1982 the London marathon alone attracted 16 350 competitors.This increase in popularity has also been observed in other sports, most notably squash, track and field athletics, and swimming.Accompanying the boom in participation has been a disturbing increase in reports-often in the media-of sudden death associated with strenuous sports such as marathon running and squash.Hence it is important to consider the strength of the association between sudden death and sporting activity.Although occasional deaths are attributed to other causes such as subarachnoid haemorrhage,2 road traffic accident,3 and acute gastrointestinal bleeding,4 the most frequent cause of death is cardiac.5-7We have therefore reviewed published reports in an attempt to determine how common such deaths are and the factors leading to death.We also provide some recommenda- tions which we hope will reduce their frequency.For this purpose we have defined sudden death in sport as death occurring either during a medically unsupervised pursuit or in the first hour thereafter.