tbuckley/cabot-search huggingface dataset:
Expanding Spectrum of Human <i>RYR2</i> -Related Disease
Authors: Zahurul A. Bhuiyan, Maarten P. van den Berg, J. Peter van Tintelen, Margreet T.E. Bink-Boelkens, Ans C.P. Wiesfeld, Marielle Alders, Alex V. Postma, Irene van Langen, Marcel M.A.M. Mannens, Arthur A.M. Wilde
Journal: Circulation (2007)

Background— Catecholaminergic polymorphic ventricular tachycardia is a disease characterized by ventricular arrhythmias elicited exclusively under adrenergic stress. Additional features include baseline bradycardia and, in some patients, right ventricular fatty displacement. The clinical spectrum is expanded by the 2 families described here. Methods and Results— Sixteen members from 2 separate families have been clinically evaluated and followed over the last 15 years. In addition to exercise-related ventricular arrhythmias, they showed abnormalities in sinoatrial node function, as well as atrioventricular nodal function, atrial fibrillation, and atrial standstill. Left ventricular dysfunction and dilatation was present in several affected individuals. Linkage analysis mapped the disease phenotype to a 4-cM region on chromosome 1q42-q43. Conventional polymerase chain reaction–based screening did not reveal a mutation in either the Ryanodine receptor 2 gene ( RYR2 ) or ACTN2 , the most plausible candidate genes in the region of interest. Multiplex ligation-dependent probe amplification and long-range polymerase chain reaction identified a genomic deletion that involved RYR2 exon-3, segregated in all the affected family members (n=16) in these 2 unlinked families. Further investigation revealed that the genomic deletion occurred in both families as a result of Alu repeat–mediated polymerase slippage. Conclusions— This is the first report on a large genomic deletion in RYR2 , which leads to extended clinical phenotypes (eg, sinoatrial node and atrioventricular node dysfunction, atrial fibrillation, atrial standstill, and dilated cardiomyopathy). These features have not previously been linked to RYR2 .
Therapeutic monitoring of continuous infusion etoposide in small-cell lung cancer.
Authors: S P Joel, P Ellis, K O'Byrne, D Papamichael, M Hall, R Penson, S Nicholls, C O'Donnell, A Constantinou, J Woodhull, M Nicholson, I Smith, D Talbot, M Slevin
Journal: Journal of Clinical Oncology (1996)

PURPOSE To investigate the feasibility of therapeutic monitoring of etoposide at different plasma concentrations of the drug, and the resulting pharmacodynamic effects of such an approach. PATIENTS AND METHODS Forty-nine previously untreated small-cell lung cancer (SCLC) patients received single-agent etoposide every 3 weeks by continuous infusion over 5 days. Plasma etoposide concentrations were monitored 18 and 66 hours into the infusion to permit dose modification. The first cohort of 15 patients began treatment with etoposide 2 micrograms/mL, with dose escalation to 3 micrograms/mL for cycles 3 and 4 and 4 micrograms/mL for cycles 5 and 6, toxicity permitting. The second cohort of 34 patients commenced at 3 micrograms/mL, with dose escalation to 4 and 5 micrograms/mL on cycles 3 and 5, respectively. RESULTS Mean plasma etoposide concentration during the first treatment cycle was 93.4% +/- 26.6% of the target level at 18 hours (57% of patients within +/- 20% of the target) and 98.9% +/- 14.5% of the target level at 66 hours (82% of patients within +/- 20%). Hematologic toxicity was more pronounced in those treated with 3 micrograms/mL versus 2 micrograms/mL (median nadir neutrophil count, 1.3 v 2.6 x 10(9)/L, P = .032). Tumor responses, typically documented by the third cycle, were similar in each cohort (71% in patients commenced at 2 micrograms/mL and 70% at 3 micrograms/mL). Treatment cohort was not independently predictive of survival. CONCLUSION Therapeutic monitoring of infusional etoposide is feasible and dramatically reduces interpatient pharmacokinetic variability. Although this was a small nonrandomized trial, the observation of different hematologic toxicity at the two starting concentrations but similar antitumor activity further suggests that these effects may be associated with different plasma etoposide concentrations.
Debilitating knee pain in a patient with "normal" radiographs
Authors: G K Meenagh
Journal: Annals of the Rheumatic Diseases (2001)

A 67 year old woman presented with a one year history of increasing pain in both knees which was worse on activity. Initial examination showed small bilateral cool knee effusions with retropatellar crepitus. Radiographs showed mild patellofemoral osteoarthritis. No other abnormality was detected in the locomotor system.

Initial management comprised advice on weight and cushioned footwear, simple analgesia, quadriceps physiotherapy, and aspiration and injection of both knee joints with 40 mg triamcinolone hexacetonide. Six months later she was admitted to hospital because of severe debilitating knee pain resulting in inability to weight bear.

Examination showed mild wasting of the quadriceps muscles with retropatellar crepitus and painful restriction of movement of both knees. Repeat weightbearing knee radiographs (fig 1) showed no obvious change from the initial study six months previously apart from the impression of a high density shadow in the region of both lateral femoral condyles. Further questioning showed excessive alcohol intake and an episode of alcoholic hepatitis complicating a paracetamol overdose two years previously. There was no history of oral corticosteroid treatment, diabetes mellitus, hyperlipidaemia, or recent trauma.



Figure 1 
Plain weightbearing knee radiographs at the time of admission, which are essentially “normal”.



Biochemical investigations showed a raised γ-glutamyltransferase 115 U/l (normal 11–51 U/l) and hypoalbuminaemia …
Adherence to Wearing Prescription Custom-Made Footwear in Patients With Diabetes at High Risk for Plantar Foot Ulceration
Authors: Roelof Waaijman, Renske Keukenkamp, Mirjam de Haart, Wojtek P. Polomski, Frans Nollet, Sicco A. Bus
Journal: Diabetes Care (2013)

Prescription custom-made footwear can only be effective in preventing diabetic foot ulcers if worn by the patient. Particularly, the high prevalence of recurrent foot ulcers focuses the attention on adherence, for which objective data are nonexisting. We objectively assessed adherence in patients with high risk of ulcer recurrence and evaluated what determines adherence.In 107 patients with diabetes, neuropathy, a recently healed plantar foot ulcer, and custom-made footwear, footwear use was measured during 7 consecutive days using a shoe-worn, temperature-based monitor. Daily step count was measured simultaneously using an ankle-worn activity monitor. Patients logged time away from home. Adherence was calculated as the percentage of steps that prescription footwear was worn. Determinants of adherence were evaluated in multivariate linear regression analysis.Mean ± SD adherence was 71 ± 25%. Adherence at home was 61 ± 32%, over 3,959 ± 2,594 steps, and away from home 87 ± 26%, over 2,604 ± 2,507 steps. In 35 patients with low adherence (<60%), adherence at home was 28 ± 24%. Lower BMI, more severe foot deformity, and more appealing footwear were significantly associated with higher adherence.The results show that adherence to wearing custom-made footwear is insufficient, particularly at home where patients exhibit their largest walking activity. This low adherence is a major threat for reulceration. These objective findings provide directions for improvement in adherence, which could include prescribing specific off-loading footwear for indoors, and they set a reference for future comparative research on footwear adherence in diabetes.
In vivo stimulation and restoration of the immune response by the noninflammatory fragment 163-171 of human interleukin 1 beta.
Authors: D Boraschi, L Nencioni, L Villa, S Censini, P Bossù, P Ghiara, R Presentini, F Perin, D Frasca, G Doria
Journal: The Journal of Experimental Medicine (1988)

The synthetic nonapeptide VQGEESNDK, corresponding to the fragment 163-171 of human IL-1 beta, showed in vivo immunomodulatory capacities qualitatively and quantitatively comparable to those of the mature human IL-1 beta protein. In fact, both IL-1 beta and the 163-171 fragment stimulated the immune response of normal mice and restored immune reactivities of immunocompromised animals. In addition, the synthetic IL-1 peptide was as efficient as the entire protein in inducing tumor rejection and radioprotection. On the other hand, the 163-171 fragment did not cause any of several inflammation-associated metabolic changes inducible by the whole IL-1 beta molecule in vivo: hypoferremia, hypoglycemia, hyperinsulinemia, increase in circulating corticosterone, SAA and fibrinogen, decrease in hepatic drug-metabolizing enzymes. Furthermore, at variance with IL-1 beta, the 163-171 peptide did not show the toxic effects causing shock and death in adrenalectomized mice. Thus, these results confirm our previous in vitro observations that functional domains are identifiable within the multipotent cytokine IL-1 beta, and demonstrate the biological relevance of this finding in a variety of in vivo systems. The identification of a selectively active fragment of a cytokine may thus represent a significant step towards a better directed and more rational immunotherapeutic approach.
Alpha-fetoprotein response correlates with EASL response and survival in solitary hepatocellular carcinoma treated with transarterial therapies: A subgroup analysis
Authors: Khairuddin Memon, Laura Kulik, Robert J. Lewandowski, Edward Wang, Robert K. Ryu, Ahsun Riaz, Paul Nikolaidis, Frank H. Miller, Vahid Yaghmai, Talia Baker, Michael Abecassis, Al B. Benson, Mary F. Mulcahy, Reed A. Omary, Riad Salem
Journal: Journal of Hepatology (2012)
Prognosis and value of adjuvant chemotherapy in stage III mucinous colorectal carcinoma
Authors: N. Hugen, R.H.A. Verhoeven, S.A. Radema, I.H.J.T. de Hingh, J.F.M. Pruijt, I.D. Nagtegaal, V.E.P.P. Lemmens, J.H.W. de Wilt
Journal: Annals of Oncology (2013)
Is the ‘spatially matched central airways’ relevant to studies of airway dimensions in COPD?
Authors: Yasutaka Nakano, Nguyen Van Tho, Harvey O Coxson
Journal: Thorax (2014)

Is the 'spatially matched central airways' relevant to studies of airway dimensions in COPD?We read with interest the comparison of spatially matched airways which reveals thinner airway walls in COPD than in controls by Smith et al. 1 While we find these results interesting, we wonder about the approach taken.First, grouping airway segments from the five prespecified paths in one given generation number (table E1) would dismiss regional differences in airway structure. 2or example, RB1 is very likely different from right lower lobe bronchus (RLL) proximal to RB7 in the 3rd generation while RB1 subsegments are different from RLL distal to RB7 in the 4th generation.The fact that the unadjusted airway wall area (Aaw) is not different between COPD and controls until the 3rd generation (table 2) suggests grouping 'central' airways leading to the lower lobes with segmental airways in the upper lobes may be affecting the results.We are not sure what the adjusted Aaw is showing because it is adjusted for so many variables.Second, we are unsure about the airway count data.The authors claim that more proximal airways were measured in COPD.We found these data confusing.What role would having less distal airways available for measurement have on the results?The software used in this study usually segments fewer airways in the lower lobes in COPD than in controls because the effects of motion artefacts are greater in COPD than in controls.It would be interesting to see if Aaw was compared regionally between COPD and controls 3 and number of subjects with incomplete segmental or subsegmental bronchimostly COPD subjects with thickened airway wall-was accounted for.Finally, we wish to take issue with the authors on the use of the term 'bias'.The authors seem to suggest that measurement approaches that do not include large central airways in their analysis are biased.Since the results are so different (opposite) when the authors compare Aaw by lumen size compared with by anatomical name, though lumen size is a more functionally important measurement, we wonder if 'bias' is a correct word to use and if, in fact, the authors' approach is not biased as well.Because airflow is determined by lumen diameter, we think that lumen area should be taken into account rather than generation number or anatomical name when comparing Aaw between subjects.If this is correct, then the results in table 2 are biased while the results in table 3 are more reasonable.
Adverse events of low- to medium-dose oral glucocorticoids in inflammatory diseases: a meta-analysis
Authors: J N Hoes, J W G Jacobs, S M M Verstappen, J W J Bijlsma, G J M G Van der Heijden
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objectives:</h3> To systematically analyse the literature on reported adverse events of low- to medium-dose glucocorticoids during ⩾1 month for inflammatory diseases. <h3>Methods:</h3> Data were systematically retrieved and selected from PUBMED, EMBASE and CINAHL databases (6097 hits). <h3>Results:</h3> A total of 28 studies (2382 patients) met the inclusion criteria. The risk of adverse events over all studies was 150 per 100 patient-years (95% confidence interval (CI) 132 to 169). Psychological and behavioural adverse events (eg, minor mood disturbances) were most frequently reported, followed by gastrointestinal events (eg, dyspepsia, dysphagia). In 14 studies comprising 796 patients with rheumatoid arthritis the risk of adverse events was 43/100 patient-years (95% CI 30 to 55), in 4 studies of 167 patients with polymyalgia rheumatica the risk of adverse events was 80/100 patient-years (95% CI 15 to146), and in 10 studies of 1419 patients with inflammatory bowel disease the risk of adverse events was 555/100 patient-years (95% CI 391 to 718). High rates of adverse events were reported in high-quality studies with short follow-up, notably in studies of patients with inflammatory bowel disease. <h3>Conclusions:</h3> The risk of adverse events depends on study design and disease. Studies on inflammatory bowel disease were often of short duration with frequent documentation of adverse events which resulted in higher adverse event rates whereas, in studies of rheumatoid arthritis, the longer follow-up may have resulted in lower adverse event rates. In most studies aimed at efficacy of glucocorticoids or other drugs, adverse events were not systematically assessed. Clear guidelines on assessment of adverse events are lacking.
The lepidopteran mitochondrial control region: structure and evolution.
Authors: M F Taylor, S W McKechnie, N Pierce, M Kreitman
Journal: Molecular Biology and Evolution (1993)

For several species of lepidoptera, most of the approximately 350-bp mitochondrial control-region sequences were determined. Six of these species are in one genus, Jalmenus; are closely related; and are believed to have undergone recent rapid speciation. Recent speciation was supported by the observation of low interspecific sequence divergence. Thus, no useful phylogeny could be constructed for the genus. Despite a surprising conservation of control-region length, there was little conservation of primary sequences either among the three lepidopteran genera or between lepidoptera and Drosophila. Analysis of secondary structure indicated only one possible feature in common--inferred stem loops with higher-than-random folding energies--although the positions of the structures in different species were unrelated to regions of primary sequence similarity. We suggest that the conserved, short length of control regions is related to the observed lack of heteroplasmy in lepidopteran mitochondrial genomes. In addition, determination of flanking sequences for one Jalmenus species indicated (i) only weak support for the available model of insect 12S rRNA structure and (ii) that tRNA translocation is a frequent event in the evolution of insect mitochondrial genomes.
CAKβ/Pyk2 Kinase Is a Signaling Link for Induction of Long-Term Potentiation in CA1 Hippocampus
Authors: Yue-Qiao Huang, Wei-Yang Lu, Declan W Ali, Kenneth A Pelkey, Graham M Pitcher, You Ming Lu, Hiroshi Aoto, John C Roder, Terukatsu Sasaki, Michael W Salter, John F MacDonald
Journal: Neuron (2001)
P107 Pulmonary imaging techniques to identify suitable patients and act as outcome measures in the UK CF Gene Therapy Consortium clinical programme
Authors: J. C. Davies, J. H. Conway, J. Fleming, M. Dewar, N. Voase, E. W. F. W. Alton, A. Greening, D. Hansell, J. A. Innes
Journal: Thorax (2010)

We are conducting a large, longitudinal study to assess outcome measures and identify optimal patients for a multidose trial of CF gene therapy. Two imaging modalities are being employed: radioisotope deposition scans and high resolution CT. Subjects have undergone these scans on a single occasion, whilst clinically stable. The purpose was: <i>Deposition scan</i>—to determine which patients would be most optimal for topical drug delivery and <i>CT</i>—to assess the suitability of various parameters as efficacy measures. Following inhalation of <sup>99m</sup>Tc-labelled human serum albumin, planar gamma camera images and SPECT were used to assess 3-D deposition. Images were scored both digitally and visually (I- no defects; II- patchy deposition; III- patchy deposition with large defects; IV- grossly abnormal). HRCT scans were scored by two radiologists on a lobar basis for the following: bronchiectasis (extent/severity), airway wall thickening, mucus plugging and gas trapping. 147 deposition scan were available; digital indices (DI) ranged from 34 (best) to 150 (severely abnormal). Visual scores correlated well with DI (R2 0.63; p&lt;0.001) and both were significantly negatively correlated with FEV<sub>1</sub>% (p&lt;0.01). Nine Grade IV subjects had a mean (SD) FEV<sub>1</sub> of 43.9(4.3)%, significantly lower than groups I-III (p&lt;0.01). On the basis of very poor deposition, this group is considered unsuitable to progress to the trial. Others have deposition scans which suggest that the gene therapy product could be delivered at least moderately well; they will be filtered through other inclusion/exclusion criteria. Potentially reversible components of the HRCT scores are being considered as efficacy outcome measures. As an example, power calculations suggest that our anticipated group size (n=100) would have 80% power to detect a change in wall thickness half that seen with intravenous antibiotics in a previous study. In conclusion, lung imaging techniques have both aided us in the identification of patients to take through into our multi-dose trial and are currently under consideration as efficacy outcomes.
An Odyssey to Viral Pathogenesis
Authors: Michael B.A. Oldstone
Journal: Annual Review of Pathology Mechanisms of Disease (2015)

This odyssey is mine from early junior high school, where my dreams for adventure were shaped by Arthur Conan Doyle's Sherlock Holmes, Percival Christopher Wren's Beau Geste, and best of all the remarkable explorers in Paul de Kruif's Microbe Hunters. My birth site was in Manhattan (my mother was a Vogue model and my father worked in retail), and I traveled to college at the University of Alabama, Tuscaloosa, where my love of history and English literature was shaped along with a sufficient exposure to biology, chemistry, and genetics to meet requirements for entering medical school. By the second year at the University of Maryland School of Medicine, through expert teachers such as Theodore (Ted) Woodward and Sheldon (Shelly) Greisman in medicine and Charles Weissmann in virology and microbiology, I found that understanding why and how people became ill was more my cup of tea than identifying and treating their illnesses. Although I was becoming competent in diagnosis and treatment, I left medical school at the end of my sophomore year to seek a more basic understanding of biology and chemistry. I achieved this by working toward a PhD in biochemistry at Johns Hopkins McCollum-Pratt Institute combined with study of rickettsial toxin at Maryland. This was a very important time in my life, because it convinced me that addressing biologic and medical questions in a disciplined scientific manner was what my life voyage should be. That voyage led me initially, through Woodward's contact, to work a summer in Joe Smadel's unit at Walter Reed (Smadel being one of the deans of American virology) and to meet several times with Carleton Gajdusek and then John Enders at Harvard, who pointed me to Frank Dixon at Scripps in La Jolla, California, for postdoctoral training. Dixon was among the founders of modern immunology and a pathfinder for immunopathology. Training by and association with Dixon and his other postdoctoral fellows, my independent position at Scripps, early polishing by Karl Habel (a superb senior virologist who left the National Institutes of Health and came to Scripps), and the gifted postdoctoral fellows who joined my laboratory over four decades form the log of my scientific voyage. The strong friendships and collaborations developed with other young but growing experimentalists like Bernie Fields and Abner Notkins are the fabric of the tale I will weave and were pivotal in the establishment of viral pathogenesis as a discipline.
Lower Respiratory Tract Colonization and Infection during Severe Acute Respiratory Distress Syndrome
Authors: CHRISTOPHE DELCLAUX, ERIC ROUPIE, FRANÇOIS BLOT, LAURENT BROCHARD, FRANÇOIS LEMAIRE, CHRISTIAN BRUN-BUISSON
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Ventilator-associated pneumonia (VAP) is difficult to detect and is often unsuspected during adult respiratory distress syndrome (ARDS). We prospectively evaluated lower respiratory tract (LRT) colonization and infection in 30 patients with severe ARDS (PaO2/FIO2 ratio < 150 mm Hg), using repeated quantitative cultures of plugged telescopic catheter (PTC) specimens taken blindly via the endotracheal tube every 48 to 72 h after onset of ARDS. All patients except one were receiving antibiotics. When VAP was suspected on the presence of clinical criteria for infection, a repeated PTC and, when possible, a bronchoalveolar lavage (BAL) were obtained before any new antimicrobials were administered; samples growing > or = 10(3) cfu/ml (PTC) or > or = 10(4) cfu/ml (BAL) were considered diagnostic of infection. Twenty-four VAP episodes were diagnosed in 18 patients (60% of patients or 4.2/100 ventilator-days) a mean of 9.8+/-5.7 d after onset of ARDS. Eighteen LRT colonization episodes were recorded; 16 of 24 (66%) VAP episodes were preceded (by 2 to 6 d) by LRT colonization with the same organism(s), and only two episodes of colonization were not followed by VAP. We conclude that although VAP is of relatively late-onset during severe ARDS, its incidence is much higher than in other conditions and can be underestimated. Lower airways colonization is consistently followed by infection with the same organisms and precedes VAP in two thirds of episodes. Repeated protected specimens taken blindly may provide a useful means to predict infection and therefore allow early antimicrobial therapy in high-risk patients with diffuse lung injury.