tbuckley/cabot-search huggingface dataset:
Glucose Metabolism in Renal Transplant Recipients
Authors: Annalisa Teutonico, Paolo F. Schena, Salvatore Di Paolo
Journal: Journal of the American Society of Nephrology (2005)

Cyclosporine A (CsA) and tacrolimus have been associated with an increased risk for diabetes after transplantation, whereas sirolimus is deemed to be devoid of any effect on glucose metabolism. This study was performed to investigate the effect of the withdrawal of calcineurin inhibitors and the switch to sirolimus on peripheral insulin resistance and pancreatic beta cell response. Twenty-six patients who received a kidney transplant and discontinued CsA and were converted to sirolimus and 15 recipients of suboptimal kidneys who were treated with tacrolimus plus sirolimus for the first 3 mo after grafting and thereafter with sirolimus alone were enrolled. All patients underwent an oral glucose tolerance test and intravenous insulin tolerance test before and 6 mo after the conversion to sirolimus-alone therapy. The withdrawal of CsA or tacrolimus was associated with a significant fall of insulin sensitivity (both P = 0.01) and with a defect in the compensatory beta cell response, as measured by the disposition index (P = 0.004 and P = 0.02, respectively). The increase of insulin resistance and the decrease of disposition index significantly correlated with the change of serum triglyceride concentration after the conversion to sirolimus-based therapy (R(2) = 0.30, P = 0.0002; and R(2) = 0.19, P = 0.004, respectively). Clinically, the switch to sirolimus was associated with a 30% increase of incidence of impaired glucose tolerance and with four patients' developing new-onset diabetes. In conclusion, the discontinuation of calcineurin inhibitors and their replacement by sirolimus fail to ameliorate the glycometabolic profile of kidney transplant recipients. Rather, it is associated with a worsening of insulin resistance and an inappropriately low insulin response.
Evidence of Plasmodium falciparum malaria resistant to atovaquone and proguanil hydrochloride: case reports
Authors: Anna Färnert, Johan Lindberg, Pedro Gil, Göte Swedberg, Yngve Berqvist, Mita M Thapar, Niklas Lindegårdh, Sándor Berezcky, A Björkman
Journal: BMJ (2003)

of the government's ambitious agenda for modernisation are likely.
Defining hip pain for population studies
Authors: F Birrell
Journal: Annals of the Rheumatic Diseases (2004)

<b>Background:</b> Identifying pain as coming from the hip joint is more complex than for other large joint sites. There is no accepted best approach to defining hip pain for use in clinical and epidemiological studies. <b>Objective:</b> To compare the use of verbal and pictorial descriptions in ascertaining hip pain. <b>Methods:</b> A cross sectional population based study on 2935 subjects compared groups reporting hip pain either using a pain diagram, or answering a question specifically asking about hip pain. The groups were compared with a group reporting no pain for various clinical indices of hip disease, including limitation of range of movement and evidence of radiographic change. <b>Results:</b> Subjects who satisfied both criteria for hip pain were substantially more likely to have used analgesics, consulted a physician, or had walking difficulty. Differences in range of movement were less clear cut but radiographic damage was more evident in those with both criteria. <b>Conclusions:</b> Subjects whose pain satisfies both a pictorial and a verbal definition (where the patient uses the word "hip") have the strongest relation to indicators of hip disease. This approach is recommended when a specific definition is required for ascertaining individuals for study.
Sex Differences in Short-term and Long-term All-Cause Mortality Among Patients With ST-Segment Elevation Myocardial Infarction Treated by Primary Percutaneous Intervention
Authors: Samir Bipin Pancholy, Ghanshyam Palamaner Subash Shantha, Toralben Patel, Lawrence J. Cheskin
Journal: JAMA Internal Medicine (2014)

Although outcomes in patients with ST-segment elevation myocardial infarction (STEMI) have improved in the past 2 decades, a sex disparity exists in survival, with women having higher mortality than men.To conduct a meta-analysis of observational studies that examined differences in mortality by sex in patients with STEMI treated with primary percutaneous coronary intervention (PPCI).MEDLINE, EMBASE, Cochrane central, and electronic databases were searched for relevant studies in all languages and without time restriction.Studies were included if (1) they studied patients who presented with STEMI, (2) primary percutaneous coronary intervention (PPCI) was the treatment for STEMI, (3) PPCI was performed within 12 hours of symptom onset, and (4) sex-specific in-hospital and/or 1-year mortality were reported.Two investigators independently reviewed retrieved citations and assessed eligibility. Discrepancies were resolved by consensus. Quality of included studies was assessed using Newcastle-Ottawa Quality Assessment Scale for cohort studies. Data were pooled using a random-effects model.Sex-specific in-hospital and 1-year all-cause mortality. Risk ratios (RRs) of mortality were used for these 2 time points, if reported.Of the 149 studies identified, 35 met inclusion criteria, representing 18 555 women and 49 981 men. In the unadjusted analyses, women were at a higher risk for in-hospital (RR, 1.93; 95% CI, 1.75-2.14 [P < .001, I2 = 14%]) and 1-year all-cause mortality (RR, 1.58; 95% CI, 1.36-1.84 [P < .001, I2 = 51%]) compared with men. However, when adjusted RRs were used, the association between women and higher risk of all-cause mortality was attenuated but still significantly elevated for in-hospital mortality (RR, 1.48; 95% CI, 1.07-2.05 [P = .02, I2 = 56%]), but the higher risk for 1-year mortality in women was no longer significant (RR, 0.90; 95% CI, 0.69-1.17 [P = .42, I2 = 58%]).An increased mortality in women with STEMI treated with PPCI was detected in this large meta-analysis but is likely confounded by baseline cardiovascular risk factors and the differences in clinical profile of male and female patients with STEMI. Intensive cardiovascular risk modification efforts in women may help to reduce this sex disparity.
Thomas Wakley, King George III and acute porphyria
Authors: Timothy Peters
Journal: Journal of the Royal Society of Medicine (2009)

In his otherwise scholarly article on the origins of The Lancet, Professor Jones has in an aside propagated the myth that George III had ‘porphyria-induced madness’.1

Recent detailed review of the 100+ volumes of the King's medical notes together with the correspondence, reports and diaries of courtiers and court officials has confirmed the fallacy of this claim first raised when the British Medical Journal unfortunately published the two articles by Drs Macalpine and Hunter in 1966–1968.2,3 It is most unlikely that The Lancet would have fallen prey to this historical temptation.

The relevant papers will appear shortly in the journal History of Psychiatry but a summary of my findings has recently been published in History Today.4 A morning in the British Library reading the relevant Willis manuscript5 would rebut the diagnostic claims of the so-called blue particulate urine (not a feature of any of the porphyrias) and shown that the diagnosis of any of the acute porphyrias cannot be substantiated.

Professor Jones is also dismissive of 18th- and 19th-century physicians; they may not have had the MRI, CT and PET scans, and other sophisticated diagnostic procedures available to today's general practitioners at the touch of a pen, but they were certainly keen observers, and in the case of Geo III knew when to call for outside help. The arrival of the Willis family of ‘mad doctors’ was followed by a remission of the King's episodes of acute mania in 1788–1789, 1801 and 1804. In doing so they helped lay the foundations of modern psychiatry, developing the recognition and approaches available today. Some CME of the history of medicine is clearly needed here.
Ruxolitinib Withdrawal Syndrome Leading to Tumor Lysis
Authors: Tong Dai, Ellen W. Friedman, Stefan K. Barta
Journal: Journal of Clinical Oncology (2013)

Case ReportA 70-year-old woman with a history of JAK2 V617F mutationpositive post-polycythemia vera (PV) myelofibrosis (MF) presented to the emergency department 4 weeks after discontinuing ruxolitinib with abdominal pain and massive splenomegaly, acute renal failure, hyperkalemia, hyperuricemia, hypocalcemia, and hyperphosphatemia.She was diagnosed with PV 10 years before admission.At that time she had a hemoglobin (Hgb) of 18 g/dL, an elevated red cell mass (51.3 mL/kg; reference range [RR], 24-30 mL/kg), and a hypercellular bone marrow (98%) with clustered megakaryocytes without fibrosis.Cytogenetic analysis showed 70% of cells with trisomy 9 and deletion 20q.She carried the JAK2 V617F mutation, and reverse transcriptase polymer chain reaction was negative for the BCR/ABL transcript.Her WBC count was 25.5 ϫ 10 3 /L (RR 4.8-10.8ϫ 10 3 /L), with a platelet count of 210 ϫ 10 3 /L (RR, 150-400 ϫ 10 3 /L).Abdominal ultrasound showed hepatosplenomegaly, and she was managed with phlebotomy.Six years later she complained of weight loss, night sweats without fever, fatigue, and left upper quadrant abdominal pain resulting from worsening splenomegaly.She was subsequently treated with pegylated interferon, which improved her symptoms and spleen size.Symptoms returned 2.5 years into the course of pegylated interferon and a CBC showed worsening anemia (Hgb, 9.9 g/dL) and thrombocytopenia (platelets, 76 ϫ 10 3 /L).A bone marrow biopsy showed hypercellular (100%) marrow with 2/4 reticulin and no significant increase in blasts (Fig 1A, reticulin stain, ϫ40).Cytogenetic analysis revealed no clonal evolution.She subsequently responded to low-dose hydroxyurea, but had recrudescence of symptoms after only 8 months.Red cell morphology was markedly abnormal with poikilocytosis, anisocytosis, and teardrop cells (Fig 2 ,ϫ100).She was started on low-dose ruxolitinib (10 mg twice daily).Within 5 weeks she experienced improvement in her systemic symptoms and splenomegaly, but had a progressive fall in her Hgb and platelet count with new bruises.Examination of her bone marrow showed marked myelofibrosis with 70% to 80% cellularity (Fig 1B, reticulin stain, 40x), and a new clone with trisomy 8 in addition to the previously seen trisomy 9 and deletion 20q.Again there was no significant increase in blasts.Seven and half weeks after treatment was started, her Hgb dropped to 8.0 g/dL, and platelets decreased to 28 ϫ 10 3 /L.The dose of ruxolitinib was reduced to 5 mg twice daily.Despite the low-dose of ruxolitinib, blood counts further deteriorated (Hgb, 7.9 g/dL; platelets, 18 ϫ 10 3 /L) and ruxolitinib was stopped after only 9 weeks.Over the next 3 weeks she developed recurrent fever, worsening shortness of breath, diarrhea, and accelerated splenomegaly.She had a gout attack and was treated with prednisone 40 mg daily.A diagnosis of ruxolitinib withdrawal syndrome was considered.Her symptoms
Abstract 2347: PSA splice variants and their expression in prostate cancer
Authors: Alice S. Yang, Thushari Alahapperuma, James N. Mubiru, Magdalena Garcia-Forey, Robert E. Shade
Journal: Cancer Research (2014)

Abstract Introduction Prostate cancer (PCa) is the second most common cancer in American men, resulting in 32,000 deaths annually. Challenges for the management of PCa include the inability to distinguish indolent from aggressive and untreatable castration-resistant PCa. These challenges can be addressed by understanding the molecular basis of cancer initiation and progression. Prostate specific antigen (PSA) is widely used for screening, diagnosing and monitoring of PCa, although it is also elevated in other disorders and therefore lacks specificity and sensitivity. Alternative splicing is a common mechanism used in nature to enhance protein diversity. Alternative splicing of the PSA gene produces at least 15 transcripts of 0.7-6.1 kb (Heuzé-Vourc'h et al 2003). Several variants of PSA have been reported and are shown to be differentially expressed in PCa compared to normal prostates or to benign prostatic hyperplasia (BPH). Here we describe the identification of four variants of PSA with the potential to improve on the specificity of the PSA test. Material and Methods Human prostate cDNAs were from cryopreserved prostate tissues collected after radical prostatectomies and have been described previously (Mubiru et al. 2004). PCR was carried out using primers that amplify the complete PSA mRNA and also those specific for the most common splice variant (Heuzé-Vourc'h et al. 2001). The PCR products were inserted into the PCR2.1-TOPO vector (Life Technologies) and sequenced. Results We identified four novel splice variants of the PSA gene. Novel PSA Splice VariantsTypeNameContaining Exons (Ex) and Introns (In)Molecular Weight (Da)pIPSA mRNAPSAEx3del246Ex1, Ex2, Partial Ex38,5949.61PSA mRNAPSA25RVEx1, Partial In111,1815.55PSA mRNAPSA Yang 28Ex1, Ex2, Ex514,1539.59PSA mRNAPSA Yang 21Ex1, Ex2, Partial Ex3, Ex4, Ex523,6986.64 Results also indicate that some transcripts are differentially expressed in tumors compared to non-tumors. References 1.Mubiru JN, et al. (2004). Gene 327: 89-98. 2.Heuzé-Vourc'h N, et al. (2003) Eur J Biochem 270: 706-714. 3.Heuzé-Vourc'h N, et al. (2001) Eur J Biochem 268: 4408-4413. Citation Format: Alice S. Yang, Thushari Alahapperuma, James N. Mubiru, Magdalena Garcia-Forey, Robert E. Shade. PSA splice variants and their expression in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2347. doi:10.1158/1538-7445.AM2014-2347
Increased gene expression of tumor necrosis factor superfamily ligands in peripheral blood mononuclear cells during chronic heart failure
Authors: A Yndestad
Journal: Cardiovascular Research (2002)

Inflammation may play a pathogenic role in chronic heart failure (CHF). The objective of the study was to characterise the imbalance in the cytokine network in CHF.cDNA expression arrays were used to analyse the gene expression of cytokines and related mediators in peripheral blood mononuclear cells (PBMC) from CHF patients (n=8) and healthy controls (n=8). Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the gene expression of individual genes in additional 12 patients and eight controls.From 375 genes, 34 were upregulated and two downregulated in CHF patients in the cDNA expression array experiments. Regulated genes included chemokines/-receptors, members of the transforming growth factor beta superfamily, orphan receptors and in particular several members of the tumor necrosis factor (TNF) superfamily. Thus, 4-1BB ligand (L), APRIL, CD27L, CD40L, FasL, LIGHT, TRAIL-receptor 4 were upregulated, while TRAIL-receptor 3 was downregulated. Real-time quantitative RT-PCR confirmed significantly upregulated gene expression of APRIL, LIGHT, FasL and CD27L in CHF patients and showed in addition significantly enhanced gene expression of TNFalpha and TRAIL.The present study demonstrates differential gene expression in PBMC of several members of the cytokine network in CHF. In particular, the enhanced expression of several ligands in the TNF superfamily may reflect a potential pathogenic role of these cytokines in CHF.
Paired analysis of TCRα and TCRβ chains at the single-cell level in mice
Authors: Pradyot Dash, Jennifer L. McClaren, Thomas H. Oguin, William Rothwell, Brandon Todd, Melissa Y. Morris, Jared Becksfort, Cory Reynolds, Scott A. Brown, Peter C. Doherty, Paul G. Thomas
Journal: Journal of Clinical Investigation (2010)

Characterizing the TCRα and TCRβ chains expressed by T cells responding to a given pathogen or underlying autoimmunity helps in the development of vaccines and immunotherapies, respectively. However, our understanding of complementary TCRα and TCRβ chain utilization is very limited for pathogen- and autoantigen-induced immunity. To address this problem, we have developed a multiplex nested RT-PCR method for the simultaneous amplification of transcripts encoding the TCRα and TCRβ chains from single cells. This multiplex method circumvented the lack of antibodies specific for variable regions of mouse TCRα chains and the need for prior knowledge of variable region usage in the TCRβ chain, resulting in a comprehensive, unbiased TCR repertoire analysis with paired coexpression of TCRα and TCRβ chains with single-cell resolution. Using CD8+ CTLs specific for an influenza epitope recovered directly from the pneumonic lungs of mice, this technique determined that 25% of such effectors expressed a dominant, nonproductively rearranged Tcra transcript. T cells with these out-of-frame Tcra mRNAs also expressed an alternate, in-frame Tcra, whereas approximately 10% of T cells had 2 productive Tcra transcripts. The proportion of cells with biallelic transcription increased over the course of a response, a finding that has implications for immune memory and autoimmunity. This technique may have broad applications in mouse models of human disease.
Digestion of proteoglycans in porcine pancreatic elastase-induced emphysema in rats
Authors: CH van de Lest, EM Versteeg, JH Veerkamp, TH van Kuppevelt
Journal: European Respiratory Journal (1995)

Pulmonary emphysema was induced in rats by a single intratracheal instillation of pancreatic elastase. The short-term effects of elastase instillation on basement membrane components were evaluated using immunohistochemical and biochemical methods. Lung alveoli showed a decrease in heparan sulphate proteoglycan content (especially of its heparan sulphate chains) 3 h to 7 days after induction. Type IV collagen, laminin and fibronectin were not affected. The glycosaminoglycan content of the lung was decreased during the first 3 days after induction, while the glycosaminoglycan concentration in urine was increased during the first 4 days by an increase of heparan sulphate and dermatan sulphate. The increase in urinary glycosaminoglycan content was positively correlated with the extent of emphysema developed after 40 days. We conclude that proteoglycans are target molecules for elastase, and may be involved in the pathogenesis of emphysema.
Understanding why some ethnic minority patients evaluate medical care more negatively than white patients: a cross sectional analysis of a routine patient survey in English general practices
Authors: N. Mead, M. Roland
Journal: BMJ (2009)

Corticosteroids play a central role in asthma management. Previous work suggests that inhaled corticosteroid (ICS) use is a risk factor for adrenal insufficiency (AI) (Woods et al. Eur J Endocrinology 2015 173, 633-642) however there is very little research into the incidence of, or risk factors for AI in adult asthma patients. We present data examining this issue in a specialist adult asthma clinic. We retrospectively examined the notes of all patients investigated for AI in our clinic from 2010-2015. Patients were tested if presenting with relevant signs and symptoms or with atypical symptoms responsive to corticosteroids. 185 patients were tested. 35 (19%) had AI, defined by an undetectable baseline cortisol or cortisol rise to &lt;500nmol/L in short Synacthen/glucagon stimulation test. In 19 (10.2%) of these cases, AI was attributable solely to ICS treatment. The remaining 16 had an additional cause identified. Compared to patients with normal cortisol, those with AI were taking higher dose ICS (p&lt;0.05). There was no significant difference in incidence of AI between ICS formulations. Factors associated with risk of AI included co-prescription of cytochrome P450 inhibitors (OR 10.17, 95% CI 2.47–41.80), systemic steroid treatment (OR 5.35, 95% CI 2.3–12.38) and ICS beclomethasone equivalent dose (BDP) &gt;2000 mcg (OR 3.12, 95% CI 1.29–7.57). Our results demonstrate that adrenal insufficiency is a significant problem in asthma clinic affecting almost 20% of those tested. Risk of AI increases with higher dose ICS irrespective of formulation. We propose routine testing for AI based on symptoms and risk factors in all patients taking ICS. Further work is ongoing to assess the effect of AI treatment on asthma control.
Effects of Dichloromethylene Diphosphonate on the Osteolytic and Osteoplastic Effects of Rat Prostate Adenocarcinoma Cells2
Authors: Morris Pollard, Phyllis H. Luckert
Journal: JNCI Journal of the National Cancer Institute (1985)

A model system of prostate adenocarcinoma (PA) in Lobund-Wistar rats is described in which the transplanted tumor cells (PA-III) were inoculated sc over the calvaria. A local tumor developed that, when attached to the bone, caused erosion and fragmentation of the bone, with adjacent osteoplastic changes and metastases to the lungs. The attachment of the tumor to the bone was enhanced if the periosteum was scratched during the inoculation of tumor cells. The destructive effect on bone structure was also induced by in vivo transplanted PA-I and PA-IV cells, but not by PA-II cells. In rats that were pretreated with dichloromethylene diphosphonate, the local PA-III tumors developed with metastases to the lungs, but the calvariae were intact.
Absolute Risk Prediction of Second Primary Thyroid Cancer Among 5-Year Survivors of Childhood Cancer
Authors: Stephanie A. Kovalchik, Cécile M. Ronckers, Lene H.S. Veiga, Alice J. Sigurdson, Peter D. Inskip, Florent de Vathaire, Charles A. Sklar, Sarah S. Donaldson, Harald Anderson, Parveen Bhatti, Sue Hammond, Wendy M. Leisenring, Ann C. Mertens, Susan A. Smith, Marilyn Stovall, Margaret A. Tucker, Rita E. Weathers, Leslie L. Robison, Ruth M. Pfeiffer
Journal: Journal of Clinical Oncology (2012)

We developed three absolute risk models for second primary thyroid cancer to assist with long-term clinical monitoring of childhood cancer survivors.We used data from the Childhood Cancer Survivor Study (CCSS) and two nested case-control studies (Nordic CCSS; Late Effects Study Group). Model M1 included self-reported risk factors, model M2 added basic radiation and chemotherapy treatment information abstracted from medical records, and model M3 refined M2 by incorporating reconstructed radiation absorbed dose to the thyroid. All models were validated in an independent cohort of French childhood cancer survivors.M1 included birth year, initial cancer type, age at diagnosis, sex, and past thyroid nodule diagnosis. M2 added radiation (yes/no), radiation to the neck (yes/no), and alkylating agent (yes/no). Past thyroid nodule was consistently the strongest risk factor (M1 relative risk [RR], 10.8; M2 RR, 6.8; M3 RR, 8.2). In the validation cohort, 20-year absolute risk predictions for second primary thyroid cancer ranged from 0.04% to 7.4% for M2. Expected events agreed well with observed events for each model, indicating good calibration. All models had good discriminatory ability (M1 area under the receiver operating characteristics curve [AUC], 0.71; 95% CI, 0.64 to 0.77; M2 AUC, 0.80; 95% CI, 0.73 to 0.86; M3 AUC, 0.75; 95% CI, 0.69 to 0.82).We developed and validated three absolute risk models for second primary thyroid cancer. Model M2, with basic prior treatment information, could be useful for monitoring thyroid cancer risk in childhood cancer survivors.