tbuckley/cabot-search huggingface dataset:
Chronic Toxicity of Methotrexate in Mice23
Authors: M. Freeman Narrod, Stuart A. Narrod
Journal: JNCI Journal of the National Cancer Institute (1977)

Daily (five times/week) administration of 0.25-2 mg methotrexate (MTX)/kg to 5- to 6-week-old male C57BL/6, DBA/2, and C3H mice for 12-18 months was well tolerated, apart from minimal cellular suppression in the lymphoid tissues, testes, and skin. Larger doses of MTX (3-6 mg/kg) given to 5- to 6-week-old mice produced well-known acute to subacute hematopoietic and gastrointestinal damage that leads to early death. These young mice did not develop other lesions that were described in humans after long-term MTX administration, nor was the toxicity cumulative. A large difference was observed in the ability of mice of different ages to withstand the toxic effects of MTX; 16-week-old mice were able to survive daily doses of 3-6 mg/kg up to 18 months. Histologic studies of these mice showed a more pronounced cellular depression of the lymphoid tissues, testes, and skin. Osteoporosis was also observed in these older mice that tolerated the drug for 10 months or longer, thus providing a laboratory animal model for further study of this MTX-induced lesion.
Ideal volume sampling in the diagnosis of malignant pleural effusions
Authors: Vasilis Anastasakos, Mpisirtzoglou Danai, Zetos Athanasio, Mpampoukos Stavros, Marketos Charalampos, Georgios Politis
Journal: European Respiratory Journal (2012)

Introduction: Management of pleural effusion is based on established guidelines deriving from scientific committees and experts on pleural diseases all over the world. Nevertheless true consensus on volume sampling in malignant pleural effusions has not yet been achieved. Only few publications have been published over the past 10 years. Further studies should take place in order to clarify this essential point in the management of malignant pleural effusions.  Hypothesis: 20 to 40 ml of pleural fluid could improve cytology yield in high risk malignancy patients.  Methods and Materials: Patients with at least medium sized pleural effusion and high risk for malignancy are enrolled.  Pleural fluid is extracted as follows:  1. 10cc of pleural fluid sent for cell typing and ALB, tPr, LDH, CHOL, TG analysis  2. 20cc of pleural fluid extracted and placed as sample A  3. 50cc of pleural fluid extracted and placed as sample B  4. 150cc of pleural fluid should be extracted and placed as sample C  Samples A, B and C are sent for cytology  Cytology results include the following:  1. Positivity or negativity for malignancy  2. Malignant cells numerosity (rare, infrequent, frequent, dense)  First data in our research strongly support our hypothesis and we feel that with our sample growing we will be able to show that a larger quantity of pleural fluid will not improve results (whilst will affect costs and laboratory man hours), but 20 to 40 ml could play a role in diagnosis and should be the target quantity. We hope our study will help to decrease time to diagnosis, reduce cost (less paracentesis, less adverse effects, less hospitalization time) and provide material for evidence based guideline development in the future.
Impact of Wnt ligand secretion on cellular phenotypes in pulmonary fibrosis
Authors: Aina Martin, Sarah Vierkotten, Melanie Königshoff
Journal: European Respiratory Journal (2014)

Introduction: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology characterized by alveolar epithelial injury, myofibroblast activation, and increased extracellular matrix deposition. Reactivation of the WNT pathway has been linked to pulmonary fibrosis. Here, we aim to study cell-specific effects of global (non)-canonical WNT inhibition in fibrotic lung cells.  Methods:  Lung tissue and bronchoalveolar lavage fluid (BALF) from experimental and human IPF were screened for Wnt ligand expression. Murine and human lung epithelial cells (MLE12 and A549) and Wnt3a L-cells, were used  in vitro  to study the effects of the Porcupine (Porcn) inhibitor IWP2 on Wnt activity. Cells were treated with different drug concentrations, DMSO as a control, or Wnt3a-conditioned medium. β-catenin-dependent gene transcription was analyzed either by TOP/FOP flash reporter assay or target gene expression by qRT-PCR.  Results:  Canonical WNT3a and WNT10b levels were significantly elevated in BALF from experimental lung fibrosis. The compound IWP2 exhibited strong dose-dependent efficacy to reduce baseline Wnt activity in MLE12, A549 ( ∼70% reduction at 500nM) and Wnt3a-induced signal activity in L-cells ( ∼75% reduction). Accordingly, the mRNA levels of the Wnt-antagonists AXIN2 and NKD1 were decreased in A549 cells (-1.2-fold and -2.4-fold decrease at 500nM, respectively).  Conclusions:  Specific Wnt ligands are secreted by epithelial cells in experimental lung fibrosis. The inhibition of Porcn by IWP2 effectively inhibited Wnt activity in lung epithelial cells. Thus, Porcn inhibition is a potent approach to study the impact of Wnt ligand secretion on cellular phenotypes in pulmonary fibrosis.
Importance of the receptor for advanced glycation end products in the respiratory mechanics
Authors: Samiya Al-Robaiy, Andreas Simm, Rolf-Edkar Silber, Angelika Bierhaus, Babett Bartling
Journal: European Respiratory Journal (2012)

Background: There is an increasing clinical interest in studying the receptor for advanced glycation end products (RAGE) and its soluble forms in pulmonary diseases. Interestingly, RAGE and its soluble forms are preferentially expressed in alveoli thereby challenging the pathophysiological role of RAGE. As we have already shown the importance of RAGE as an adhesion molecule in alveolar cells, this study aimed to investigate the age-dependent physiological significance of RAGE in respiratory mechanics. Methods: Lungs of young ( 24) RAGE knock out ( k.o. ) and wild-type mice were analyzed ex vivo using the perfused isolated lung system with negative-pressure ventilation at weight-matched constant tidal volume. Elastin expression was assessed by gene array and histochemistry. Results: Dynamic lung compliance increased gradually with the age in RAGE k.o. as well as in wild-type mice. Independent of age, the lungs of RAGE k.o. mice showed higher compliance than that of the wild-type. In this context, old wild-type and young-adult RAGE k.o. mice had similar lung dynamic compliance. According to the effect of RAGE deficiency on lung compliance, we determined a reduced elastin mRNA and protein expression in the lung tissue of RAGE k.o. mice. However, lack of RAGE had no significant effect on airway resistance and epithelial layer permeability. Conclusion: Our study suggests the physiological importance of RAGE and/or its soluble forms in mediating an appropriate lung compliance in which its/their impact on the elastin expression might play a critical role.
Pattern of breathing and respiratory rhythm variability in patients with different level of bronchial asthma control
Authors: Dmitry L. Nakhamchen, Juliy M. Perelman, Victor P. Kolosov, Leonid G. Nakhamchen
Journal: European Respiratory Journal (2012)

Background: It is unknown how the loss of bronchial asthma (BA) control effects on the control of breathing.  Aim: To study relationship between the level of BA control and pattern of breathing and respiratory rhythm variability.  Methods: 97 BA patients and 21 healthy people were examined. BA patients were divided on two groups: 15 patients with controlled BA (CBA) and 82 patients with uncontrolled BA (UBA). The pattern of quiet breathing and respiratory rhythm variability were studied by spirointervalometry. Quiet breathing was registered through the mouth during 15 minutes.  Results: In the group of healthy people compared with the asthmatics the inspiratory time (1.76±0.1 and 1.54±0.03 sec., respectively, p=0.04) and the effective inspiratory time (0.40±0.009 and 0.38±0.004, p=0.029) were significantly longer and the effective expiratory time (0.60±0.009 and 0.62±0.005, p=0.036) was shorter. In the UBA group in comparison with the CBA group there were shortening of the quiet expiration(2.53±0.007 and 2.91±0.18 sec., p=002), reduction of effective expiratory time (0.61±0.006 and 0.64±0.012, p=0.013) and increase of effective inspiratory time (1.53±0.032 and 0.36±0.012, p=0.014). The respiratory rhythm variability in CBA was significantly less than in UBA: mean-square discrepancy of respiratory rate was 0.60±0.03 and 0.82±0.127 (p=0.019).  Conclusion: The obtained data suggested the peculiarities of the control of breathing in BA patients leading to changes in time structure of breathing pattern and respiratory rhythm variability especially in patients with uncontrolled disease.
Molecular and cytogenetic studies in the diagnosis of patients with poorly differentiated carcinomas of unknown primary site.
Authors: R J Motzer, E Rodriguez, V E Reuter, G J Bosl, M Mazumdar, R S Chaganti
Journal: Journal of Clinical Oncology (1995)

PURPOSE A minority of patients with poorly differentiated carcinoma achieve a complete response to cisplatin therapy. Recently, specific chromosomal abnormalities have been described for several solid tumor malignancies. Molecular and cytogenetic techniques were used to study tumors of patients with midline carcinoma of unknown primary site. MATERIALS AND METHODS Forty patients with poorly differentiated carcinoma of unknown primary site had fresh tumor samples studied by cytogenetic analysis, Southern blot analysis for 12p copy number, and fluorescence in situ hybridization (FISH) for the identification of i(12p) and chromosome 12 aneuploidy. The response to cisplatin therapy was correlated to the diagnosis provided by the genetic studies. RESULTS In 17 (42%) patients, a diagnosis was suggested by the genetic studies. This included a germ cell tumor in 12 (30%) patients by the finding of i(12p), increased 12p copy number, or a deletion of the long arm of chromosome 12. In five patients, a specific diagnosis other than germ cell tumor was suggested by tumor karyotype. These were neuroepithelioma, lymphoma, desmoplastic small-cell tumor, melanoma, and clear-cell sarcoma. The 75% response proportion to cisplatin therapy in patients with tumors showing chromosome structural abnormalities of germ cell tumor was greater than the 18% response proportion in patients for whom no diagnosis was provided (P = .002). CONCLUSION Molecular and cytogenetic studies are useful in establishing specific diagnoses in patients with poorly differentiated carcinomas of unknown primary site. This group of tumors is heterogeneous and is composed of germ cell tumors, melanoma, lymphoma, neuroepithelioma, and desmoplastic small-round-cell tumor in addition to some that are not yet classifiable. Response to cisplatin therapy correlates with the finding of i(12p) in tumor by either molecular or cytogenetic studies.
A Case of Solitary Rectal Ulcer Syndrome
Authors: M Mercer-Jones, R Jenkins, C Garvey, T L Norris, M J Hershman
Journal: Journal of the Royal Society of Medicine (1994)

Case report A 27-year-old man presented with lower abdominal pain, bloody diarrhoea, tenesmus and excessive straining at stool. These symptoms had been present intermittently for the past 10 years but had worsened in the previous 3 months during which time he had lost 2 stone in weight. Several years previously, he had a provisional diagnosis ofulcerative colitis made elsewhere, despite inadequate biopsy. He was treated with local steroids with no symptomatic improvement but moved abroad and became lost to follow up. General and rectal examination were unremarkable. Sigmoidoscopy and colonoscopy revealed a 2 cm solitary ulcer 5 cm from the anal margin. A biopsy showed focal ulceration, fibrosis and bands ofsmooth muscle obliterating the lamina propria. Anorectal physiology studies demonstrated increased rectal sensitivity and a defaecating proctogram revealed recto-rectal intussusception with poor emptying of the upper rectum (Figure 1). A diagnosis ofSRUS was made. Initially he was treated conservatively with bulk laxatives and advice to avoid straining. His symptoms failed to improve and a transabdominal rectopexy was performed. This operation involved mobilizing and straightening the rectum and fixing it in place with a synthetic material. Nine months later he is asymptomatic. Sigmoidoscopy showed that the ulcer had healed and a repeat defaecating proctogram was normal. Interestingly, he still had increased rectal sensation.
Weight change in women treated with adjuvant therapy or observed following mastectomy for node-positive breast cancer.
Authors: J K Camoriano, C L Loprinzi, J N Ingle, T M Therneau, J E Krook, M H Veeder
Journal: Journal of Clinical Oncology (1990)

Six hundred forty-six women with node-positive breast cancer from two prospective, randomized, adjuvant breast cancer trials were evaluated for changes in weight during and after receiving 60 weeks of chemotherapy, chemohormonal therapy, or observation. The median weight change in the 545 patients remaining on protocol at 60 weeks for observed postmenopausal patients was +1.8 kg, for treated postmenopausal patients +3.6 kg, and for treated premenopausal patients +5.9 kg (P less than .001). After a median follow-up of 6.6 years, premenopausal women who gained more than the median weight at 60 weeks had a risk of relapse 1.5 times greater (covariate P = .17) and a risk of death 1.6 times greater (covariate P = .04) than premenopausal women who had gained less than the median weight. In the postmenopausal patients, the trend for inferior relapse-free and overall survival in those who gained more than the median weight at 60 weeks was not significant (P = .05). We conclude that, relative to observation, adjuvant chemotherapy is associated with greater weight gain in node-positive, postmenopausal breast cancer patients; the amount of weight gain appears greater for premenopausal than postmenopausal women, and in premenopausal women, excessive weight gain may be associated with an increase in relapse and cancer-related deaths in the selected patients who show no evidence of recurrence during 60 weeks of adjuvant chemotherapy. This last point must be interpreted with caution because of the exploratory nature of the analyses.
Outcomes of NSCLC patients with positive EGFR mutation
Authors: Sarah Diver, Mohammed Haris, Shahul Leyakathali khan, Jane Kerr, Jane Edwards, Mohammed Munavvar
Journal: European Respiratory Journal (2012)

Background: Tyrosine kinase inhibitors (TKIs) have been shown to offer an increased progression-free survival and response rate in non small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activating mutations. Screening is recommended in patients with advanced NSCLC, particularly in those with adenocarcinoma.  Aims: To evaluate the outcomes of NSCLC patients who underwent EGFR mutation testing.  Methods: Retrospective of 135 patients between Jan 2010 and Dec 2011.  Results: Of the 135 patients, 13(10%) had positive EGFR mutation. Further information was not available for 1 and hence excluded from analysis. 9 had stage IV, 2 had stage IIIb and 1 had stage IIa. All had adenocarcinoma except 1, adenosquamous. Performance status (n=11), median (IQR), 2(1-2).  Of the 12 patients with positive mutation, 8 received TKIs; mean duration of treatment was 7 months (SD 4). 1 had an insertion in exon 20 usually regarded as resistant to TKI. 1 had palliative chemotherapy and 1 had metastatic brain lesion resected with palliative radiotherapy prior to receiving TKI. Median survival was 10 months in those who received TKIs and 7 in those who did not; there was no survival difference in both groups (p=0.785, 95% CI 0.23-6.74).  Conclusion: Most of our patients had advanced disease and despite the use of TKIs in selected patients the prognosis remained poor. Common mutations were deletions in exon 19 and point mutations in exon 21.
Guidelines of care for the management of atopic dermatitis
Authors: Robert Sidbury, Dawn M. Davis, David E. Cohen, Kelly M. Cordoro, Timothy G. Berger, James N. Bergman, Sarah L. Chamlin, Kevin D. Cooper, Steven R. Feldman, Jon M. Hanifin, Alfons Krol, David J. Margolis, Amy S. Paller, Kathryn Schwarzenberger, Robert A. Silverman, Eric L. Simpson, Wynnis L. Tom, Hywel C. Williams, Craig A. Elmets, Julie Block, Christopher G. Harrod, Wendy Smith Begolka, Lawrence F. Eichenfield
Journal: Journal of the American Academy of Dermatology (2014)
A patient with elderly-onset atypical hydroa vacciniforme with an indolent clinical course
Authors: H. Nomura, H. Suzuki, S. Egami, T. Yokoyama, M. Sugiura, K. Tomita, M. Imada, K. Taniguchi, T. Yoshino, K. Iwatsuki
Journal: British Journal of Dermatology (2015)

Hydroa vacciniforme (HV) is a rare photodermatosis that mainly affects children and manifests as vesiculopapular eruptions in sun-exposed areas without systemic symptoms. HV-like lymphoma (HVLL) is one of the Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPD) of childhood. Its diagnosis is based on monoclonal T-cell proliferation; however, its degree of malignancy is controversial owing to its variable prognosis. Elderly-onset cases of these diseases are extremely rare, and the clinical features remain unknown. It has been shown that late onset is closely associated with a severe phenotype in EBV-associated LPD including atypical HV. Here we describe a case of elderly-onset atypical HV accompanied by T-cell monoclonality, but with a very indolent clinical course. Our patient indicates a possible case with elderly-onset atypical HV manifesting a favourable course, and that T-cell monoclonality and age of onset cannot always predict the disease severity, and highlights the difficulty of prognosis prediction in elderly-onset atypical HV.
Molecular and Clinical Features of Non-Burkitt’s, Diffuse Large-Cell Lymphoma of B-Cell Type Associated With the c-MYC/Immunoglobulin Heavy-Chain Fusion Gene
Authors: Takashi Akasaka, Hiroshi Akasaka, Chiyoko Ueda, Noboru Yonetani, Yoshitomo Maesako, Akira Shimizu, Hirohiko Yamabe, Shirou Fukuhara, Takashi Uchiyama, Hitoshi Ohno
Journal: Journal of Clinical Oncology (2000)

PURPOSE: t(8;14)(q24;q32) and/or c-MYC/immunoglobulin heavy-chain (IGH) fusion gene have been observed not only in Burkitt’s lymphoma (BL) but also in a proportion of non-BL, diffuse large-cell lymphoma of B-cell type (DLCL). We explored molecular features of DLCL with c-MYC/IGH fusion and the impact of this genetic abnormality on clinical outcome of DLCL. PATIENTS AND METHODS: A total of 203 cases of non-BL DLCL were studied. Genomic DNA extracted from tumor tissues was subjected to long-distance polymerase chain reaction (LD-PCR) using oligonucleotide primers for exon 2 of c-MYC and for the four constant region genes of IGH. RESULTS: Twelve cases (5.9%) showed positive amplification; one had a c-MYC/Cμ, nine had a c-MYC/Cγ, and two had a c-MYC/Cα fusion sequence. Restriction and sequence analysis of the LD-PCR products, ranging from 2.3 to 9.4 kb in size, showed that breakage in the 12 cases occurred within a 1.5-kb region that included exon 1 of c-MYC in combination with breakpoints at the switch regions of IGH (10 of 12). In 10 cases, Myc protein encoded by the fusion genes demonstrated mutations and/or deletions. Six cases had additional molecular lesions in BCL-2 or BCL-6 and/or p53 genes. The age range of the 12 patients was 44 to 86 years, with a median age of 65.5 years. Five patients had stage I/II disease, and seven had stage III/IV disease. Lactate dehydrogenase was elevated in nine of 11 subjects. Seven showed involvement of the gastrointestinal tract. All patients were treated by surgery and/or chemoradiotherapy; six died of the disease within 1 year, resulting in the poorest 1- and 2-year survival rates among DLCL subgroups. CONCLUSION: The c-MYC/IGH fusion gene of DLCL is identical to that of the sporadic type of BL (sBL). DLCL with c-MYC/IGH shares clinical features with sBL but is characterized further by an older age distribution.
Reasons Why Physicians and Advanced Practice Clinicians Work While Sick
Authors: Julia E. Szymczak, Sarah Smathers, Cindy Hoegg, Sarah Klieger, Susan E. Coffin, Julia S. Sammons
Journal: JAMA Pediatrics (2015)

When clinicians work with symptoms of infection, they can put patients and colleagues at risk. Little is known about the reasons why attending physicians and advanced practice clinicians (APCs) work while sick.To identify a comprehensive understanding of the reasons why attending physicians and APCs work while sick.We performed a mixed-methods analysis of a cross-sectional, anonymous survey administered from January 15 through March 20, 2014, in a large children's hospital in Philadelphia, Pennsylvania. Data were analyzed from April 1 through June 1, 2014. The survey was administered to 459 attending physicians and 470 APCs, including certified registered nurse practitioners, physician assistants, clinical nurse specialists, certified registered nurse anesthetists, and certified nurse midwives.Self-reported frequency of working while experiencing symptoms of infection, perceived importance of various factors that encourage working while sick, and free-text comments written in response to open-ended questions.Of those surveyed, we received responses from 280 attending physicians (61.0%) and 256 APCs (54.5%). Most of the respondents (504 [95.3%]) believed that working while sick put patients at risk. Despite this belief, 446 respondents (83.1%) reported working sick at least 1 time in the past year, and 50 (9.3%) reported working while sick at least 5 times. Respondents would work with significant symptoms, including diarrhea (161 [30.0%]), fever (86 [16.0%]), and acute onset of significant respiratory symptoms (299 [55.6%]). Physicians were more likely to report working with each of these symptoms than APCs (109 [38.9%] vs 51 [19.9%], 61 [21.8%] vs 25 [9.8%], and 168 [60.0%] vs 130 [50.8%], respectively [P < .05]). Reasons deemed important in deciding to work while sick included not wanting to let colleagues down (521 [98.7%]), staffing concerns (505 [94.9%]), not wanting to let patients down (494 [92.5%]), fear of ostracism by colleagues (342 [64.0%]), and concern about continuity of care (337 [63.8%]). Systematic qualitative analysis of free-text comments from 316 respondents revealed additional reasons why attending physicians and APCs work while sick, including extreme difficulty finding coverage (205 [64.9%]), a strong cultural norm to come to work unless remarkably ill (193 [61.1%]), and ambiguity about what constitutes "too sick to work" (180 [57.0%]).Attending physicians and APCs frequently work while sick despite recognizing that this choice puts patients at risk. The decision to work sick is shaped by systems-level and sociocultural factors. Multimodal interventions are needed to reduce the frequency of this behavior.
Private health care: modernisation stops here
Authors: J. Keen
Journal: BMJ (2000)

The Care Standards Bill,1 which has recently started its passage through parliament, provides the British government with an opportunity to address problems that have become apparent in the delivery of private health care in the United Kingdom. Many of these problems were clearly set out in a recent House of Commons Health Committee report on the regulation of private health care2 and include the difficulties that patients face in determining the quality and value for money of private care and the lack of coordination between the NHS and private providers. Underlying these problems is the failure of unregulated healthcare markets to protect patients' interests or deliver efficient and equitable health care to a nation. The private healthcare sector in the United Kingdom is now substantial and not effectively regulated, so government action should be welcome.

The bill could also allow the government to show its modernising credentials …