tbuckley/cabot-search huggingface dataset:
Palifermin-induced flexural hyperpigmentation: a clinical and histological study of five cases
Authors: L A G Sibelt, N Aboosy, W J F M van der Velden, N M A Blijlevens, W A M Blokx, M M B Seyger
Journal: British Journal of Dermatology (2008)

Palifermin is a human keratinocyte growth factor that is efficacious in reducing duration and severity of oral mucositis during autologous haematopoietic stem‐cell transplantation for haematological cancer as well as chemotherapy for colorectal cancers. We report the clinical and histological characteristics of a series of five patients who developed flexural hyperpigmentation after treatment with palifermin. All patients showed ill‐defined symmetrical hyperpigmented papillomatous plaques with slight erythema in the skin folds, especially affecting axillary and inguinal areas. The most striking histological finding was the thickened granular layer in all patients. We demonstrate that filaggrin, an essential component in the terminal differentiation of the epidermis, was upregulated in these cases. Palifermin‐induced flexural hyperpigmentation is a newly defined clinical and histological entity. The possible aetiology is discussed.
Endothelin reverses the effects of acidosis on the intracellular Ca2+ transient and contractility in ferret myocardium.
Authors: J Wang, J P Morgan
Journal: Circulation Research (1992)

Endothelin may play an important role in modulating myocardial contractility under certain pathophysiological conditions. To determine whether endothelin beneficially modulates myocardial contractility in the common clinical condition of acidosis, we compared the effects of endothelin-1 on intracellular Ca2+ transients and isometric contractions under normal (extracellular pH [pH(o)] 7.4) and acidotic (pH(o) 6.4) conditions in ferret papillary muscles (n = 33) loaded with the Ca(2+)-regulated bioluminescent indicator aequorin. A pH(o) of 6.4 was induced by replacing 92% of HCO3- with Cl- in the bathing medium. The effects of endothelin at pH(o) 6.4 differed from the effects at pH(o) 7.4 in that 1) the minimally effective concentration of endothelin was 30-fold lower (1 x 10(-10) M at pH(o) 6.4; 3 x 10(-9) M at pH(o) 7.4) and the concentration-response curve of endothelin was significantly shifted to the left with a decrease in log EC50 from -7.83 +/- 0.13 to -8.92 +/- 0.10 (p less than 0.001), indicating an increased sensitivity of myocardium to endothelin; 2) endothelin produced an increase of approximately 375% in tension development at pH(o) 6.4 (approximately 62% at pH(o) 7.4) (p less than 0.001) without increasing peak [Ca2+]i (approximately 13% increase at pH(o) 7.4, p less than 0.001), indicating an increase in myofilament Ca2+ responsiveness; and 3) endothelin significantly abbreviated (approximately -19%, p less than 0.001) the prolonged intracellular Ca2+ transient induced by acidosis (pH(o) 6.4). In addition, pretreatment with 10 microM of the Na(+)-H+ exchange inhibitor 5-(N-methyl-N-isobutyl)-amiloride significantly attenuated endothelin-induced effects on the intracellular Ca2+ transient and contraction during acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Homeobox D10 Induces Phenotypic Reversion of Breast Tumor Cells in a Three-Dimensional Culture Model
Authors: Meritxell Carrio, Gemma Arderiu, Connie Myers, Nancy J. Boudreau
Journal: Cancer Research (2005)

Abstract Homeobox (Hox) genes are master regulatory genes that direct organogenesis and maintain differentiated tissue function. We previously reported that HoxD10 helps to maintain a quiescent, differentiated phenotype in endothelial cells by suppressing expression of genes involved in remodeling the extracellular matrix and cell migration. Here we investigated whether HoxD10 could also promote or maintain a differentiated phenotype in epithelial cells. We observed that HoxD10 expression is progressively reduced in epithelial cells as malignancy increases in both breast and endometrial tumors. Retroviral gene transfer to restore expression of HoxD10 in the malignant breast tumor cells MDA-MB-231 significantly impaired migration, and when these cells were cultured in a three-dimensional laminin-rich basement membrane (3DlrBM) model, they formed polarized, acinar structures. This phenotypic reversion was accompanied by decreased α3 integrin expression and reduced proliferation. Importantly, expression of HoxD10 in the MDA-MB-231 cells inhibited their ability to form tumors in mouse xenografts. Taken together, our results suggest that HoxD10 has tumor-suppressive functions for mammary epithelial cells.
Fever Control Using External Cooling in Septic Shock
Authors: Ariel Jaitovich, Peter H. S. Sporn
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

the effects of external cooling among febrile patients with septic shock (1).This clinical trial adds further evidence to the growing efforts to define an evidence-based approach to fever control in critically ill patients.They found that external cooling with a cooling blanket or cold bed sheets and ice packs was strongly associated with (1) a decrease in the dose of vasopressor required to maintain a mean arterial pressure of at least 65 mm Hg at 12 and 24 hours after randomization; and (2) a decrease in early (14-d) mortality in febrile patients with septic shock.This beneficial impact on early mortality was not maintained upon discharge from the intensive care unit (ICU), or hospital, and contrasts with previous observational studies and clinical trials investigating the effects of antipyretic therapy among adult patients admitted to ICUs (2-4).These previous investigations found fever control with pharmacologic and/or physical antipyretic therapy had either neutral (2) or harmful (3, 4) effects on mortality.This discrepancy may be a result of differences in the study populations (septic shock vs. cohorts of general critically ill patients), the chosen antipyretic modality (external cooling vs. pharmacologic therapy), the timing of fever control, and/or important cointerventions.In our experience, controlling for cointervention with other antipyretic therapy is an important component to any clinical trial investigating fever control strategies (5).This was a major issue in a double-blind study comparing ibuprofen to placebo in patients with sepsis (2), and is potentially even more important in an openlabel study such as the Sepsiscool trial (1).Furthermore, two recently published cohort studies suggest that the majority of febrile critically ill patients receive some form of antipyretic therapy often without an explicit order to guide this management strategy (4, 6).The authors of the Sepsiscool trial did not explicitly indicate how pharmacologic antipyretic therapy was regulated among study participants during the treatment period, nor did they outline the antipyretic modalities applied to study participants that developed a fever after completing the 48-hour treatment period.This information may help to explain why unlike previous studies, external cooling reduced early mortality but not that upon discharge from the ICU.
The Hypoxia-Associated Factor Switches Cells from HIF-1α- to HIF-2α-Dependent Signaling Promoting Stem Cell Characteristics, Aggressive Tumor Growth and Invasion
Authors: Mei Yee Koh, Robert Lemos, Xiuping Liu, Garth Powis
Journal: Cancer Research (2011)

Most solid tumors and their metastases experience periods of low oxygen or hypoxia, which is of major clinical significance as it promotes both tumor progression and resistance to therapy. Critical mediators of the hypoxic response are the hypoxia-inducible factors HIF-1α and HIF-2α. The HIFs are nonredundant and regulate both overlapping and unique downstream target genes. Here, we describe a novel mechanism for the switch between HIF-1α- and HIF-2α-dependent transcription during tumor hypoxia caused by the hypoxia associated factor (HAF). HAF is overexpressed in a variety of tumors and its levels are decreased during acute hypoxia, but increased following prolonged hypoxia. We have previously identified HAF as an E3 ubiquitin ligase that binds and ubiquitinates HIF-1α by an oxygen and pVHL-independent mechanism, thus targeting HIF-1α for proteasomal degradation. Here, we show that HAF also binds to HIF-2α, but at a different site than HIF-1α, and increases HIF-2α transactivation without causing its degradation. HAF, thus, switches the hypoxic response of the cancer cell from HIF-1α-dependent to HIF-2α-dependent transcription and activates genes involved in invasion such as MMP9, PAI-1, and the stem cell factor OCT-3/4. The switch to HIF-2α-dependent gene expression caused by HAF also promotes an enriched tumor stem cell population, resulting in highly aggressive tumors in vivo. Thus, HAF, by causing a switch from a HIF-1α- to HIF-2α-dependent response to hypoxia, provides a mechanism for more aggressive growth of tumors under prolonged hypoxia.
Apolipoprotein E &amp;isin;4 allele distributions in late-onset Alzheimer's disease and in other amyloid-forming diseases
Authors: A.M Saunders, A.D Roses, M.A Pericak-Vance, K.C Dole, W.J Strittmatter, D.E Schmechel, M.H Szymanski, N McCown, M.G Manwaring, K Schmader, J.C.S Breitner, D Goldgaber, M.D Benson, L Goldfarb, W.T Brown
Journal: The Lancet (1993)
Involvement of inferior turbinate mucosa in chronic sinusitis – localization of T‐cell subset
Authors: G. Grevers, A. Klemens, C. Sturm, F. Menauer
Journal: Allergy (2000)

Background : In chronic sinusitis (CS), different subsets of leukocytes are involved in development of persistent inflammation of the nasal mucosa. The localization and differentiation of these infiltrating lymphocytes may help us to understand the inflammatory interactions in the epithelium, lamina propria, and seromucous glands of the nasal mucosa in CS. Methods : We examined frozen sections of inferior turbinates from 14 patients with nonallergic CS and 10 normal nonallergic controls. We used the avidin‐biotin‐peroxidase (ABC) technique with monoclonal antibodies against CD3 (total T cells), CD4 (T‐helper/inducer cells), CD8 (T‐suppressor/cytotoxic cells), CD22 (B cells), CD56 (natural killer cells), elastase (neutrophil granulocytes), eosinophil cationic protein (eosinophil granulocytes), and CD68 (macrophages). Results : We found significant increases ( P &lt;0.05) of CD3, CD4, and CD8 T cells and B cells in the nasal mucosa of patients with CS. The number of CD68 cells and eosinophils showed no significant rise. Conclusions : The different types of leukocytes play a key role in the defense of the respiratory tract. The analysis of the distribution of cells in the epithelium, mucosa, and glands of the inferior turbinate confirmed that nonallergic CS is, in fact, chronic, bacterial rhinosinusitis involving the inferior turbinates, and that the pathomechanism is therefore different from that of nasal polyposis.
Characteristics Associated With Recurrence Among Women With Ductal Carcinoma In Situ Treated by Lumpectomy
Authors: K. Kerlikowske
Journal: JNCI Journal of the National Cancer Institute (2003)

Clinical and histopathologic characteristics that may predict risks of recurrence in women with ductal carcinoma in situ (DCIS) have not been consistently identified. We identified factors associated with recurrence as DCIS versus invasive breast cancer and determined the 5-year absolute risks of recurrence as a function of these factors.We conducted a population-based cohort study among 1036 women in the San Francisco Bay Area who were aged 40 years or older when diagnosed with DCIS and treated by lumpectomy alone from January 1983 through December 1994. Standardized pathology reviews were conducted to determine disease recurrence, defined as DCIS or invasive breast cancer diagnosed in the ipsilateral breast containing the initial DCIS lesion or at a distant site more than 6 months after the initial diagnosis and treatment of DCIS. Conditional logistic regression models were used to determine factors associated with recurrence. All statistical significance tests were two-sided.During a median follow-up of 77.9 months, 209 women (20.2%) experienced a recurrence. Overall, the 5-year risks of recurrence as invasive cancer and as DCIS were 8.2% (95% confidence interval [CI] = 6.6% to 9.8%) and 11.7% (95% CI = 9.9% to 13.3%), respectively. The 5-year risks of recurrence as invasive cancer and as DCIS were 4.8% (95% CI = 3.7% to 6.8%) and 4.8% (95% CI = 3.8% to 5.8%), respectively, for women with low-nuclear-grade DCIS; 11.8% (95% CI = 9.9% to 14.1%) and 17.1% (95% CI = 15.5% to 18.7%), respectively, for women with high-nuclear-grade DCIS; 11.6% (95% CI = 11.3% to 12.0%) and 8.6% (95% CI = 7.1% to 10.2%), respectively, for women whose initial DCIS lesion was detected by palpation; and 6.6% (95% CI = 6.2% to 7.1%) and 14.1% (95% CI = 11.4% to 17.8%), respectively, for women with DCIS detected by mammography alone. High- (versus low-) nuclear-grade DCIS lesions and detection of the initial DCIS lesion by palpation (versus mammography) were associated with recurrence as invasive cancer. High- (versus low-) nuclear-grade lesions; resection margins that were positive, uncertain, or less than 10 mm disease-free (versus > or = 10 mm disease-free); and age 40-49 years at diagnosis (versus > or =50 years) were associated with recurrence as DCIS.Nuclear grade is strongly associated with recurrence but not with the type of recurrence. Women with high-nuclear-grade DCIS or DCIS detected by palpation who are treated by lumpectomy alone are at relatively high risk of having an invasive breast cancer recurrence, compared with women with low-nuclear-grade or mammographically detected DCIS, and may be appropriate candidates for additional treatment.
Melanotropic peptides: more than just ‘Barbie drugs’ and ‘sun-tan jabs’?
Authors: E.A. Langan, Z. Nie, L.E. Rhodes
Journal: British Journal of Dermatology (2010)

While ultraviolet radiation (UVR) is a major cause of skin ageing and carcinogenesis, public pursuit of a novel tanning strategy circumventing the need for UVR is increasingly reported in the media and scientific press. This involves the subcutaneous self-administration of unregulated products labelled as melanotan I and/or II, synthetic analogues of α-melanocyte stimulating hormone (α-MSH), as obtained via the internet, tanning salons and gyms. The Medicines and Healthcare products Regulatory Authority has recently raised awareness of the public health risk of transmission of blood-borne viruses from the needle sharing that may occur, and of the potential impurity of these products. Dermatologists should also be aware that these agents can complicate the clinical presentation of patients with pigmented lesions; their use may be suspected in unexpectedly tanned individuals with rapidly pigmenting naevi. Meanwhile, the regulated α-MSH analogue afamelanotide (Clinuvel Pharmaceuticals Ltd, Melbourne, Australia) is showing promise for its photoprotective potential, and is undergoing phase II and III clinical trials in people with photosensitivity disorders and those prone to nonmelanoma skin cancer. The photoprotective and other biological effects of α-MSH analogues await full determination.
Surgical pathology of the thymus: 20 years' experience.
Authors: S R Large, J M Shneerson, P G Stovin, J Wallwork
Journal: Thorax (1986)

Fifty five patients underwent thymic surgery at Papworth Hospital from April 1964 to March 1984. The number presenting and the percentage with symptoms annually remained unchanged during this period. Forty four of these 55 patients had tumours. Twenty eight had thymomas (18% of whom had myasthenia gravis and 7% red cell aplasia), nine Hodgkin9s disease, four germ cell tumours, and three secondary carcinomatous tumours. Five tumours were cystic. Six further patients had non-tumourous cystic lesions (four simple, one foregut, one lymphangiectatic). The remaining five patients had follicular hyperplasia; all of these had myasthenia gravis. Complete excision was performed in 41 of the 55 patients. So far survival is 100% in those with benign lesions other than benign thymomas, where the survival was 70% at five years. Those with malignant thymomas had a 60% survival rate at five years and those with Hodgkin9s disease 29%.
Research Misconduct, Retraction, and Cleansing the Medical Literature: Lessons from the Poehlman Case
Authors: Harold C. Sox, Drummond Rennie
Journal: Annals of Internal Medicine (2006)

The scientific literature is a record of the search for truth. Publication of faked data diverts this search. The scientific community has a duty to warn people to ignore an article containing faked data and must try to prevent inadvertent citation of it. The scientific community accomplishes these tasks by publishing a retraction and linking it to the fraudulent article's citation in electronic indexes of the medical literature, such as PubMed. This mechanism is far from perfect, as shown by a case history of scientific fraud perpetrated by Eric Poehlman, PhD. His institution notified 3 journals that they had published tainted articles. Two journals failed to retract. The third journal retracted immediately, but other authors continued to cite the retracted article. Another duty of the scientific community is to verify the integrity of other articles published by the author of a fraudulent article. This task falls to the author's institution and requires coauthors to vouch for their article's integrity by convincing institutional investigators that the suspect author could not have altered the raw scientific data from their study. Two universities are currently investigating Poehlman's published research. Maintaining the integrity of the scientific literature requires governmental institutions that have the authority to investigate and punish guilty scientists and requires that research institutions investigate alleged fraud. It requires journal editors to issue a retraction when they learn that their journal has published a tainted article. It requires research institutions to accept their responsibility to investigate every article published by a scientist who has published even 1 fraudulent article. Finally, it requires authors to take pains to avoid citing retracted articles and to issue a correction when they inadvertently cite a retracted article.
Hunt should issue guidance on "do not resuscitate" directions, court hears
Authors: C. Dyer
Journal: BMJ (2014)

Hospitals regularly breach patients’ human rights by putting “do not attempt cardiopulmonary resuscitation” (DNACPR) directions in their notes without consultation, the Court of Appeal has been told.

Philip Havers QC told three senior judges that the health secretary for England, Jeremy Hunt, must step in and issue national guidance to end the confusion and uncertainty that can distress families and patients.

The judges, headed by John Dyson, the master of the rolls, were hearing a claim by David …
Second-person social neuroscience: Connections to past and future theories, methods, and findings
Authors: Nicolas Vermeulen, Gordy Pleyers, Martial Mermillod
Journal: Behavioral and Brain Sciences (2013)

Abstract We argue that Schilbach et al. have neglected an important part of the social neuroscience literature involving participants in social interactions. We also clarify some part of the models the authors discussed superficially. We finally propose that social neuroscience should take into consideration the effect of being observed and the complexity of the task as potentially influencing factors.
Suicide Rates Among Physicians: A Quantitative and Gender Assessment (Meta-Analysis)
Authors: Eva S. Schernhammer, Graham A. Colditz
Journal: American Journal of Psychiatry (2004)

Physicians' suicide rates have repeatedly been reported to be higher than those of the general population or other academics, but uncertainty remains. In this study, physicians' suicide rate ratios were estimated with a meta-analysis and systematic quality assessment of recent studies.Studies of physicians' suicide rates were located in MEDLINE, PsycINFO, AARP Ageline, and the EBM Reviews: Cochrane Database of Systematic Reviews with the terms "physicians," "doctors," "suicide," and "mortality." Studies were included if they were published in or after 1960 and gave estimates of age-standardized suicide rates of physicians and their reference population or reported extractable data on physicians' suicide; 25 studies met the criteria. Reviewers extracted data and scored each study for quality. The studies were tested for heterogeneity and publication bias and were stratified by publication year, follow-up, and study quality. Effect sizes were pooled by using fixed-effects (women) and random-effects (men) models.The aggregate suicide rate ratio for male physicians, compared to the general population, was 1.41, with a 95% confidence interval (CI) of 1.21-1.65. For female physicians the ratio was 2.27 (95% CI=1.90-2.73). Visual inspection of funnel plots from tests of publication bias revealed randomness for men but some indication of bias for women, with a relative, nonsignificant lack of studies in the lower right quadrant.Studies on physicians' suicide collectively show modestly (men) to highly (women) elevated suicide rate ratios. Larger studies should help clarify whether female physicians' suicide rate is truly elevated or can be explained by publication bias.
Bone Marrow–Derived Cells Are Sufficient and Necessary Targets to Mediate Glomerulonephritis and Vasculitis Induced by Anti-Myeloperoxidase Antibodies
Authors: Adrian Schreiber, Hong Xiao, Ronald J. Falk, J. Charles Jennette
Journal: Journal of the American Society of Nephrology (2006)

Clinical and experimental evidence indicate that ANCA cause pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) and systemic small vessel vasculitis in humans. One of the major target antigens for ANCA is myeloperoxidase (MPO). An animal model that closely resembles the human disease is induced by intravenous injection of anti-MPO IgG into mice. The likely primary pathogenic targets for the anti-MPO IgG are circulating neutrophils and monocytes, although other cells have been implicated, including endothelial cells and epithelial cells. Herein is reported a new model for anti-MPO–mediated glomerulonephritis and vasculitis that further documents the pathogenic potential of ANCA and demonstrates that bone marrow (BM)-derived cells are sufficient targets to cause anti-MPO disease in the absence of MPO in other cell type. MPO knockout (Mpo−/−) mice that were immunized with mouse MPO were exposed to irradiation and received a transplant of Mpo+/+ or Mpo−/− BM. Engraftment in mice with circulating anti-MPO resulted in development of pauci-immune NCGN in all mice and pulmonary capillaritis and splenic necrotizing arteritis in some. Anti-MPO IgG also was introduced intravenously into chimeric mice by transplantation of Mpo+/+ BM into irradiated Mpo−/− mice or Mpo−/− BM into irradiated Mpo+/+ mice. Chimeric Mpo−/− mice with circulating MPO-positive neutrophils developed NCGN, whereas chimeric Mpo+/+ mice with circulating MPO-negative neutrophils did not, thereby indicating that BM-derived cells are not only sufficient but also necessary for induction of anti-MPO disease. This novel animal model further documents ANCA IgG interactions with neutrophils as a cause of ANCA-associated glomerulonephritis and vasculitis.