tbuckley/cabot-search huggingface dataset:
Fruit consumption and risk of type 2 diabetes: results from three prospective longitudinal cohort studies
Authors: I. Muraki, F. Imamura, J. E. Manson, F. B. Hu, W. C. Willett, R. M. van Dam, Q. Sun
Journal: BMJ (2013)

The CD20 mAb ofatumumab (OFA) induces complement-mediated lysis of B cells. In an investigator-initiated phase II trial of OFA plus chemotherapy for chronic lymphocytic leukemia (CLL), OFA treatment promoted partial CLL B cell depletion that coincided with reduced complement titers. Remaining CLL B cells circulated with bound OFA and covalently bound complement breakdown product C3d, indicative of ongoing complement activation. Presumably, neither complement- nor effector cell-based mechanisms were sufficiently robust to clear these remaining B cells. Instead, almost all of the bound OFA and CD20 was removed from the cells, in accordance with previous clinical studies that demonstrated comparable loss of CD20 from B cells after treatment of CLL patients with rituximab. In vitro experiments with OFA and rituximab addressing these observations suggest that host effector mechanisms that support mAb-mediated lysis and tumor cell clearance are finite, and they can be saturated or exhausted at high B cell burdens, particularly at high mAb concentrations. Interestingly, only a fraction of available complement was required to kill cells with CD20 mAbs, and killing could be tuned by titrating the mAb concentration. Consequently, maximal B cell killing of an initial and secondary B cell challenge was achieved with intermediate mAb concentrations, whereas high concentrations promoted lower overall killing. Therefore, mAb therapies that rely substantially on effector mechanisms subject to exhaustion, including complement, may benefit from lower, more frequent dosing schemes optimized to sustain and maximize killing by cytotoxic immune effector systems.
Routine screening for ovarian cancer harms more than it helps, says US authority
Authors: B. Roehr
Journal: BMJ (2012)

A US medical advisory body has reaffirmed its opposition to broad population screening for ovarian cancer.1 It said existing screening measures are insensitive, they do not reduce mortality, and do result in unnecessary surgery that puts women at increased risk of injury and death.

The US Preventive Services Task Force acknowledged the high mortality associated with ovarian cancer, as the fifth leading cause of cancer death among women in the nation.

The age adjusted incidence is just 13 cases per 100 000 women, however, and the positive predictive value of the screening test is low; “most women with a positive screening test will have a false-positive result.”

“Adequate evidence shows that screening for ovarian cancer can …
Evidence for involvement of tumor necrosis factor-? in apoptotic death of bone marrow cells in myelodysplastic syndromes
Authors: Suneel D. Mundle, Ambereen Ali, Jonathan D. Cartlidge, Samina Reza, Sairah Alvi, Margaret M. Showel, B. Yifwayimare Mativi, Vilasini T. Shetty, Parameswaran Venugopal, Stephanie A. Gregory, Azra Raza
Journal: American Journal of Hematology (1999)

We previously reported excessive apoptosis and high levels of tumor necrosis factor-alpha (TNF-alpha) in the bone marrows of patients with myelodysplastic syndromes (MDS), using histochemical techniques. The present studies provide further circumstantial evidence for the involvement of TNF-alpha in apoptotic death of the marrow cells in MDS. Using our newly developed in situ double-labeling technique that sequentially employs DNA polymerase (DNA Pol) followed by terminal deoxynucleotidyl transferase (TdT) to label cells undergoing apoptosis, we have characterized DNA fragmentation patterns during spontaneous apoptosis in MDS bone marrow and in HL60 cells treated with TNF-alpha or etoposide (VP16). Clear DNA laddering detected by gel electrophoresis in MDS samples confirmed the unique length of apoptotic DNA fragments (180-200 bp). Surprisingly, however, phenotypically heterogeneous population of MDS cells as well as the homogenous population of HL60 cells showed three distinct labeling patterns after double labeling--only DNA-Pol reaction, only TdT reaction, and a combined DNA Pol + TdT reaction, albeit in different cohorts of cells. Each labeling pattern was found at all morphological stages of apoptosis. MDS mononuclear cells, during spontaneous apoptosis in 4 hr cultures, showed highest increase in double-labeled cells (DNA Pol + TdT reaction). Interestingly, this was paralleled by TNF-alpha-induced apoptosis in HL60 cells. In contrast, VP16 treatment of HL60 cells led to increased apoptosis in cells showing only TdT reaction. The double-labeling technique was applied to normal bone marrow and peripheral blood mononuclear cells after treatment with known endonucleases that specifically cause 3' recessed (BamHI), 5' recessed (PstI), or blunt ended (DraI) double-stranded DNA breaks. It was found that the DNA-Pol reaction in MDS and HL60 cells corresponds to 3' recessed DNA fragments, the TdT reaction to 5' recessed and/or blunt ended fragments, and a combined "DNA Pol + TdT reaction" corresponds to a copresence of 3' recessed with 5' recessed and/or blunt ended fragments. Clearly, therefore, apoptotic DNA fragments, in spite of a unique length, may have differently staggered ends that could be cell (or tissue) specific and be selectively triggered by different inducers of apoptosis. The presence of TNF-alpha-inducible apoptotic DNA fragmentation pattern in MDS supports its involvement in these disorders and suggests that anti-TNF-alpha (or anticytokine) therapy may be of special benefit to MDS patients, where no definitive treatment is yet available.
Automatic Valve Clip.
Authors: J. RAWSON PENNINGTON
Journal: JAMA (1900)

This mechanical device was designed more especially for making a safe, permanent and bloodless division of annular, semiannular and other rectal strictures and obstructions located in the middle and upper portion of the rectum. These pathologic conditions are usually built on the semilunar, rectal, or Houston's valves, and are frequently a prime factor in the etiology of chronic constipation, obstipation, intestinal obstruction, mucous discharges, etc. It may also be used for the removal of neoplasms, prolapse, etc. Fig. 1 is a valve forceps; Fig. 2, I have designated as the clip introducer. Each is 25 cm. long; H is a reversible handle controlled by the set-screw, S; T is a thumb-rest connected by the slide-bar B, for opening and closing the beak F of the forceps; O is a ring connected by the slide-bar B for opening and closing the beak M of the clip introducer. Fig. 3 is a
Causes of Perinatal Mortality in the US Collaborative Perinatal Project
Authors: Richard L. Naeye
Journal: JAMA (1977)

The underlying causes of 80% of perinatal deaths were identified in a study of 53,518 pregnacies in the United States: 17% of the deaths were due to amniotic fluid infections, 11% to abruptio placentae, 10% to premature rupture of the membranes, 9% to congenital anomalies, 6% to large placental infarcts, and the rest to more than 20 other specific disorders.
What is the most effective treatment of interstitial cystitis?
Authors: J. L Onwude
Journal: BMJ (2008)

The treatment of interstitial cystitis has many uncertainties, including which treatment is the most effective. Interstitial cystitis is a chronic inflammatory bladder disease that mostly affects women. It can present as recurrent non-bacterial cystitis or as chronic pelvic pain associated with frequency and urgency. It can take up to five years and five doctors to reach the correct diagnosis.w1 Patients with interstitial cystitis are not a homogeneous population. Two distinct types of disease—classic and non-ulcer interstitial cystitis—have been described on the basis of pathological findings, and some treatments might work better for one type than for the other.1 Currently no treatment ladder exists. Oral treatments should be first line and intravesical therapies second line.

Interstitial cystitis can be a debilitating disease and has been described in the United States as a major health problem.w2 The prevalence ranges from 5 per 100 000 women in Japan to 197 per 100 000 women and 41 per 100 000 men in the US.w3 w4 We have no prevalence estimates for the United Kingdom.

Because interstitial cystitis is a distinct pathologic entity, a biopsy can provide definitive diagnosis.w5 However, criteria from the US National Institute of Diabetes and Digestive and Kidney Diseases, which required cystoscopy and bladder distension, need no longer be used.w6 Instead, validated questionnaires like the O’Leary-Sant symptom index and the University of Wisconsin symptom index are now used to diagnose this condition and measure response to treatment.w7

In addition, the International Continence Society now recommends the term interstitial cystitis/painful bladder …
Derivation of Serum Transferrin-Reply
Authors: Harold O. Douglass
Journal: JAMA (1981)

<h3>In Reply.—</h3> Drs Miller and Finley and Ms Morath have correctly emphasized that the relationships between calculated serum transferrin levels using the formula serum transferrin=0.8×TIBC—43 and measured transferrin levels are approximations. Nevertheless, the "transferrin" calculated from TIBC and that directly measured bear a fairly constant mathematical relationship. Both the formula we have used and the formula used in the Miami Valley Burn Unit (transferrin=0.7 TIBC+24) recognized these constant, albeit different, relationships. As long as the TIBC-derived "transferrin" and the directly measured "transferrin" remain proportional, TIBC derivations of "transferrin" remain useful chemical tools. We wish to thank Dr Miller and co-workers for clarifying this distinction. Although normal values for transferrin (whether directly measured or derived) may vary from hospital to hospital, the serum transferrin values, when measured before nutritional support and again after two weeks of total parenteral nutrition, appear to be predictive of the success of nutritional repletion.
Pattern of expression of c-Myc, Max and Bin1 in human anagen hair follicles
Authors: I. Barajon, C. Rumio, E. Donetti, A. Imberti, M. Brivio, P. Castano
Journal: British Journal of Dermatology (2001)

We recently reported the presence of c-Myc immunoreactivity in two distinct regions of the inner root sheath (IRS) of human anagen hair follicles; they corresponded to the regions where keratinocytes of Henle's and Huxley's layers enter the terminal differentiation phase that will lead to their exfoliation in the pilary canal. These regions were denoted lower (LR) ring and upper ring (UR).To extend these observations to other genes connected to c-Myc and specifically to Max and Bin1. Max is the best known heterodimeric partner of c-Myc, interacting with its C-terminal domain, and Bin1 is an adaptor protein interacting with its N-terminal domain.Human anagen hair follicles were processed for c-Myc, Max and Bin1 immunohistochemistry and immunofluorescence. The presence of different isoforms of Bin1 was evaluated by Western blot analysis.Analysis of sections cut in several planes, including tangential, demonstrated the presence of a third ring of c-Myc-positive cells (intermediate ring; IR) in the cuticle of the IRS corresponding to the region where this thin layer undergoes keratinization. Max immunoreactivity was observed in the three layers of the IRS starting in the lower bulbar region and ending in each of them at the level of the corresponding c-Myc-positive ring. Bin1 immunoreactivity was clearly distinguished only in Huxley's layer and in the cuticle, starting in some cells below the UR and terminating at the level of the latter. The companion layer of the outer root sheath was also labelled up to the infundibular region. Max and Bin1 immunostaining were less consistently observed in other skin adnexae and in the epidermis.The results indicate that the asynchronous differentiation along the axis of the hair follicle of the different layers of the IRS and of the companion layer involves the expression of different genes that are interrelated in the so-called 'Myc network'. The specific localization of c-Myc in the IRS only at the level of the discrete and limited regions of the three rings appears to be the hallmark of the switch from differentiation to terminal differentiation/cell deletion.
Ombudsman calls for national system for reporting adverse incidents in Scotland
Authors: B. Christie
Journal: BMJ (2012)

A standard system is needed to record adverse incidents across the NHS in Scotland to improve the care of patients, the country’s public service ombudsman, Jim Martin, has said.

His request comes after a BBC investigation found wide discrepancies in what were considered to be adverse incidents and how they were reported. They ranged from fatal medication errors to a nurse being injured while hanging Christmas decorations.

The investigation was based on freedom of information requests …
Small Molecule Inhibition of GDC-0449 Refractory Smoothened Mutants and Downstream Mechanisms of Drug Resistance
Authors: Gerrit J. P. Dijkgraaf, Bruno Alicke, Lasse Weinmann, Thomas Januario, Kristina West, Zora Modrusan, Dan Burdick, Richard Goldsmith, Kirk Robarge, Dan Sutherlin, Suzie J. Scales, Stephen E. Gould, Robert L. Yauch, Frederic J. de Sauvage
Journal: Cancer Research (2010)

Inappropriate Hedgehog (Hh) signaling has been directly linked to medulloblastoma (MB), a common malignant brain tumor in children. GDC-0449 is an Hh pathway inhibitor (HPI) currently under clinical investigation as an anticancer agent. Treatment of a MB patient with GDC-0449 initially regressed tumors, but this individual ultimately relapsed with a D473H resistance mutation in Smoothened (SMO), the molecular target of GDC-0449. To explore the role of the mutated aspartic acid residue in SMO function, we substituted D473 with every amino acid and found that all functional mutants were resistant to GDC-0449, with positively charged residues conferring potential oncogenic properties. Alanine scan mutagenesis of SMO further identified E518 as a novel prospective mutation site for GDC-0449 resistance. To overcome this form of acquired resistance, we screened a panel of chemically diverse HPIs and identified several antagonists with potent in vitro activity against these GDC-0449-resistant SMO mutants. The bis-amide compound 5 was of particular interest, as it was able to inhibit tumor growth mediated by drug resistant SMO in a murine allograft model of MB. However, focal amplifications of the Hh pathway transcription factor Gli2 and the Hh target gene cyclin D1 (Ccnd1) were observed in two additional resistant models, indicating that resistance may also occur downstream of SMO. Importantly, these HPI resistant MB allografts retained their sensitivity to PI3K inhibition, presenting additional opportunities for the treatment of such tumors.
Regional distribution of pulmonary epithelial permeability in normal subjects and patients with asbestosis.
Authors: A R Gellert, C A Lewis, J A Langford, S E Tolfree, R M Rudd
Journal: Thorax (1985)

The overall and regional clearance of an inhaled isotope labelled solute from the lungs was examined on the basis of a 15 minute period of data collection, for which a technique was developed that does not require intravenous injection to correct for blood-tissue background activity. The technique was applied to 52 normal subjects (31 non-smokers and 21 smokers) and to 37 patients with asbestosis (21 non-smokers and 16 smokers). In normal smokers solute clearance was faster in the upper and middle zones, with a mean ratio of T1/2 LB (half time solute clearance from lungs to blood) in the upper two thirds to the lower one third of the lungs of 0.66 (0.28-1.33), compared with 1.24 (0.43-2.77) in normal non-smokers (p less than 0.002). In patients with asbestosis solute clearance was accelerated throughout the lungs even though radiographic abnormalities were limited to lower or lower to middle zones. Regional distribution of clearance was not affected by posture in normal subjects. Overall solute clearance was significantly faster in normal current smokers and in patients with asbestosis than in normal non-smokers (p less than 0.001 respectively). Among patients with asbestosis, smokers had faster overall clearance than non-smokers (p less than 0.01). Among normal non-smokers T1/2 LB was not significantly different between those who had never smoked and ex-smokers. Regional abnormalities in pulmonary epithelial permeability may offer insight into the pathogenesis of interstitial lung diseases and smoking related disorders.
Proinflammatory potential of the airway epithelium in bronchial asthma
Authors: D Raeburn, SE Webber
Journal: European Respiratory Journal (1994)

Histopathological studies of asthmatic airways removed postmortem or by bronchial biopsy show marked inflammatory changes, notably epithelial cell disruption and damage, and the presence of large numbers of eosinophils. The epithelial damage is seen in mild, asymptomatic asthmatics as well as in patients who have died in status asthmaticus. Damage to the epithelium may also correlate with bronchial hyperreactivity. The epithelium has been suggested to be a target for inflammatory cell mediators and cytokines. Recently, the airway epithelium has itself been shown to produce and release several proinflammatory mediators and cytokines, and to express adhesion molecules for inflammatory cells. The epithelium, thus, may actively participate in the inflammatory changes in asthma, where it may be a source as well as a target. Drug therapy aimed at preventing inflammatory changes in the epithelium, such as cytokine and adhesion molecule expression, may be an important step forward in halting disease progression in asthma.
Comparisons of IgE, IgG, and IgG4 responsiveness to <i>Dermatophagoides farinae</i> in children by immunobulotting
Authors: E. Noguchi, M. Shibasaki, S. Isoyama, H. Takita
Journal: Allergy (1996)

Although asthmatic children are often sensitized to the house‐dust mite (HDM) during early childhood, it is not clear what antigenic components are associated with the early immune response of these children. To investigate this problem, we evaluated IgE, IgG, and IgG4 antibody responses to Dermatophagoides farinae (Df) by immunoblotting among three groups of children: group I aged 0–4 years, group II aged 5–9 years, and group III aged 10–14 years. In the group I subjects, positive IgE‐binding reactions to 15– and 25‐kDa components were found in 76% and 44% of sera, respectively. Those to other components were generally low in frequency. In contrast, positive IgG‐binding reactions to 15– and 25‐kDa components were found in 44% and 24% of sera, and those to 30– and 110‐kDa components in 48% and 88% of sera, respectively. Positive IgG4 reactions to 15– and 25‐kDa components were found in 48% and 24%, respectively, and those to other components were very low. Positive IgE‐binding reactions to these components gradually became more frequent with increasing age in groups II and III, while IgG and IgG4 reactivities were not markedly different in these age groups. These results suggest that the 15‐and 25‐kDa proteins of Df are important antigens associated with the initial IgE response to HDM in early childhood, while the 30– and 110‐kDa proteins are associated with IgG and 15‐kDa components with IgG4.
What to tell the occupational physician.
Authors: R E Fisher
Journal: BMJ (1977)

ratios above 1:1 at about 32 weeks "would probably have been induced at 32 weeks' gestation; but combining such serious pre- maturity with severe haemolytic disease had resulted in almost a 400% neonatal mortality."It seems that you misread this very easily understood statement.It is a pity that your readers should be thus misinformed.
Blood Examination for Malaria Parasites
Authors: T. Crawford
Journal: BMJ (1944)

Many practitioners, medical officers, ship surgeons, and laboratory workers formerly not familiar with malaria are now being confronted with its diagnostic problems.The technique involved in the blood examinations is simple enough, but it is not widely realized that a staining technique giving the best results for blood cells does not do so for malaria parasites.Faulty methods often lead to a failure to detect parasites present in small numbers, so the following brief notes may guide workers inexperienced in this field.
Near-infrared labeled, ovalbumin loaded polymeric nanoparticles based on a hydrophilic polyester as model vaccine: In vivo tracking and evaluation of antigen-specific CD8 + T cell immune response
Authors: Sima Rahimian, Jan Willem Kleinovink, Marieke F Fransen, Laura Mezzanotte, Henrik Gold, Patrick Wisse, Hermen Overkleeft, Maryam Amidi, Wim Jiskoot, Clemens W Löwik, Ferry Ossendorp, Wim E Hennink
Journal: Biomaterials (2014)
Increased state of activation of CD4 positive T cells and elevated interferon γ production in pouchitis
Authors: A Stallmach, F Schäfer, S Hoffmann, S Weber, I Müller-Molaian, T Schneider, G Köhne, K-W Ecker, G Feifel, M Zeitz
Journal: Gut (1998)

Background —Immunoregulatory abnormalities of T cells might be of importance in the pathogenesis of pouchitis after ileoanal pouch anastomosis (IAP). Aims —To characterise T cell subsets, their state of activation, and production of cytokines in inflamed and non-inflamed pouches in patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP). The influence of T cell activation on mucosal transformation was also studied. Patients —Mucosal biopsy specimens were taken from 42 patients with IAP (33 with UC and nine with FAP). Methods —Mononuclear cells were isolated by standard techniques and characterised by three colour flow cytometry. Interferon γ (IFN-γ) production was studied using the ELISPOT technique. Results —In patients with UC with pouchitis there was a significant increase in the CD4:CD8 ratio, expression of activation markers on CD3+ cells, and number of IFNγ producing mononuclear cells compared with patients with UC without pouchitis (CD4:CD8 ratio 1.3 (range 0.7–2.7) versus 0.6 (0.1–1.0), p=0.012). In addition, a positive correlation between increased crypt depth and the number of CD4+ cells ( r =0.57) was shown. Conclusion —The observed increase in activated mucosal CD4+ T cells and IFN-γ production might lead to mucosal destruction and crypt hyperplasia as seen in pouchitis.
Cornelius Jeremiah Griffin
Authors: Mary Heaney
Journal: BMJ (2004)

Former general practitioner Manchester (b London 1910; q University College Hospital, London, 1939; DObst RCOG), d 15 May 2004.

Con left school at 16 and became an articled clerk to be an actuary, but in his mid-20s decided he wanted to be a doctor. Barely had he started his first job after qualifying before the second world war broke out, and Con joined the Royal Air Force as a medical officer. After the war, Con became an assistant general practitioner in Bournemouth. In 1954 he successfully applied for his own practice in Crumpsall, Manchester. He was active in the North Manchester Medical Society. In retirement he completed an Open University degree in mathematics. Predeceased by his wife, Nell, he leaves four children and 15 grandchildren.