tbuckley/cabot-search huggingface dataset:
BSE and vCJD: What is the Future?
Authors: A J Beale
Journal: Journal of the Royal Society of Medicine (2001)

In 1989, when the Southwood Working Party1 reported on the apparently new disease bovine spongiform encephalopathy (BSE), there were few hard scientific data from which to assess the danger to public health. In particular the nature of the agent causing the disease was obscure. The working party was presented with the plausible hypothesis that BSE was derived from scrapie agent present in meat and bone meal (MBM) fed to cattle; and the correctness of this idea2 became plain when, with the ban on MBM as an animal feed, the incidence of BSE declined. Twelve years on from Southwood (on 21 February), the RSM's Section of Comparative Medicine met to debate subsequent developments including the advent of variant Creutzfeldt—Jakob disease (vCJD) in man.
Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial through up to 3 years
Authors: A.B. Kimball, K.B. Gordon, S. Fakharzadeh, N. Yeilding, P.O. Szapary, B. Schenkel, C. Guzzo, S. Li, K.A. Papp
Journal: British Journal of Dermatology (2012)

An unmet need remains for safe and effective long-term treatments of psoriasis.To evaluate ustekinumab efficacy and safety for up to 3 years in the PHOENIX 1 trial.Patients (n = 766) with moderate-to-severe psoriasis were randomized to ustekinumab 45 mg or 90 mg at weeks 0 and 4, and then every 12 weeks, or placebo at weeks 0 and 4, with crossover to ustekinumab at week 12. Ustekinumab responders [≥ 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at weeks 28 and 40] were re-randomized at week 40 to continue or withdraw from treatment until psoriasis recurrence. Partial responders (week 28: PASI 50-74; week 40: < PASI 75) switched to dosing every 8 weeks. Clinical efficacy was assessed by PASI, the Physician's Global Assessment (PGA), and the Dermatology Life Quality Index (DLQI) measures.Overall, 79·8% of the ustekinumab-treated patients remained in the study for 3 years. PASI 75 response rates (45 mg: 61·2%; 90 mg: 72·4%) at week 76 were maintained through year 3 (45 mg: 62·7%; 90 mg: 72·2%); PGA response was similarly durable. At year 3, 80·9% (45 mg) and 82·7% (90 mg) of week 40 responders continuing treatment every 12 weeks achieved a PASI 75 response, while 42·6% (45 mg) and 58·0% (90 mg) achieved a PASI 90 response. Among partial responders adjusted to dosing every 8 weeks, 50·9% (45 mg) and 52·0% (90 mg) had a PASI 75 response at year 3. DLQI responses paralleled the PASI responses. Through year 3, no dose response was observed in rates of adverse events (AEs), overall infections, serious AEs, or AEs leading to discontinuation; nor was there evidence of cumulative organ toxicity. CONCLUSIONS; Continuous, stable, maintenance dosing with ustekinumab was generally well tolerated and sustained durable efficacy for up to 3 years of treatment.
Aristophanes’ Wealth: Ancient Alternative Medicine and its Modern Survival
Authors: N Koutouvidis, E Papamichael, A Fotiadou
Journal: Journal of the Royal Society of Medicine (1996)

The miraculous cure of the blind god Plutos (‘Wealth’) in Aristophanes’ play illuminates some of the reasons why people have sought help in alternative medicine over the ages. Apart from limitations of conventional medicine these factors can be social, political, religious, psychological, and scientific. Alternative medicine may function in a complementary way to the conventional. Nevertheless, an overestimation of its therapeutic potentials by the public can lead to the domination of irrationalism, all in the name of liberation from the shackles of a mechanistic rationalism.
Access to Palliative Care in the USA: Why Emphasize Vulnerable Populations?
Authors: Joseph O'Neill, Katherine Marconi
Journal: Journal of the Royal Society of Medicine (2001)

How we recognize and address the palliative care needs of marginalized, vulnerable, or socially excluded populations may very well be the measure of our success in integrating palliative care into current health systems. LuAnn Aday, who has written about access for under-served populations in the USA, defines vulnerable populations as being ‘at risk of poor physical, psychological, and/or social health’1. If we deconstruct her definition, being ‘at risk’ signifies a high probability of illness and inappropriate or no healthcare, and the possible causes include lack of access to preventive services, disease screening and treatment as well as lack of access to the housing, employment and other supportive structures that many of us take for granted. Aday then identifies some of the at-risk populations in the USA—the chronically ill and disabled, persons with AIDS, the mentally ill, alcohol and substance abusers, homeless people, immigrants and refugees and combinations of these1. We would add another category that crosses this list—membership of a minority or ethnic community. Because of our history of discrimination and unequal investment in health, social, and economic resources in these communities, they are disproportionately at risk.

We already have some indication of differences among vulnerable populations in their knowledge of end-of-life care. For example, Silveira and DiPiero2 identified non-white race and low educational level as factors associated with lack of such knowledge and Shapiro et al.3, in the HIV Cost and Services Utilization Study (HCSUS), found differences in use of medical care and pharmaceuticals by race, gender, and insurance status. Another study followed Medicare patients admitted to hospital in three American States (Illinois, New York, and Pennsylvania) with principal diagnoses of congestive heart failure and pneumonia4; on a series of measures, black patients were found to receive lower-quality care than non-black patients, and these differences persisted when groups with equivalent poverty levels were compared.

In the USA, lack of insurance may complicate access. But data from other countries indicate that universal health coverage does not always result in universal access. For example, a Canadian study found that access to cardiac services decreased, and mortality rates after acute myocardial infarction increased, by income grouping: the lower the income quintile, the more adverse the health consequences5. We know which populations are at high risks of illness and we have studied the barriers to their obtaining good-quality healthcare. In our palliative care planning we need to discuss how to lessen the chances of excluding them as we integrate palliative care with primary and specialty healthcare and end-of-life care such as hospice.
Silencing of <i>CXCR4</i> Blocks Breast Cancer Metastasis
Authors: Zhongxing Liang, Younghyoun Yoon, John Votaw, Mark M. Goodman, Larry Williams, Hyunsuk Shim
Journal: Cancer Research (2005)

Abstract RNA interference technology, silencing targeted genes in mammalian cells, has become a powerful tool for studying gene function. For the first time in cancer research, we show that direct injection of a pool of naked small interfering RNA (siRNA) duplexes can prevent tumorigenesis in an animal model, suggesting a novel preventive and therapeutic strategy for cancer management. As a model system, we used siRNA duplexes of CXCR4 to block breast cancer metastasis. Here, we show that blocking CXCR4 expression at the mRNA level by a combination of two siRNAs impairs invasion of breast cancer cells in Matrigel invasion assay and inhibits breast cancer metastasis in an animal model. Targeting more than one site of the target gene may be important to overcome the functional redundancy of other variants of a single gene, especially in in vivo experiments. Moreover, our studies confirm the necessity of CXCR4 in breast cancer metastasis.
Prognostic factors related with prolong length of stay in community acquired pneumonia
Authors: Sotiria Makrodimitri, Myrsini Melaxroinidou, Katerina Dimakou, Michael Toumbis, Adamantia Liapikou
Journal: European Respiratory Journal (2014)

Introduction: Community-acquired pneumonia (CAP) is associated with sub- stantial morbidity and mortality among adults. The early recognition of prognostic factors for prolong hospital stay it will be helpful to decrease the cost of CAP and its morbidity.  Methods: An observational, retrospective study of consecutive CAP patients was performed at the Sotiria Hospital, during 2 years period. We compare the CAP patients with prolonged length of stay (PLOS)-hospitalization higher than the mean length of stay- with the others with short length of stay (SLOS).  Results: Of a total 354 patients (54% men, 63,7 years (SD 19), with a mean length of hospital stay of 11 days (SD 10), 108 patients had PLOS of 20,8 days (SD14). These patients were older (68 y vs. 62y; p=0,02), had more comorbidities (81% vs. 71%; p=0,05), especially cancer (12% vs.5%; p=0,024). They presented with higher CURB65 score (2,6 vs.1, 7; p  Conclusions: The severity of CAP(CURB65>3), the pleural effusion and the multilobar involvement, are related with a prolonged hospitalization in CAP patients admitted to hospital.
Tumor suppressor p53 stole the AKT in hypoxia
Authors: Zhong Yun, Peter M. Glazer
Journal: Journal of Clinical Investigation (2015)

The presence of hypoxia within a tumor is associated with poor clinical outcome, which is often exacerbated by loss of the tumor suppressor p53. In the presence of functional p53, hypoxic conditions promote apoptosis; however, the p53-dependent genes that mediate this process are not well understood. In this issue of the JCI, Leszczynska and colleagues identify a p53-dependent six-gene signature that is specifically induced in hypoxia and mediates apoptosis. In patients with a variety of cancers, downregulation of this gene signature was associated with poor clinical outcome. Induction of p53-dependent apoptosis under hypoxia was mediated by AKT inhibition, and treatment with the combination of an AKT inhibitor and ionizing radiation decreased tumor size in a p53-deficient xenograft model more substantially than either single-agent treatment. The results of this study provide important insight into p53-mediated apoptosis under hypoxia and suggest that AKT inhibition has therapeutic potential for inducing apoptosis in hypoxic, p53-deficient cancers.
Surface plasmon resonance as a high throughput method to evaluate specific and non-specific binding of nanotherapeutics
Authors: Craig S. Schneider, Adip G. Bhargav, Jimena G. Perez, Aniket S. Wadajkar, Jeffrey A. Winkles, Graeme F. Woodworth, Anthony J. Kim
Journal: Journal of Controlled Release (2015)

Surface plasmon resonance (SPR) is a powerful analytical technique used to quantitatively examine the interactions between various biomolecules, such as proteins and nucleic acids. The technique has been particularly useful in screening and evaluating binding affinity of novel small molecule and biomolecule-derived therapeutics for various diseases and applications including lupus medications, thrombin inhibitors, HIV protease inhibitors, DNA gyrase inhibitors and many others. Recently, there has been increasing interest in nanotherapeutics (nanoRx), due to their unique properties and potential for controlled release of encapsulated drugs and structure-specific targeting to diseased tissues. NanoRx offer the potential to solve many drug delivery challenges by enabling, specific interactions between molecules on the surface of the nanoparticle and molecules in the diseased tissue, while minimizing off-target interactions toward non-diseased tissues. These properties are largely dependent upon careful control and balance of nanoRx interactions and binding properties with tissues in vivo. Given the great promise of nanoRx with regard to engineering specific molecular interactions, SPR can rapidly quantify small aliquots of nanoRx formulations for desired and undesired molecular interactions. Moving forward, we believe that utilization of SPR in the screening and design of nanoRx has the potential to greatly improve the development of targeted nanoRx formulations and eventually lead to improved therapeutic efficacy. In this review, we discuss (1) the fundamental principles of SPR and basic quantitative analysis of SPR data, (2) previous applications of SPR in the study of non-particulate therapeutics and nanoRx, and (3) future opportunities for the use of SPR in the evaluation of nanoRx.
Identification of broadly conserved cross-species protective <i>Leishmania</i> antigen and its responding CD4 <sup>+</sup> T cells
Authors: Zhirong Mou, Jintao Li, Thouraya Boussoffara, Hiroyuki Kishi, Hiroshi Hamana, Peyman Ezzati, Chuanmin Hu, Weijing Yi, Dong Liu, Forough Khadem, Ifeoma Okwor, Ping Jia, Kiyomi Shitaoka, Shufeng Wang, Momar Ndao, Christine Petersen, Jianping Chen, Sima Rafati, Hechmi Louzir, Atsushi Muraguchi, John A. Wilkins, Jude E. Uzonna
Journal: Science Translational Medicine (2015)

A Leishmania protein vaccine elicited immune responses and mediated strong cross-species protection.
Targeting of dornase alpha therapy in adult cystic fibrosis
Authors: M J Ledson, Z Wahbi, R P Convery, C Cowperthwaite, D P Heaf, M J Walshaw
Journal: Journal of the Royal Society of Medicine (1998)

Although dornase alpha (recombinant human DNase) can thin the viscid pulmonary secretions of cystic fibrosis (CF), clinical trials in groups of unselected patients have shown only modest average improvements in pulmonary function. The product is very expensive, so in conjunction with purchasers we designed selection criteria and a protocol for a 2-week trial to target CF individuals who might gain most benefit. Treatment was to be continued in those showing ≥10% improvement in pulmonary function. Those who had a trial of dornase alpha were followed up for 2 years. Of 25 patients who had a 2-week trial of dornase alpha, 17 met the criteria for continuation (average gain in forced expiratory volume 37%). The 11 of these who were still alive at 2 years had a greater initial average FEV1 improvement than those who had died (45% versus 22%), and still had an average improvement of 31% at 2 years. The 8 patients who did not meet the criteria for continuation were older and had required fewer intravenous antibiotic courses. All these were alive at 2 years with unchanged clinical indices. This method of selection for dornase alpha treatment allows targeting to those who gain most benefit without disadvantaging the remaining patients. Furthermore, production of such guidelines in conjunction with purchasers obviates funding difficulties and allows rational prescribing.
The impact of mother-child interaction on the development of borderline personality disorder
Authors: S Bezirganian, P Cohen, J S Brook
Journal: American Journal of Psychiatry (1993)

Two major psychodynamic theories of the etiology of borderline personality disorder posit two aspects of mother-child interaction as uniquely pathogenic: maternal over-involvement with the child and mismanagement and inappropriateness of maternal guidance and support of the child. This study is an attempt to examine these putative risk factors empirically, using epidemiologic methods.Mother-child interaction, father-child interaction, maternal personality, and adolescent diagnoses of personality disorders were measured on two occasions, 2.5 years apart, in a random sample of 776 adolescents.Maternal inconsistency in upbringing of the child predicted a persistence or an emergence of borderline personality disorder, but not of any other axis II disorder. However, this effect occurred only in the presence of high maternal overinvolvement. Neither maternal overinvolvement nor maternal inconsistency alone predicted emergence of borderline personality disorder. Pathological features of maternal personality did not account for the combined effect of maternal overinvolvement and inconsistency on borderline personality disorder.The two child-rearing risk factors hypothesized to be important by two psychodynamic models of borderline personality disorder were found to be pathogenic only when they coexisted. Their effect could not be accounted for by the biological or environmental vulnerability represented by maternal borderline personality traits.
THE INTERNAL ENVIRONMENT AND BEHAVIOR
Authors: NATHAN W. SHOCK
Journal: American Journal of Psychiatry (1941)

Considering the experimental results obtained it is evident that all too often we must rely on rather casual observations, and that the number of experiments planned to determine relationship between behavior and shifts in acid-base equilibrium is relatively few. However, from the literature we can see that extensive dis-placement in any direction from the normal area will result in impaired mental function and loss of consciousness, although few quantitative measurements of mental functions or behavior are available. However, certain facilitative reactions may be discovered when acid-base equilibrium is displaced within physiological limits. Slight increases in pH and decrease in CO2 tension tend to increase motor reactivity to stimuli, particularly at the reflex level, but to decrease functions involving higher levels of the central nervous system. On the other hand, a slight decrease in pH or increase in CO2 tension may have a facilitative response to a small extent. It is possible that these effects may be due to vaso-motor changes in the cerebral cortex, although proof is still lacking. No data on the effects of changes in bicarbonate content of blood on behavior are available. With the exception of the experiments on cerebral stimulation in schizophrenia from high CO2 tension, all the results tend to indicate impairment of function rather than facilitation when the acid-base equilibrium is displaced. The consideration of the possible mechanisms of action indicate the complexity and interrelationship between a variety of variables ranging from ionic strength to shifts in water. In order to obtain a conception of the effects of alterations in acid-base equilibrium on behavior it is obvious that many experiments will need to be performed in which the wide range of variables are measured simultaneously. Even though it may be impossible to control each factor independently by experimental technique, it may be possible to submit the observational data to analysis by other methods.
Final results of a randomized phase III study evaluating the addition of oxaliplatin first line to 5-FU followed by irinotecan at progression in advanced colorectal cancer (LIFE study)
Authors: A. Pluzanska, P. Mainwaring, J. Cassidy, B. Utracka-Hutka, J. Zalucki, R. Glynne-Jones, P. Koralewski, J. Bridgewater, H. Wasan, D. Cunningham
Journal: Journal of Clinical Oncology (2005)

3517 Background: The LIFE study was designed to demonstrate a 10% absolute improvement in survival at 2 years (from 20 to 30%), with the addition of oxaliplatin in first line to the 5-FU followed by irinotecan sequence in advanced colorectal cancer (ACRC). Method: A total of 725 ACRC patients from UK (46%), Poland (39%), other countries (15%), were randomized from March 2001 to March 2002 to receive 5-FU monotherapy (Lockich or de Gramont regimens) or the same regimen plus oxaliplatin 85mg/m2, repeated every 2 weeks. Second line therapy was standardized with irinotecan 350 mg/m2 single agent repeated every 3 weeks, in both arms. Results: Patients’characteristics were well balanced except for metastatic sites (liver + other in 88% versus 76% of patients receiving oxaliplatin/5FU or 5FU respectively). Safety results are in line with the safety profiles of the drugs, without any unexpected toxicities (Cassidy, ASCO 2003). Median number of cycles (10) was the same in both arms, with a higher dose of 5-FU in the control arm. Median cumulative dose of oxaliplatin was 845 mg/m2. Relative oxaliplatin dose intensity was 87%. Direct efficacy evaluation of the first line treatment showed improvement in response rate -RR- (54% versus 30%, p< 0.0001) and progression free survival -PFS- (7.9 versus 5.9 months, p <0.0001) in the oxaliplatin arm in accordance with previously reported trials. This did not translate into overall survival advantage (15.9 versus 15.2 months) with a median in the oxaliplatin arm below the 19–20 months obtained in more recent studies. Conclusion: These results confirm the improvement in RR and PFS observed with combination therapy in first line ACRC. Overall survival results could be explained by the low number of patients receiving second line irinotecan therapy in the oxaliplatin arm (41%) and thus exposed to the 3 active agents: 5-FU, oxaliplatin and irinotecan. No significant financial relationships to disclose.
A novel method for mutation analyses using genomic DNA obtained from IHC-stained sections
Authors: Rupal Desai, Lukas Amler, Rajesh Patel, Howard Stern, Rajiv Raja
Journal: Clinical Cancer Research (2010)

Abstract Biopsies obtained from patients are often limited in size. The ability to perform multiple diagnostic assays is dependent on the quantity and quality of tissue samples available from patients. Over the last few years, our laboratory has focused our efforts on developing novel methodologies for increased efficiency in use of tissue samples. Here we describe a method for performing immunohistochemistry (IHC) and genotyping using the same tissue section. We isolated genomic DNA (gDNA) from IHC-stained and unstained formalin-fixed paraffin-embedded (FFPE) tissue sections obtained from the same paraffin block. Quality and quantity of gDNA obtained from either section were compared. We demonstrate that quality of gDNA obtained is acceptable for down-stream analysis using PCR techniques. We also show comparable specificity and sensitivity in detecting mutations using either sources of gDNA. This method has proven highly valuable in performing mutation analysis in certain tissue types such as lung cancer where tissue can be extremely limited.
Assessment of ventilation heterogeneity by impulse oscillometry in patients with mild asthma
Authors: Gakuya Tamagaki, Hiroshi Kanazawa, Yukari Kon, Naoko Yoshii, Yukikazu Ichimaru, Kazuhisa Asai, Yoshihiro Tochino, Kazuto Hirata
Journal: European Respiratory Journal (2012)

Ventilation heterogeneity is an independent determinant of airway hyperresponsiveness (AHR) in asthma, and its measurement is complex and technically difficult. Impulse oscillometry (IOS) is increasingly used to obtain information on the state of the respiratory system. In this study, we determined the clinical validity of IOS as a novel and simple method for the assessment of ventilation heterogeneity in asthma.

Serial measurement of resistance at 5 Hz (R5) or 20 Hz (R20) by IOS was performed in 23 mild asthmatic patients and 28 normal control subjects; the measurements were made at baseline, after methacholine (maximal dose) provocation test for asthma and subsequent salbutamol administration. Further, exhaled nitric oxide (eNO) levels were examined and pulmonary function test was also performed.

The baseline R5, but not R20, was significantly higher in asthmatic patients than in controls. Both R5 and R20 were not significantly correlated with the degree of airway obstruction and eNO levels. However, R5 was significantly correlated with the severity of AHR (r = -0.55, P = 0.01), whereas R20 was not. The change in forced expiratory volume in 1 s (FEV1) (mean, 30%) after methacholine challenge was almost similar to the change in R20 (20%). However, the change in R5 (77%) after methacholine challenge was significantly greater than the change in FEV1, and this finding is consistent with its greater sensitivity to airway dilated responses after salbutamol administration.

The proportional change in R5 after methacholine and salbutamol administration is attributable to variable small airway functions, suggesting that R5 may potentially represent ventilation heterogeneity in asthma patients.