Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance

Women with late-stage ovarian cancer usually develop chemotherapeutic-resistant recurrence. It has been theorized that a rare cancer stem cell, which is responsible for the growth and maintenance of the tumor, is also resistant to conventional chemotherapeutics. We have isolated from multiple ovarian cancer cell lines an ovarian cancer stem cell-enriched population marked by CD44, CD24, and Epcam (3+) and by negative selection for Ecadherin (Ecad-) that comprises less than 1% of cancer cells and has increased colony formation and shorter tumor-free intervals in vivo after limiting dilution. Surprisingly, these cells are not only resistant to chemotherapeutics such as doxorubicin, but also are stimulated by it, as evidenced by the significantly increased number of colonies in treated 3+Ecad- cells. Similarly, proliferation of the 3+Ecad- cells in monolayer increased with treatment, by either doxorubicin or cisplatin, compared with the unseparated or cancer stem cell-depleted 3-Ecad+ cells. However, these cells are sensitive to Mullerian inhibiting substance (MIS), which decreased colony formation. MIS inhibits ovarian cancer cells by inducing G1 arrest of the 3+Ecad- subpopulation through the induction of cyclin-dependent kinase inhibitors. 3+Ecad- cells selectively expressed LIN28, which colocalized by immunofluorescence with the 3+ cancer stem cell markers in the human ovarian carcinoma cell line, OVCAR-5, and is also highly expressed in transgenic murine models of ovarian cancer and in other human ovarian cancer cell lines. These results suggest that chemotherapeutics may be stimulative to cancer stem cells and that selective inhibition of these cells by treating with MIS or targeting LIN28 should be considered in the development of therapeutics.     

Minimal Neuropsychological Assessment of MS Patients: A Consensus Approach

Cognitive impairment is common in multiple sclerosis (MS), yet patients seen in MS clinics and neurologic practices are not routinely assessed neuropsychologically. In part, poor utilization of NP services may be attributed to a lack of consensus among neuropsychologists regarding the optimal approach for evaluating MS patients. An expert panel composed of neuropsychologists and psychologists from the United States, Canada, United Kingdom, and Australia was convened by the Consortium of MS Centers (CMSC) in April, 2001. Our objectives were to: (a) propose a minimal neuropsychological (NP) examination for clinical monitoring of MS patients and research, and (b) identify strategies for improving NP assessment of MS patients in the future. The panel reviewed pertinent literature on MS-related cognitive dysfunction, considered psychometric factors relevant to NP assessment, defined the purpose and optimal characteristics of a minimal NP examination in MS, and rated the psychometric and practical properties of 36 candidate NP measures based on available literature. A 90-minute NP battery, the Minimal Assessment of Cognitive Function in MS (MACFIMS), emerged from this discussion. The MACFIMS is composed of seven neuropsychological tests, covering five cognitive domains commonly impaired in MS (processing speed/working memory, learning and memory, executive function, visual-spatial processing, and word retrieval). It is supplemented by a measure of estimated premorbid cognitive ability. Recommendations for assessing other factors that may potentially confound interpretation of NP data (e.g., visual/sensory/motor impairment, fatigue, and depression) are offered, as well as strategies for improving NP assessment of MS patients in the future.     

Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism

In recent years, the central nervous system (CNS) has emerged as a principal site of insulin action. This notion is supported by studies in animals relying on intracerebroventricular insulin infusion and by experiments in humans that make use of the intranasal pathway of insulin administration to the brain. Employing neurobehavioural and metabolic measurements as well as functional imaging techniques, these studies have provided insight into a broad range of central and peripheral effects of brain insulin. The present review focuses on CNS effects of insulin administered via the intranasal route on cognition, in particular memory function, and whole-body energy homeostasis including glucose metabolism. Furthermore, evidence is reviewed that suggests a pathophysiological role of impaired brain insulin signaling in obesity and type 2 diabetes, which are hallmarked by peripheral and possibly central nervous insulin resistance, as well as in conditions such as Alzheimer's disease where CNS insulin resistance might contribute to cognitive dysfunction.     

Free Health Care for Under 5 Year Olds Increases Access to Surgical Care in Sierra Leone: An Analysis of Case Load and Patient Characteristics

Background

In April 2010 Sierra Leone launched a nationwide program that provides free health care to all pregnant and lactating women and children under 5 years old. This study evaluates the effect that the free health-care program had on pediatric surgical activities of Connaught Hospital.

Methods

The study period was defined as the 20 months before and after April 27, 2010, the start date of the free health-care program. Data on age, gender, diagnosis, and procedure for patients under 5 years of age and the total number of operations were collected from the Connaught Hospital operating room logbook.

Results

The number of operations on children under 5 increased by 500 %, from 42 to 210 cases. This increase was significantly larger than the 17 % increase of 1,393–1,630 seen with operations for patients 5 years and older (p < 0·01).

Conclusion

The decision by the Sierra Leone President to institute a program of free health care for children under 5 has resulted in an increased number of pediatric surgical cases at Connaught Hospital. Efforts should be undertaken to provide additional supplies and equipment and to develop training programs for surgeons and support staff to care for the children in need of surgical care.     

Endolumenal colon occlusion device for transanal and transrectal surgery—a porcine feasibility study

Purpose

Although several studies have demonstrated the feasibility of transrectal natural orifice translumenal endoscopic surgery (NOTES), its clinical application has been hindered by concerns regarding potential infectious complications. The aim of this study was to evaluate the feasibility of a newly developed device for endolumenal colon occlusion (ColoShield) in an acute porcine model.

Methods

The principle of the ColoShield device is based on two balloons, with negative pressure in between. The ColoShield device and a gauze tamponade as a control group were evaluated in a non-survival study on 16 pigs. The efficacy of the occlusion system in establishing a leak-proof pneumorectum and in sealing the colon from proximal (watertight sealing) was tested by a standardized study course. Finally, the colon/rectum was explanted for macroscopic and microscopic examination.

Results

A 20-mmHg leak-proof pneumorectum over a period of 10 min could be achieved in seven of eight (87 %) animals with the ColoShield device and in none of eight (0 %) animals with gauze tamponade (p?<?0.001). In the watertight sealing test, mean intracolonic pressures of 23.5?±?18.1 (0–53) mmHg using the ColoShield device and 0?±?1.1 (0–3) mmHg using gauze tamponade (p?=?0.003) were documented proximal to the occlusion system before a leakage occurred. Macroscopic and histopathological examinations revealed no significant impairment of the colon specimen in either group.

Conclusions

ColoShield proved to be a safe and effective device for a reversible endolumenal colon occlusion. Further studies should evaluate its impact on procedural sterility during transrectal NOTES.     

Treatment of cognitive impairment in multiple sclerosis: position paper

Cognitive impairment in multiple sclerosis (MS) is common, debilitating and burdensome. Key evidence from trials was reviewed to enable recommendations to be made to guide clinical practice and research. Behavioural and pharmacological interventions on cognition reported in published studies were reviewed. Most studies evaluating behavioural treatment for impairment in learning and memory, deficits of attention and executive function have demonstrated some improvement. Controlled studies in relapsing remitting MS indicate interferon (IFN) β-1b and IFN β-1a were associated with modest cognitive improvement. The effects of symptomatic therapies such as modafinil and donepezil are inconsistent. Most studies yielding positive findings have significant methodological difficulties limiting the confidence in making any broad treatment recommendations. There are no published reports of glatiramer acetate, natalizumab and fingolimod being effective in improving cognition in controlled trials. The effects of disease modifying therapies in other forms of MS and clinically isolated syndrome have not yielded positive results. Data linking behavioural therapy, symptomatic treatment or disease modifying treatment, to either reducing cognitive decline or improving impaired cognition are limited and inconsistent. The treatment and prevention of cognitive impairment needs to remain a key research focus, identifying new interventions and improving clinical trial methodology.     

Rating a Sports Medicine Surgeon’s “Quality” in the Modern Era: an Analysis of Popular Physician Online Rating Websites

Background

Consumer-driven healthcare and an increasing emphasis on quality metrics have encouraged patient engagement in the rating of healthcare. As such, online physician rating websites have become mainstream and may play a potential role in future healthcare policy.

Questions/Purposes

The purpose of this study was to evaluate online patient ratings for US sports medicine surgeons, determine predictors of positive ratings and analyze for inter-website scoring correlation.

Methods

The American Orthopedic Society for Sports Medicine (AOSSM) member directory was sampled. Surgeon demographic and rating data were searched on three online physicians rating websites: HealthGrades.com (HG), RateMDs.com (RM) and Vitals.com (V). Written rating comments were categorized as relating to the following: surgeon competence, surgeon affability and process of care. Bivariate linear regression, Pearson correlation and multivariable analyses were used to determine factors associated with positive ratings.

Results

Two hundred seventy-five sports medicine surgeons were included. Two hundred seventy-one (99%) had ratings on at least one of the three websites. Sports surgeons were rated highly across all three websites (mean >4.0/5); however, there was only a low to moderate degree of correlation among websites. On HG, female surgeons and surgeons in academia were more likely to receive higher overall ratings. Across all three websites, increased number of years in practice inversely correlated with ratings; this relationship neared significance for HG and was significant for RM. A surgeon’s online presence or geographic location was not associated with higher ratings. In multivariable regression analysis for ratings on HG, female sex was the only significant predictor of higher ratings. Two thousand three hundred forty-one written comments were analyzed: perceived surgeon competence and communication influenced the direction of ratings for the top and bottom tier surgeons.

Conclusion

There was a low degree of correlation among online websites for surgeon ratings. Female surgeons and those with fewer years in practice appear to have higher ratings on these websites; comment content analysis suggests that high and low ratings are influenced by perceived surgeon competence and affability.