Optimizing Glioblastoma Temozolomide Chemotherapy Employing Lentiviral-based Anti-MGMT shRNA Technology

Despite treatments combining surgery, radiation-, and chemotherapy, patients affected by glioblastoma (GBM) have a limited prognosis. Addition of temozolomide (TMZ) to radiation therapy is the standard therapy in clinical application, but effectiveness of TMZ is limited by the tumor''s overexpression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). The goal of this study was to use the highly specific and efficient RNA interference (RNAi) pathway to modulate MGMT expression to increase TMZ efficiency in chemotherapy resistant GBM. Using lentiviral-based anti-MGMT small hairpin RNA (shRNA) technology we observed a specific inhibition of the MGMT expression in GBM cell lines as well as in subcutaneous tumors. Tumor growth inhibition was observed following TMZ treatment of xenografts with low MGMT expression in contrast to xenografts with high MGMT expression. Bioluminescence imaging (BLI) measurements indicated that luciferase and shRNA-expressing lentiviruses were able to efficiently transduce the GBM xenografts in vivo. Treatment combining injection of a lentivirus expressing an anti-MGMT shRNA and TMZ induced a reduction of the size of the tumors, in contrast with treatment combining the lentivirus expressing the control shRNA and TMZ. Our data suggest that anti-MGMT shRNA therapy could be used in combination with TMZ chemotherapy in order to improve the treatment of resistant GBM.     

Chronic pancreatitis and extrapancreatic cancer A retrospective study among 181 patients with chronic pancreatitis

Summary The relationship between chronic pancreatitis (CP) and extrapancreatic cancer has been debated in the recent years. In prospective studies, it has been found that pancreatic cancer develops in 0–5% of patients with chronic pancreatitis. Many papers describe an increased relative risk for developing extrapancreatic cancer in patients suffering from chronic pancreatitis. In this study including 181 patients with CP, we found 14 patients with extrapancreatic cancer (three of these had two different types of cancer). No patient had pancreatic cancer. It was found that the respiratory airways and upper gastrointestinal tract were the dominating locations (five and four cases, respectively), but also genital and hemolymphopoietic cancers were represented (four and two cases, respectively). Two patients had metastatic cancer with unknown primary tumor. The patients with cancer tended to be older than those without cancer. The patients with CP had a 2.43 times greater risk of developing cancer than the general Danish population (age and sex standardized comparison). The relatively large number of cancers in the upper gastrointestinal tract and respiratory airways suggest that tobacco and alcohol may be responsible, as these organs have the highest exposure to these compounds, which are well known carcinogens.     

Pressure on Sports Medicine Clinicians to Prematurely Return Collegiate Athletes to Play After Concussion

Context

 Anecdotal and qualitative evidence has suggested that some clinicians face pressure from coaches and other personnel in the athletic environment to prematurely return athletes to participation after a concussion. This type of pressure potentially can result in compromised patient care.

Objective

 To quantify the extent to which clinicians in the collegiate sports medicine environment experience pressure when caring for concussed athletes and whether this pressure varies by the supervisory structure of the institution''s sports medicine department, the clinician''s sex, and other factors.

Design

 Cross-sectional study.

Setting

 Web-based survey of National College Athletic Association member institutions.

Patients or Other Participants

 A total of 789 athletic trainers and 111 team physicians from 530 institutions.

Main Outcome Measure(s)

 We asked participants whether they had experienced pressure from 3 stakeholder populations (other clinicians, coaches, athletes) to prematurely return athletes to participation after a concussion. Modifying variables that we assessed were the position (athletic trainer, physician) and sex of the clinicians, the supervisory structure of their institutions'' sports medicine departments, and the division of competition in which their institutions participate.

Results

 We observed that 64.4% (n = 580) of responding clinicians reported having experienced pressure from athletes to prematurely clear them to return to participation after a concussion, and 53.7% (n = 483) reported having experienced this pressure from coaches. Only 6.6% (n = 59) reported having experienced pressure from other clinicians to prematurely clear an athlete to return to participation after a concussion. Clinicians reported greater pressure from coaches when their departments were under the supervisory purview of the athletic department rather than a medical institution. Female clinicians reported greater pressure from coaches than male clinicians did.

Conclusions

 Most clinicians reported experiencing pressure to prematurely return athletes to participation after a concussion. Identifying factors that are associated with variability in pressure on clinicians during concussion recovery can inform potential future strategies to reduce these pressures.Key Words: conflict of interest, organizational structure, sex, college

Key Points

• More than half of sports medicine clinicians had experienced pressure from coaches and athletes to return athletes to participation prematurely after a concussion.
• Clinicians experienced greater pressure from coaches at schools where the sports medicine department reported to the athletic department than at schools where the sports medicine department reported to an independent medical institution.
• Female clinicians experienced greater pressure from coaches than male clinicians experienced.
• More research is needed to determine how pressure affects clinical practice and whether pressure on clinicians affects return-to-participation decisions.

Addressing the health burden of mild traumatic brain injury from sport is increasingly considered a public health priority.¹ More than 450 000 college students participate in organized interscholastic sports each year.^2,3 Among collegiate athletes in contact and collision sports, Daneshvar et al⁴ estimated that 43 concussions are sustained per 100 000 athlete-exposures to a game or practice, which is nearly twice the rate of diagnosed concussions sustained by high school athletes competing in the same sports. This estimate likely understates the true incidence of concussions because many are undiagnosed.^5–8 Recent evidence^9–14 has suggested that repeated concussive and subconcussive brain trauma can lead to neurologic problems later in life, including changes in cognition and behavior.Conflict of interest in the care of concussed athletes is a topic of growing ethical discourse.^15–19 Writing for the Chronicle of Higher Education about US collegiate sport, Wolverton²⁰ painted a picture of colleges fraught with pressure on physicians and athletic trainers (ATs) from coaches and athletic administrators. A total of 101 clinicians who provide patient care for football teams in the National Collegiate Athletic Association (NCAA) Division I Football Bowl Subdivision participated in the non–peer-reviewed study, and more than half reported that they had “felt pressure from football coaches to return concussed players to action before they were medically ready.”²⁰ Some of this pressure was attributed to conflicts of interest inherent in the organizational structure and incentives of sports medicine departments. In some instances, ATs reported directly to head football coaches.²⁰ Even in substantially lower-stakes youth sports, Bramley et al²¹ reported that a sample of hockey coaches indicated they would be more likely to allow an athlete who had sustained a concussion to continue participating if the game was considered important, such as for a championship. Consequently, clinicians in collegiate sports medicine departments may find themselves in a challenging situation: having ethical responsibilities to provide appropriate medical care to their patients while facing perceived or real pressure from their employers to return athletes to participation.^15–19,22 In a survey of sports medicine physicians in New Zealand, Anderson and Gerrard²³ observed that whereas all respondents expressed a sense of responsibility to their athlete patients, 72% also believed they had a responsibility to the team coach, and 55% believed they had a responsibility to team management.The National Athletic Trainers'' Association recently released a consensus statement detailing best practices for sports medicine management in secondary schools and colleges, including the advantages and disadvantages of different models of supervisory relationships in sports medicine.²⁴ Supervisory models in which ATs or team physicians are employed by athletic departments are described as having the potential for conflict of interest in the medical care provided to athletes. Pecci and Laursen²⁵ and Laursen²⁶ have advocated for sports medicine departments to be nested within medical units, such as university health centers, rather than athletic departments. They suggested that this organizational structure would reduce real and perceived conflicts of interest in the care of athletes and would have additional benefits, such as easier access to other health care providers and more centralized oversight of medical care.^25,26 Whereas these arguments are intuitive, no researchers have conducted an empirical evaluation of whether supervisory structure is systematically associated with different types of pressure on clinicians regarding the care of collegiate athletes who have sustained concussions.Another potentially important variable that could modify the pressure that clinicians experience is their sex. Approximately half of all ATs are women, but women represent only about one-quarter of full-time staff ATs and only 1 in 8 head ATs in collegiate sports medicine departments.^27–30 Some investigators³¹ have suggested that male and female ATs may have different experiences interacting with coaches and other ATs in the collegiate athletic environment. Mazerolle et al³¹ conducted qualitative interviews with 14 female NCAA Division I ATs and described how they “often encountered gender discrimination when working with a team sport coached by a man.” They described a perception that coaches view female ATs as “more sympathetic and less pragmatic” than male ATs and that this judgment undermines the coaches'' confidence in the care they provide athletes. This differential perception is reinforced by 2 surveys^32,33 in which male collegiate athletes reported being more comfortable receiving care from male ATs. Stereotypical judgments about women in the workplace tend to be strongest when women are an underrepresented minority, as is the case with female ATs in collegiate sports environments, and can inform the control strategies of individuals in positions of power.³⁴ Quantifying the extent to which pressure is experienced in the care of concussed athletes and whether it is modified by clinician characteristics such as sex are important steps in understanding whether institution-level intervention is needed.Therefore, the purpose of our study was to obtain empirical evidence about whether clinicians who provide care to US collegiate sports teams experienced pressure to prematurely clear athletes for participation after a concussion. We hypothesized that clinicians in sports medicine departments reporting to the athletic department would experience greater pressure from coaches and athletes than clinicians in departments reporting to medical institutions and that female clinicians would experience greater pressure from coaches and athletes than male clinicians would experience.     

Upper respiratory tract infections in general practice: diagnosis,antibiotic prescribing,duration of symptoms and use of diagnostic tests

A diagnosis/antibiotic prescribing study was performed in 5 counties in Sweden for 1 week in November 2000. As part of this study, the characteristics and clinical management of patients with upper respiratory tract infections (n = 2899) in primary care were analyzed. Almost half of the patients were aged < 15 y and one-fifth of the patients consulted out of hours. Of all patients seeking primary care for upper respiratory tract infections, 56.0% were prescribed an antibiotic. Almost all patients who were given the diagnoses streptococcal tonsillitis, acute otitis media or acute sinusitis were prescribed antibiotics, compared to 10% of patients with common cold or acute pharyngitis. The most frequently prescribed antibiotic was penicillin V (79.2%) and this was even more pronounced out of hours, when the diagnoses otitis media and streptococcal tonsillitis were more frequently used. In patients with common cold and acute pharyngitis, the percentage who received antibiotics increased with increasing length of symptoms and increasing CRP levels. In patients with acute pharyngitis or streptococcal tonsillitis, antibiotics were prescribed less frequently provided streptococcal tests were performed. The management of patients with upper respiratory tract infections in general practice seems to be in good agreement with current Swedish guidelines. However, the study indicates some areas for improvement. The diagnosis of acute sinusitis seems to have been overestimated and used only to justify antibiotic treatment.     

Variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in the Framingham Heart Study

OBJECTIVE: To examine the association between variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in men and women. DESIGN: In 1780 unrelated members of the community-based Framingham Heart Study offspring cohort, systolic blood pressure and diastolic blood pressure were measured over a total of six examination cycles encompassing 24 years of follow-up. Multivariate regression analyses were used to assess the relation between untreated cross-sectional and longitudinal blood pressure and polymorphisms at the estrogen receptor-alpha (ESR1), estrogen receptor-beta (ESR2), aromatase (CYP19A1), and nuclear receptor coactivator 1 (NCOA1) genes after adjustment for common risk factors. RESULTS: In men, systolic blood pressure and pulse pressure (systolic blood pressure minus diastolic blood pressure) were associated with two polymorphisms in ESR1, while pulse pressure was also associated with variations in NCOA1 and CYP19A1. Polymorphisms in ESR1, CYP19A1, and NCOA1 were associated with diastolic blood pressure in women. CONCLUSIONS: Although the underlying relations between genes involved in estrogen action and hypertension remain to be completely understood, our findings provide suggestive evidence of gender-specific contributions of estrogen-related genes to blood pressure variation. As no correction for multiple testing was performed in the analyses, we view these results as suggestive and not definitive. Further studies are warranted to confirm these results using a comprehensive set of polymorphisms in order to shed more light on the involvement of estrogen in blood pressure regulation.     

Amount of systemic steroid medication is a strong predictor for the use of complementary and alternative medicine in patients with inflammatory bowel disease: results from a German national survey

OBJECTIVES: Previous studies have suggested that inflammatory bowel disease (IBD) patients rank high among users of complementary and alternative medicine (CAM). To further elucidate this phenomenon, we sent questionnaires to a large sample of IBD patients in Germany to determine the patterns and predictors of their CAM use. METHODS: Pretested 73-item questionnaires were mailed to a randomly selected representative sample of 1000 IBD patients from the approximately 16,000 members and associates of the German Crohn's and Colitis Association. Predictors of CAM use were evaluated by logistic regression models. RESULTS: Completed questionnaires were returned by 684 patients (female patients, 61.4%; Crohn's disease patients, 58.3%; ulcerative colitis patients, 38.2%). Of the 671 adult respondents, 344 (51.3%) had experience with CAM, and significantly more of the ulcerative colitis patients (59.8%) than the Crohn's disease patients (48.3%) had experience with CAM. There was no difference by gender. Homeopathy (52.9%) and herbal medicine (43.6%) were the most commonly used types of CAM. The most frequent personal reasons for CAM use were the search for an "optimum treatment" (78.9%) and the wish to stop taking steroids (63.8%). Using logistic regression, we found that total cortisone intake (P = 0.0077), but not duration of disease, was a strong predictor of CAM use. Other predictors were experience with psychosomatic and psychotherapeutic support (P = 0.0029), relaxation techniques (P = 0.0284), an academic education (P = 0.0173), a diet utilizing whole grains (P = 0.0123), and a normal body weight (P = 0.0215). Although 80% of patients indicated that they were interested in using CAM in the future, only 24.7% felt sufficiently informed about it. CONCLUSIONS: More than 50% of a large group of German IBD patients had used CAM. Prolonged or intensive steroid treatment, an academic education, active ways of coping, and a health-conscious life-style are associated with CAM use. Given the potential side effects and interactions, the treating physician should focus on thorough information about the benefits and limitations of conventional and complementary treatment options, especially for IBD patients who have received prolonged or intensive steroid treatment.     

Omeprazole 20 mg three days a week and 10 mg daily in prevention of duodenal ulcer relapse. Double-blind comparative trial

In a double-blind, parallel-group clinical trial of 195 patients with duodenal ulcers who after a short-term study had relief of pain and healed ulcers proved endoscopically, 65 were randomized to receive 20 mg omeprazole 3 days a week (once in the morning from Friday to Sunday), 64 to receive 10 mg omeprazole once daily in the morning, and 66 to receive placebo for up to 6 months. The patients underwent repeat endoscopy with biopsy of the gastric fundic mucosa (qualitative assessment of argyrophilic cell population), assessment of symptoms, and laboratory screening with measurement of basal serum gastrin concentrations at 3 and 6 months or more often if indicated by recurrence of symptoms. At 3 months, endoscopically proved ulcer relapse occurred in 16% receiving 20 mg omeprazole 3 days a week; 21% receiving 10 mg omeprazole daily; and 50% receiving placebo. At 6 months, corresponding rates were 23%, 27%, and 67% with 95% confidence intervals of difference between the placebo group and omeprazole groups of 28%-60% and 24%-56% (P less than 0.00001), respectively, and between omeprazole groups of -19%-11% (NS). No major clinical or laboratory side effects were noted. Thus both omeprazole regimens are effective and safe in preventing duodenal ulcer relapse.