The curious case of the 1960 Nobel Prize to Burnet and Medawar

The 1960 Nobel Prize was awarded to Macfarlane Burnet and Peter Medawar for immunological tolerance. The Nobel Archives reveal that the two were never nominated together by anyone; Burnet had repeatedly been nominated for his virology studies, and the Medawar group (including Rupert Billingham and Leslie Brent) had been nominated independently for their transplantation work. A review of the 1950s literature suggests that tolerance had not yet, by 1960, reached the level of acceptance and acclaim in the immunological community to appear to justify the award. Burnet probably should have received the Prize for his virus work, and perhaps also for his Clonal Selection Theory, whereas Billingham and Brent should have shared in a Prize with Medawar for transplantation. If a Prize were to be given for tolerance, most agree that Ray Owen should have shared in it, for his work on cattle chimerism. It is suggested that the 1960 Nobel Prize to Burnet and Medawar for immunological tolerance may have been given for the wrong reasons and to the wrong associates.     

Management of type 2 diabetes in youth: an update

Although type 1 diabetes historically has been more common in patients eight to 19 years of age, type 2 diabetes is emerging as an important disease in this group. Type 2 diabetes accounts for 8 to 45 percent of new childhood diabetes. This article is an update from the National Diabetes Education Program on the management of type 2 diabetes in youth. High-risk youths older than 10 years have a body mass index greater than the 85th percentile for age and sex plus two additional risk factors (i.e., family history, high-risk ethnicity, acanthosis nigricans, polycystic ovary syndrome, hypertension, or dyslipidemia). Reducing overweight and impaired glucose tolerance with increased physical activity and healthier eating habits may help prevent or delay the development of type 2 diabetes in high-risk youths. The American Academy of Pediatrics does not recommend population-based screening of high-risk youths; however, physicians should closely monitor these patients because early diagnosis may be beneficial. The American Diabetes Association recommends screening high-risk youths every two years with a fasting plasma glucose test. Patients diagnosed with diabetes should receive self-management education, behavior interventions to promote healthy eating and physical activity, appropriate therapy for hyperglycemia (usually metformin and insulin), and treatment of comorbidities.     

Elevating your breast program to the next level

This paper describes a series of steps taken to elevate the Hoag Breast Program to the next level. The hope is that some of our ideas will be useful to you and your breast program.     

Surgical delivery of drug releasing poly(lactic-co-glycolic acid)/poly(ethylene glycol) paste with in vivo effects against glioblastoma

Introduction

The median survival of patients with glioblastoma multiforme (astrocytoma grade 4) remains less than 18 months despite radical surgery, radiotherapy and systemic chemotherapy. Surgical implantation of chemotherapy eluting wafers into the resection cavity has been shown to improve length of survival but the current licensed therapy has several drawbacks. This paper investigates in vivo efficacy of a novel drug eluting paste in glioblastoma.

Methods

Poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) self-sintering paste was loaded with the chemotherapeutic agent etoposide and delivered surgically into partially resected tumours in a flank murine glioblastoma xenograft model.

Results

Surgical delivery of the paste was successful and practical, with no toxicity or surgical morbidity to the animals. The paste was retained in the tumour cavity, and preliminary results suggest a useful antitumour and antiangiogenic effect, particularly at higher doses. Bioluminescent imaging was not affected significantly by the presence of the paste in the tumour.

Conclusions

Chemotherapy loaded PLGA/PEG paste seems to be a promising technology capable of delivering active drugs into partially resected tumours. The preliminary results of this study suggest efficacy with no toxicity and will lead to larger scale efficacy studies in orthotopic glioblastoma models.     

Primary care physician PSA screening practices before and after the final U.S. Preventive Services Task Force recommendation

ObjectivesIn May 2012, United States Preventive Services Task Force (USPSTF) finalized its recommendation against prostate-specific antigen (PSA) screening in all men. We aimed to assess trends in PSA screening frequency amongst primary care physicians (PCPs) surrounding the May 2012 USPSTF recommendation.Methods and materialsThe electronic data warehouse was used to identify men aged between 40 and 79 years with no history of prostate cancer or urology visit who were evaluated by an internal medicine or family practice physician between 2007 and 2012. Analyses were directed toward PSA testing within 6-month time period from June to November, with particular focus on the 2011 (pre-USPSTF recommendation) and 2012 (post-USPSTF recommendation) cohorts. The primary outcome measure was proportion of men with at least 1 PSA test during the 6-month pre- and post-USPSTF recommendation periods.ResultsA total of 112,221 men met inclusion criteria. There was a significant decrease in screening frequency between the 2011 and 2012 cohorts (8.6% vs. 7.6%, P = 0.0001; adjusted odds ratio 0.89, 95% confidence interval 0.83–0.95). This decrease was most evident amongst patients aged 40 to 49 years (5.6% vs. 4.6%, P = 0.004) and 70 to 79 years (7.9% vs. 6.2%, P = 0.01). A significant decrease was also observed in patients with highest previous PSA value<1.0 (P<0.0001) and 1.0 to 2.49 ng/ml (P = 0.0074).ConclusionsSince the USPSTF recommendation was finalized, there is evidence of continuing decreases in PSA testing by PCPs. PCPs may be shifting toward more selective screening practices, as decreases in screening are most pronounced in the youngest and oldest patients and in those with history of PSA values<2.5 ng/ml.     

Proliferation and cytogenetic analysis of hairy cell leukemia upon stimulation via the CD40 antigen

Using the CD40 system, in vitro proliferation of hairy cell leukemia (HCL) was examined in 43 patients. In this culture system, cells were stimulated by interleukin-4 (IL-4) and anti-CD40 monoclonal antibodies (MoAbs) that were added in soluble form or were cross-linked via their Fc part using Fc gamma RII-transfected mouse fibroblast cells. Proliferation was induced and confirmed by 3H-thymidine incorporation in 14 cases and by the presence of metaphases in 42 cases. 3H-thymidine incorporation showed a heterogeneous pattern: cross-linking of anti- CD40 gave the highest proliferation in 8 cases; in 11 cases, stimulation with anti-CD40 MoAbs alone, without cross-linking also resulted in proliferation; the addition of IL-4 further enhanced 3H- thymidine incorporation in 5 cases, but suppressed this phenomenon in 5 other cases. The CD40 system proved to be very effective in obtaining cytogenetic data. With a success rate of 42 of 43 patients tested, we found clonal abnormalities in 8 cases (19%) and nonclonal abnormalities with involvement of one or two abnormal metaphases in another 7 cases. The chromosomes most frequently involved in the abnormal karyotypes, both structurally and numerically, were chromosomes 5, 7, and 14. By fluorescence-activated cell-sorting analysis of the cultured cells, and by immunophenotypic analysis of metaphase spreads, T-cell growth could be excluded and the HCL-lineage confirmed. Stimulation via the CD40 antigen is an excellent tool for growing hairy cell leukemia cells.     

Inhibition and complexation of activated protein C by two major inhibitors in plasma

To determine the major physiologic inhibitors of activated protein C (APC), plasma was incubated with APC or with Protac C and subjected to immunoblotting. APC:inhibitor complexes gave two major bands reacting with antiprotein C antibodies when immunoblotted on nondenaturing gels, and additional minor bands that varied between serum and plasma. Formation of one of the two major bands of APC:inhibitor complex, but not the other, was stimulated by heparin and only this band reacted with antibodies to the previously described APC inhibitor that is here designated PCI-1. Plasma immunodepleted of PCI-1 formed complexes with APC as visualized with antiprotein C but not anti-PCI-1 antibodies, and exhibited heparin-independent inhibition of APC activity, providing evidence for the existence of a second major physiologic APC inhibitor, PCI-2. Formation of APC:PCI-2 complexes in PCI-1-depleted plasma paralleled inhibition of APC amidolytic activity. PCI-2 was separated from PCI-1 and partially purified using column chromatography. PCI-2 formed inactive complexes of approximately 110,000 molecular weight (mol wt) with APC suggesting PCI-2 has an approximate mol wt of 50,000. Thus, inhibition of APC in plasma involves two major distinct 50,000 mol wt inhibitors, the heparin-dependent PCI-1 and the heparin- independent PCI-2.     

Grandmothers raising grandchildren: family structure and well-being in culturally diverse families

PURPOSE: This study addressed well-being of grandmothers raising grandchildren in coparenting and custodial households in a sample of African American, Latino, and White grandmothers. DESIGN AND METHODS: A sample of 1,058 grandmothers was recruited through the schools and media. Grandmothers raising or helping to raise school-aged grandchildren in Los Angeles were interviewed, and analyses were conducted within ethnic groups. RESULTS: African American grandmothers experienced equal well-being in coparenting and custodial families; however, if the stresses related to the parents' problems were removed by statistical control, they favored the custodial arrangement. Latino grandmothers had greater well-being in coparenting families, reflecting a tradition of intergenerational living. White custodial grandmothers experienced somewhat higher levels of affect (positive and negative) but showed no difference in other types of well-being. IMPLICATIONS: The cultural lens through which grandparenthood is viewed has a marked impact on the adaptation to custodial or coparenting family structures.