Prediagnostic blood levels of organochlorines and risk of non-Hodgkin lymphoma in three prospective cohorts in China and Singapore

Specific organochlorines (OCs) have been associated with non-Hodgkin lymphoma (NHL) with varying degrees of evidence. These associations have not been evaluated in Asia, where the high exposure and historical environmental contamination of certain OC pesticides (e.g., dichlorodiphenyltrichloroethane [DDT], hexachlorocyclohexane [HCH]) are different from Western populations. We evaluated NHL risk and prediagnostic blood levels of OC pesticides/metabolites and polychlorinated biphenyl congeners in a case–control study of 167 NHL cases and 167 controls nested within three prospective cohorts in Shanghai and Singapore. Conditional logistic regression was used to analyze lipid-adjusted OC levels and NHL risk. Median levels of p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE), the primary DDT metabolite, and β-HCH were up to 12 and 65 times higher, respectively, in samples from the Asian cohorts compared to several cohorts in the United States and Norway. An increased risk of NHL was observed among those with higher β-HCH levels both overall (3rd vs. 1st tertile OR = 1.8, 95%CI = 1.0–3.2; p_trend = 0.049) and after excluding cases diagnosed within 2 years of blood collection (3rd vs. 1st tertile OR = 2.0, 95%CI = 1.1–3.9; p_trend = 0.03), and the association was highly consistent across the three cohorts. No significant associations were observed for other OCs, including p,p′-DDE. Our findings provide support for an association between β-HCH blood levels and NHL risk. This is a concern because substantial quantities of persistent, toxic residues of HCH are present in the environment worldwide. Although there is some evidence that DDT is associated with NHL, our findings for p,p′-DDE do not support an association.     

Use of oral and topical agents for acne in pregnancy

Dermatologists frequently are consulted by a pregnant patient or a woman of childbearing age who desires acne therapy. Because there are no published studies in which women took acne medications throughout pregnancy, information about safety must be obtained indirectly from studies in which the agents were taken for another indication during some portion of pregnancy. Oral tetracycline is associated with maternal liver toxicity and deciduous tooth staining in the infant, and tetracycline occasionally has been associated with other congenital anomalies. Maternal isotretinoin ingestion is associated with major craniofacial and cardiac deformities, as well as other congenital anomalies. Erythromycin, however, appears to be safe. Topical acne medications never have been implicated as a cause of fetal deformities in human beings. Dermatologists should be aware of potential toxic and teratogenic effects of acne medicines before prescribing them to women of childbearing age. Prompt reporting of adverse effects is encouraged.     

Clinical and roentgenographic evaluation of hydroxyapatite-augmented and nonaugmented porous total hip arthroplasty

Sixty osteoarthritic patients undergoing primary, uncemented total hip arthroplasty were matched for age and weight and randomized into one of four groups with respect to implant coating and postoperative, protected weight-bearing status: group 1, hydroxyapatite-augmented, 12 weeks; group 2, nonaugmented, 12 weeks; group 3, hydroxyapatite-augmented, 6 weeks; and group 4, nonaugmented, 6 weeks. Tantalum spheres were implanted periprosthetically into the femur at the time of the arthroplasty, thus providing constant references for stereoscopic radiographs. Patients were then evaluated over a 2-year period with clinical examination, plain radiography, and roentgen stereophotogrammetric analysis. Clinical evaluation using the Charnley scoring system showed no significant preoperative or postoperative intergroup differences, whereas visual analog testing noted less thigh pain with hydroxyapatite-augmented stems at the 12-week and 6-month follow-up evaluations. Plain radiographic analysis produced no significant differences, with no instability detected, and bony ingrowth was uniform in all groups. Stereographic evaluation showed migration in all groups, but there were no significant differences between the augmented and non-augmented stems or the 6-week and 12-week partial weight-bearing protocols. Charnley, plain radiographic, and stereogrammetric evaluations all suggest that migration is unaltered by enhanced surfaces and early, unprotected weight bearing does not jeopardize implant fixation regardless of coating design. The lower incidence of visual analog thigh pain with the hydroxyapatite-augmented stems, however, may be a reflection of bony ingrowth and, as such, add some validity to the theoretic advantages of enhanced surface prostheses.     

Anatomic analysis of pedicle cortical and cancellous diameter as related to screw size

The effective thoracic and lumbar pedicle diameter as related to screw size for that pedicle was studied in six fresh-frozen human cadaver spines. Measurements of the pedicle were obtained before screw insertion using axial and coronal reformatted computed tomographic (CT) images, as well as graduated sounding of the pedicle. After sequentially loading each pedicle with increasingly larger screws, measurements were taken of the outer cortical diameters. Plastic deformation of the pedicle preceded pedicle fracture or cutout when the screw thread diameter became larger than the endosteal diameter or within 80% of the outer cortical diameter as measured from the CT scan. Pedicle screws did not obtain cortical purchase within the pedicle.     

Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells

An attractive target for therapeutic intervention is constitutively activated, mutant FLT3, which is expressed in a subpopulation of patients with acute myelocyic leukemia (AML) and is generally a poor prognostic indicator in patients under the age of 65 years. PKC412 is one of several mutant FLT3 inhibitors that is undergoing clinical testing, and which is currently in late-stage clinical trials. However, the discovery of drug-resistant leukemic blast cells in PKC412-treated patients with AML has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to override drug resistance. Here, we report the potent and selective antiproliferative effects of the novel mutant FLT3 inhibitor NVP-AST487 on primary patient cells and cell lines expressing FLT3-ITD or FLT3 kinase domain point mutants. NVP-AST487, which selectively targets mutant FLT3 protein kinase activity, is also shown to override PKC412 resistance in vitro, and has significant antileukemic activity in an in vivo model of FLT3-ITD(+) leukemia. Finally, the combination of NVP-AST487 with standard chemotherapeutic agents leads to enhanced inhibition of proliferation of mutant FLT3-expressing cells. Thus, we present a novel class of FLT3 inhibitors that displays high selectivity and potency toward FLT3 as a molecular target, and which could potentially be used to override drug resistance in AML.     

A resident Golgi protein is excluded from peri-Golgi vesicles in NRK cells

To understand the structure and the function of the Golgi apparatus, it is essential to establish how resident Golgi enzymes are localized in only a few Golgi cisternae. In particular it is crucial to establish whether Golgi enzymes are retained specifically in cisternae, or if they are continuously transported from cisterna to cisterna. Here we report that a resident Golgi enzyme is largely excluded from peri-Golgi transport vesicles in normal rat kidney cells, a cell type in which conflicting results have been reported. Analysis of the lateral distribution of two markers within Golgi cisternae led to the same conclusion: a protein incorporated in vesicles (KDEL receptor) is concentrated at the rims of cisternae where vesicles form, while mannosidase II is not. These results suggest that localization of resident Golgi enzymes is achieved primarily by selective retention within cisternae and exclusion from transport vesicles. These observations cannot easily be reconciled with the vision of rapidly maturing Golgi cisternae as the principal means of intra-Golgi transport.     

A randomized trial of a primary care-based disease management program to improve cardiovascular risk factors and glycated hemoglobin levels in patients with diabetes

PURPOSE: To assess the efficacy of a pharmacist-led, primary care-based, disease management program to improve cardiovascular risk factors and glycated hemoglobin (A(1C)) levels in vulnerable patients with poorly controlled diabetes. METHODS: A randomized controlled trial of 217 patients with type 2 diabetes and poor glycemic control (A(1C) level >or=8.0%) was conducted at an academic general medicine practice from February 2001 to April 2003. Intervention patients received intensive management from clinical pharmacists, as well as from a diabetes care coordinator who provided diabetes education, applied algorithms for managing glucose control and decreasing cardiovascular risk factors, and addressed barriers to care. Control patients received a one-time management session from a pharmacist followed by usual care from their primary care provider. Outcomes were recorded at baseline and at 6 and 12 months. Primary outcomes included blood pressure, A(1C) level, cholesterol level, and aspirin use. Secondary outcomes included diabetes knowledge, satisfaction, use of clinical services, and adverse events. RESULTS: For the 194 patients (89%) with 12-month data, the intervention group had significantly greater improvement than did the control group for systolic blood pressure (-9 mm Hg; 95% confidence interval [CI]: -16 to -3 mm Hg) and A(1C) level (-0.8%; 95% CI: -1.7% to 0%). Change in total cholesterol level was not significant. At 12 months, aspirin use was 91% in the intervention group versus 58% among controls (P <0.0001). Intervention patients had greater improvements in diabetes knowledge and satisfaction than did control patients. There were no significant differences in use of clinical services or adverse events. CONCLUSION: Our comprehensive disease management program reduced cardiovascular risk factors and A(1C) levels among vulnerable patients with type 2 diabetes and poor glycemic control.