Methylphenidate transdermal system: clinical applications for attention-deficit/hyperactivity disorder

The methylphenidate transdermal system (MTS) provides a novel method of delivery for methylphenidate, a well-studied and effective medication for attention-deficit/hyperactivity disorder. The MTS achieves two major goals. First, the delivery system allows for administration throughout the day with a single patch, thus improving adherence. Second, it is the first approved attention-deficit/hyperactivity disorder medication that is not administered orally, thus bypassing gastrointestinal absorption and first-pass metabolism through the enteric circulation. In this article, we review the current data on MTS, including preclinical, clinical and post-marketing studies, and compare efficacy and tolerability to currently available treatments.     

Statistical positivity criteria for the analysis of ELISpot assay data in HIV-1 vaccine trials

The enzyme-linked immunospot (ELISpot) assay is one of the leading technologies used to measure cellular responses in many settings including HIV vaccine clinical trials. HIV-1-specific effector T lymphocyte responses are considered necessary in the control of infection. Accurate measurement and summary of cellular immune responses are critical to HIV research. ELISpot assay readout is often dichotomized into positive/negative responses according to some pre-specified criteria. Given the increase in the number of replicates used for each stimulation with current assay configurations in the HIV Vaccine Trials Network (HVTN) laboratories, a new approach is now possible. We propose an objective criteria based on a hypothesis-driven method that controls the false positive rate while maintaining sensitivity to each of the antigen-specific responses under study. The new approach is compared to other commonly employed criteria using real and simulated data.     

A mysterious case of normalising blood sugar: insulinoma in a long-standing diabetic patient

We report a case of recurrent hypoglycaemia in a long-standing type 2 diabetic patient, despite dramatic reduction in her anti-diabetic therapy. Subsequent investigations revealed an insulinoma as the cause. This patient was treated medically with diazoxide therapy, as multiple co-morbidities were felt to preclude surgical intervention. Although insulinoma is rare in the elderly and exceedingly rare in the context of type 2 diabetes, it should be given due consideration when no other exacerbating factor is found.     

TNP-470 fails to block the onset of angiogenesis and early tumor establishment in an intravital minimal disease model

BACKGROUND AND AIMS: The angiogenesis inhibitor TNP-470 (AGM-1470) has shown encouraging results in animal models of established tumors. However, results of recent clinical trials using TNP-470 have been disappointing. Since little is known about the effects of TNP-470 at the minimal disease stage, we analyzed the effects of TNP-470 on the early stages of tumor establishment. METHODS: Twenty thousand green fluorescent protein (GFP)-transfected murine CT-26 (colonic carcinoma) or Panc-02-H0 (pancreatic adenocarcinoma) cells were inoculated in dorsal skin-fold chambers in BALB/c or C57BL6 mice. Tumor area and microvessel density (MVD) were quantified by intravital microscopy (IVM). Body weight was also monitored. Effects were compared with those in a conventional model involving subcutaneous (s.c.) inoculation of 10(6) tumor cells, followed by measurement of tumor volume, endogenous plasma VEGF/endostatin (ELISA) and proliferation/apoptosis/microvessel density (Ki-67/TUNEL/CD-34). TNP-470 was injected s.c. over the 10-day experimental period (30 mg/kg every 2 days [n=6] to 100 mg/kg/day [n=5 dorsal skin-fold chamber model, n=4 s.c. tumor model]). RESULTS: At 30 mg/kg/every second day neither CT-26 nor PANC-02-H0 tumors were inhibited in neither of the two models. TNP-470 dosage was escalated in CT-26-bearing animals until an antiangiogenic effect could be observed. In the IVM model, only TNP-470 100 mg/kg/day reduced MVD (P=0.006), but failed to block the onset of angiogenesis and tumor area increase. Body weight decreased by 25% (P<0.05). In the subcutaneous tumor model, tumor growth was reduced (P=0.045) but not blocked, while vascular endothelial growth factor (VEGF)/endostatin synthesis and Ki67/TUNEL/CD-34 were not significantly affected. CONCLUSION: While capable of reducing tumor growth in a conventional model, treatment with TNP-470 does not block the onset of angiogenesis and tumor establishment in a model of minimal disease. When used as a single agent TNP-470 does not control minimal tumor disease in experimental colonic carcinoma.     

Severe folate deficiency in pregnancy with normal red cell folate level

We report here a case of megaloblastic anaemia in late pregnancy, which leads us to question whether folate supplements should be recommended in the UK routinely throughout pregnancy and not just in the preconception period and first trimester.