Does HAART Efficacy Translate to Effectiveness? Evidence for a Trial Effect

Background: Patients who participate in clinical trials may experience better clinical outcomes than patients who initiate similar therapy within clinical care (trial effect), but no published studies have evaluated a trial effect in HIV clinical trials. Methods: To examine a trial effect we compared virologic suppression (VS) among patients who initiated HAART in a clinical trial versus in routine clinical care. VS was defined as a plasma HIV RNA #400 copies/ml at six months after HAART initiation and was assessed within strata of early (1996–99) or current (2000–06) HAART periods. Risk ratios (RR) were estimated using binomial models. Results: Of 738 persons initiating HAART, 30.6 % were women, 61.7 % were black, 30 % initiated therapy in a clinical trial and 67 % (n = 496) had an evaluable six month HIV RNA result. HAART regimens differed between the early and current periods (p,0.001); unboosted PI regimens (55.6%) were more common in the early and NNRTI regimens (46.4%) were more common in the current period. Overall, 78 % (95%CI 74, 82%) of patients achieved VS and trial participants were 16 % more likely to achieve VS (unadjusted RR 1.16, 95%CI 1.06, 1.27). Comparing trial to non-trial participants, VS differed by study period. In the early period, trial participants initiating HAART were significantly more likely to achieve VS than non-trial participants (adjusted RR 1.33; 95%CI 1.15, 1.54), but not in the current period (adjusted RR 0.98; 95%CI 0.87, 1.11). Conclusions: A clear clinical trial effect on suppression of HIV replication was observed in the early HAART period but not i

Exposure to N-Ethyl-N-Nitrosourea in Adult Mice Alters Structural and Functional Integrity of Neurogenic Sites

BACKGROUND: Previous studies have shown that prenatal exposure to the mutagen N-ethyl-N-nitrosourea (ENU), a N-nitroso compound (NOC) found in the environment, disrupts developmental neurogenesis and alters memory formation. Previously, we showed that postnatal ENU treatment induced lasting deficits in proliferation of neural progenitors in the subventricular zone (SVZ), the main neurogenic region in the adult mouse brain. The present study is aimed to examine, in mice exposed to ENU, both the structural features of adult neurogenic sites, incorporating the dentate gyrus (DG), and the behavioral performance in tasks sensitive to manipulations of adult neurogenesis. METHODOLOGY/PRINCIPAL FINDINGS: 2-month old mice received 5 doses of ENU and were sacrificed 45 days after treatment. Then, an ultrastructural analysis of the SVZ and DG was performed to determine cellular composition in these regions, confirming a significant alteration. After bromodeoxyuridine injections, an S-phase exogenous marker, the immunohistochemical analysis revealed a deficit in proliferation and a decreased recruitment of newly generated cells in neurogenic areas of ENU-treated animals. Behavioral effects were also detected after ENU-exposure, observing impairment in odor discrimination task (habituation-dishabituation test) and a deficit in spatial memory (Barnes maze performance), two functions primarily related to the SVZ and the DG regions, respectively. CONCLUSIONS/SIGNIFICANCE: The results demonstrate that postnatal exposure to ENU produces severe disruption of adult neurogenesis in the SVZ and DG, as well as strong behavioral impairments. These findings highlight the potential risk of environmental NOC-exposure for the development of neural and behavioral deficits

MR myelography for identification of spinal CSF leak in spontaneous intracranial hypotension.

Background and purposeCT myelography has historically been the test of choice for localization of CSF fistula in patients with spontaneous intracranial hypotension. This study evaluates the additional benefits of intrathecal gadolinium MR myelography in the detection of CSF leak.Materials and methodsWe performed a retrospective review of patients with spontaneous intracranial hypotension who underwent CT myelography followed by intrathecal gadolinium MR myelography. All patients received intrathecal iodine and off-label gadolinium-based contrast followed by immediate CT myelography and subsequent intrathecal gadolinium MR myelography with multiplanar T1 fat-suppressed sequences. CT myelography and intrathecal gadolinium MR myelography images were reviewed by an experienced neuroradiologist to determine the presence of CSF leak. Patient records were reviewed for demographic data and adverse events following the procedure.ResultsTwenty-four patients met both imaging and clinical criteria for spontaneous intracranial hypotension and underwent CT myelography followed by intrathecal gadolinium MR myelography. In 3/24 patients (13%), a CSF leak was demonstrated on both CT myelography and intrathecal gadolinium MR myelography, and in 9/24 patients (38%), a CSF leak was seen on intrathecal gadolinium MR myelography (P = .011). Four of 6 leaks identified independently by intrathecal gadolinium MR myelography related to meningeal diverticula. CT myelography did not identify any leaks independently. There were no reported adverse events.ConclusionsPresent data demonstrate a higher rate of leak detection with intrathecal gadolinium MR myelography when investigating CSF leaks in our cohort of patients with spontaneous intracranial hypotension. Although intrathecal gadolinium is an FDA off-label use, all patients tolerated the medication without evidence of complications. Our data suggest that intrathecal gadolinium MR myelography is a well-tolerated examination with significant benefit in the evaluation of CSF leak, particularly for patients with leak related to meningeal diverticula