Maternal Obesity during Pregnancy is Associated with Lower Cortical Thickness in the Neonate Brain.

BACKGROUND AND PURPOSE: Recent studies have suggested that maternal obesity during pregnancy is associated with differences in neurodevelopmental outcomes in children. In this study, we aimed to investigate the relationships between maternal obesity during pregnancy and neonatal brain cortical development. MATERIALS AND METHODS: Forty-four healthy women (28 normal-weight, 16 obese) were prospectively recruited at <10 weeks' gestation, and their healthy full-term neonates (23 boys, 21 girls) underwent brain MR imaging. All pregnant women had their body composition (fat mass percentage) measured at ∼12 weeks of pregnancy. All neonates were scanned at ∼2 weeks of age during natural sleep without sedation, and their 3D T1-weighted images were postprocessed by the new iBEAT2.0 software. Brain MR imaging segmentation and cortical surface reconstruction and parcellation were completed using age-appropriate templates. Mean cortical thickness for 34 regions in each brain hemisphere defined by the UNC Neonatal Cortical Surface Atlas was measured, compared between groups, and correlated with maternal body fat mass percentage, controlled for neonate sex and race, postmenstrual age at MR imaging, maternal age at pregnancy, and the maternal intelligence quotient and education. RESULTS: Neonates born to obese mothers showed significantly lower (P ≤ .05, false discovery rate-corrected) cortical thickness in the left pars opercularis gyrus, left pars triangularis gyrus, and left rostral middle frontal gyrus. Mean cortical thickness in these frontal lobe regions negatively correlated (R = -0.34, P = .04; R = -0.50, P = .001; and R = -0.42, P = .01; respectively) with the maternal body fat mass percentage measured at early pregnancy. CONCLUSIONS: Maternal obesity during pregnancy is associated with lower neonate brain cortical thickness in several frontal lobe regions important for language and executive functions.

Neural activity during attentional conflict predicts reduction in tinnitus perception following rTMS.

BACKGROUND: Subjective idiopathic tinnitus is an intrusive, distracting, and potentially disabling disorder characterized by phantom perception of sounds. Although tinnitus has no approved pharmacologic treatment, recent evidence supports the use of repetitive transcranial magnetic stimulation (rTMS) to alleviate tinnitus symptoms. OBJECTIVE/HYPOTHESIS: Repetitive TMS delivered over the middle superior temporal gyrus (STG) may alter ratings of tinnitus awareness and annoyance more than loudness due to change in attentional processing. STG has reciprocal connections to regions of the prefrontal cortex that mediate attention. To probe the hypothesized influence of STG stimulation on attention, a subset of patients with tinnitus enrolled in an rTMS clinical trial [n = 12, 9 male, mean (sd) age = 49 (15) years] underwent an attentional conflict task before and after rTMS treatment in a repeated-measures functional magnetic resonance imaging (fMRI) study. METHODS: The Multi-Source Interference Task (MSIT), a Stroop-based visual attentional conflict fMRI task, was used to map participants' neural processing of attentional conflict prior to rTMS intervention (Baseline) and after three rTMS intervention arms: Sham, 1 Hz, and 10 Hz (four sessions per arm, 1800 pulses per session, delivered @110% of the motor threshold over the posterior superior temporal gyrus). RESULTS: All measures of tinnitus severity (awareness, loudness, and annoyance) improved with 1 Hz rTMS intervention; however, the greatest and most robust changes were observed for ratings of tinnitus awareness (mean 16% reduction in severity from Baseline, p < 0.01). The MSIT elicited a similar pattern of neural activation among tinnitus participants at Baseline compared to an independent sample of 43 healthy comparison adults (r = 0.801, p = 0.001). Linear regression with bootstrap resampling showed that greater recruitment of bilateral prefrontal and bilateral parietal regions by MSIT at Baseline corresponded with poorer treatment response. Individual regions' activities explained 37-67% variance in participant treatment response, with left dorsolateral prefrontal cortex's MSIT activity at Baseline explaining the greatest reduction in tinnitus awareness following 1 Hz stimulation. Although left dorsolateral prefrontal cortex activity at Baseline also predicted reduction in tinnitus loudness and annoyance (∼50% variance explained), these symptoms were more strongly predicted by right middle occipital cortex (∼70% variance explained) - suggesting that the neural predictors of symptom-specific treatment outcomes may be dissociable. CONCLUSION: These candidate neural reactivity markers of treatment response have potential clinical value in identifying tinnitus sufferers who would or would not therapeutically benefit from rTMS intervention.

Does daily kangaroo care provide sustained pain and stress relief in preterm infants?

OBJECTIVES: 1. Determine whether stress in preterm infants, measured with salivary cortisol, decreases after five days of Kangaroo Care (KC) compared to five days of Standard Care (SC). 2. To determine whether kangaroo care provides sustainable pain relief beyond the period of skin-to-skin holding. STUDY DESIGN: Preterm infants (n = 38) born at 27-30 weeks gestational age were randomized to either the KC or the SC group and received the allocated intervention starting on day of life (DOL) five and continuing for five days. Salivary cortisol was collected on DOL five and again on DOL ten. Differences were analyzed using repeated measures ANOVA and t tests. Pain during nasal suctioning over five days was assessed using the Premature Infant Pain Profile (PIPP). RESULT: 1. Adequate saliva samples for salivary cortisol were collected for 13 KC infants and 11 SC infants. There was no main effect of group (p = 0.49), but there was a significant main effect of age (DOL five versus DOL ten), with salivary cortisol levels decreasing in both groups (p = 0.02). 2. Pain scores for both groups (n = 38) indicted mild to moderate pain during suctioning, with no significant difference in pain scores between groups. CONCLUSION: 1. KC did not affect salivary cortisol levels in preterm neonates, but levels in both the KC and SC groups decreased over time from DOL five to ten. Salivary cortisol may vary with age of infant. 2. Infants experience pain during routine suctioning and may require pain management.

Observational study of cerebral hemodynamics during dopamine treatment in hypotensive ELBW infants on the first day of life.

OBJECTIVE: To evaluate cerebral hemodynamics during dopamine treatment in hypotensive (mean arterial blood pressure (MABP)

Multiple dosing of ephedra-free dietary supplements: hemodynamic, electrocardiographic, and bacterial contamination effects.

Four popular ephedra-free dietary supplements were evaluated for their effects on heart rate (HR), blood pressure (BP), and electrocardiographic (ECG) parameters. Twelve healthy men participated in a study randomized for product sequence, with a 21-day washout period between supplement-administration phases. Throughout the study, Holter monitors were used to assess ECG and HR activity. BP was assessed automatically on multiple occasions. The supplements were ingested three times daily for 3 days. Caffeine content, microbial load, and serum caffeine concentrations were determined. Mean systolic (SBP) and diastolic BP (DBP) readings showed significant increases relative to baseline (10.8 ± 2.5 and 5.3 ± 3.1 mm Hg, respectively; P < 0.05). All supplements significantly increased HR and decreased bradycardia runs; abnormal atrial/ventricular events were frequently noted. Gastrointestinal and sympathomimetic symptoms were also common. Two supplements were heavily contaminated with Bacillus species. In light of these findings, the use of ephedra-free dietary supplements should be discouraged in individuals with hypertension, diabetes, or other cardiovascular diseases.

Laterality, frequency and replication of rTMS treatment for chronic tinnitus: pilot studies and a review of maintenance treatment.

This manuscript reports on findings of three open-label, pilot studies and it reviews studies using rTMS as a maintenance treatment for any disorder. The first pilot study examined whether a patient's original treatment response to 1 Hz rTMS over temporal cortex could be replicated by stimulating a homologous region of the opposite hemisphere. The second study examined whether a patient's response to 1 Hz rTMS could be replicated by applying 10 Hz rTMS over the same treatment site. The third study applied a 3-day course of maintenance rTMS, either at 1 or 10 Hz, when subjects indicated that the benefit of their last course of treatment was waning. Patients with bilateral subjective tinnitus of at least 6 months duration were recruited from a prior, sham controlled study with treatment crossover that applied 1 Hz rTMS over temporal cortex. Both treatment responders and non-responders were recruited. Results indicated, first, that the original treatment response, both positive and negative, is replicated after stimulating a homologous region of the opposite hemisphere; second, patients respond similarly to 1 and 10 Hz stimulation of the same treatment site (an exception was one patient who initially failed 1 Hz stimulation but responded positively to 10 Hz stimulation); and, third, maintenance rTMS had a sustained and additive benefit for tinnitus among treatment responders. Conclusions are that rTMS-induced effects on tinnitus are neither hemisphere specific nor frequency dependent; although, different frequencies of rTMS may have greater potency for a given subject. Maintenance treatment is a well tolerated approach with demonstrated feasibility for managing chronic tinnitus in persons who respond positively to an initial course of treatment.

Chronic anti-phencyclidine monoclonal antibody therapy decreases phencyclidine-induced in utero fetal mortality in pregnant rats.

Illicit drug use during pregnancy is a serious social and public health problem inflicting an array of deleterious effects on both mother and offspring. We investigated the hypothesis that a murine anti-phencyclidine (PCP) monoclonal antibody (mAb6B5; K(D)=1.3 nM) can safely protect mother and fetus from PCP-induced adverse health effects in pregnant rats. Pregnant Sprague-Dawley rats (n=4-5) were intravenously administered bolus injections of PCP (1mg/kg) on multiple days during pregnancy. They were also chronically treated with anti-PCP mAb6B5 at 45 mg/kg as a PCP antagonist. This dose provided one mAb-PCP binding site for every four PCP molecules. Therapeutic and safety study endpoints included pregnancy outcome (litter size, number of live vs. dead pups), maternal hemodynamic status and locomotor activity. Maternal hemodynamic changes (i.e., blood pressure and heart rate) and locomotor activity were measured in dams from gestation days 6-21 (one day antepartum) using a radiotelemetry-tracking device with a femoral arterial pressure catheter. This mAb6B5 treatment regimen significantly (p=0.008) reduced the number of PCP-induced in utero fetal deaths (odds ratio=3.2; 95%CI 1.3 to 7.9) and significantly (p<0.05) reduced acute PCP-induced maternal locomotor effects in the second trimester. Maternal hemodynamic responses to PCP were not significantly affected by mAb6B5 treatment. In conclusion, these data suggest that anti-PCP mAb treatments administered during pregnancy can safely protect a mother and her fetus(es) from PCP-related morbidity and mortality even when the mAb dose is too low to significantly prevent other PCP-induced maternal pharmacological effects.

The effects of closed tracheal suctioning plus volume guarantee on cerebral hemodynamics.

OBJECTIVE: To compare the effects of open tracheal suctioning (OS) plus intermittent mandatory ventilation (IMV) vs. closed tracheal suctioning (CS) plus volume guarantee ventilation (VG) on changes in mean cerebral blood-flow velocity (CBFv) of ventilated very low birth weight (VLBW) infants. STUDY DESIGN: A total of 75 normotensive, ventilated VLBW infants (with normal cranial ultrasounds) had monitoring of mean CBFv, PCO2 and mean arterial blood pressure (MABP) before, during and after 220 tracheal suctioning sessions during the first week of life. Multiple linear regression analysis was used to determine the factor(s) influencing the magnitude of relative changes from baseline in mean CBFv after suctioning. RESULT: In all, 49 VLBW infants receiving IMV had monitoring during 124 OS sessions between July 2002 and May 2005; 26 VLBW infants receiving VG had monitoring during 96 CS sessions between January 2006 and July 2007. The average magnitude of relative changes in mean CBFv was significantly less with CS+VG, and was associated with the magnitude of relative changes in PCO2 and suctioning-ventilator group. CONCLUSION: The average magnitude of relative changes in mean CBFv was reduced in VLBW infants with CS+VG vs. OS+IMV.

Developmental alterations in olivary climbing fiber distribution following postnatal ethanol exposure in the rat.

Ethanol exposure during postnatal days (PN) 4-6 in rats alters cerebellar development resulting in significant loss of Purkinje cells. There is little knowledge, however, on what happens to the neurons that survive. In this study, rat pups were treated with a daily dose of ethanol (either 3.6 or 4.5 g/kg body weight) delivered by intragastric intubation on PN4, PN4-6, or PN7-9. Then the interactions between climbing fibers and Purkinje cells were examined on PN14 using confocal microscopy. Mid-vermal cerebellar sections were stained with antibodies to calbindin-D28k (to visualize Purkinje cells) and vesicular glutamate transporter 2 (VGluT2, to visualize climbing fibers). Confocal z-stack images were obtained from Lobule 1 and analyzed with Imaris software to quantify the staining of the two antibodies. The VGluT2 immunostaining was significantly reduced in the PN4 and PN4-6 ethanol groups for the 4.5 g/kg dose level, compared to controls, indicating that the cerebellar circuitry was significantly altered following developmental ethanol exposure. Not only were there fewer Purkinje cells following ethanol exposure, but the surviving neurons had significantly fewer VGluT2-labeled synapses. These alterations in the synaptic integrity were both dose dependent and temporally dependent.

Gamma band unit activity and population responses in the pedunculopontine nucleus.

The pedunculopontine nucleus (PPN) is involved in the activated states of waking and paradoxical sleep, forming part of the reticular activating system (RAS). The studies described tested the hypothesis that single unit and/or population responses of PPN neurons are capable of generating gamma band frequency activity. Whole cell patch clamp recordings (immersion chamber) and population responses (interface chamber) were conducted on 9- to 20-day-old rat brain stem slices. Regardless of cell type (I, II, or III) or type of response to the nonselective cholinergic receptor agonist carbachol (excitation, inhibition, biphasic), almost all PPN neurons fired at gamma band frequency, but no higher, when subjected to depolarizing steps (50 +/- 2 Hz, mean +/- SE). Nonaccommodating neurons fired at 18-100 Hz throughout depolarizing steps, while most accommodating neurons exhibited gamma band frequency of action potentials followed by gamma band membrane oscillations. These oscillations were blocked by the sodium channel blocker tetrodotoxin (TTX), suggesting that at least some are mediated by sodium currents. Population responses in the PPN showed that carbachol induced peaks of activation in the theta and gamma range, while glutamatergic receptor agonists induced overall increases in activity at theta and gamma frequencies, although in differing patterns. Gamma band activity appears to be a part of the intrinsic membrane properties of PPN neurons, and the population as a whole generates different patterns of gamma band activity under the influence of specific transmitters. Given sufficient excitation, the PPN may impart gamma band activation on its targets.

Tracheal suctioning is associated with prolonged disturbances of cerebral hemodynamics in very low birth weight infants.

OBJECTIVES: Examining the effects of tracheal suctioning on cerebral hemodynamics of normotensive ventilated very low birth weight (VLBW) infants with normal cranial ultrasounds; determining the factor(s) influencing changes in mean cerebral blood flow velocity (CBFv) after suctioning. METHODS: Seventy-three VLBW infants had continuous monitoring of mean arterial blood pressure (MABP), PaCO(2), PaO(2) and mean CBFv before, during, and after 202 suctioning sessions during the first week of life. Peak (or nadir) and relative changes of the four variables for 45 min after suctioning were calculated. Multiple linear regression was used to determine the factor(s) influencing changes in mean CBFv after suctioning. RESULT: Birth weight was 928+/-244 g; gestational age was 27.0+/-2.0 weeks. Mean CBFv increased to 31.0+/-26.4% after suctioning and remained elevated for 25 min. PaCO(2) was highly associated with mean CBFv (P<0.001), whereas MABP and PaO(2) were not. CONCLUSION: We observed prolonged increases of mean CBFv following suctioning in ventilated VLBW infants that were previously unrecognized. This is concerning since disturbances of CBF may be associated with subsequent brain injury.

Supplementation with goldenseal (Hydrastis canadensis), but not kava kava (Piper methysticum), inhibits human CYP3A activity in vivo.

The effects of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on human CYP3A activity were evaluated using midazolam (MDZ) as a phenotypic probe. Sixteen healthy volunteers were randomly assigned to receive either goldenseal or kava kava for 14 days. Each supplementation phase was followed by a 30-day washout period. MDZ (8 mg, per os) was administered before and after each phase, and pharmacokinetic parameters were determined using standard non-compartmental methods. Comparisons of pre- and post-supplementation MDZ pharmacokinetic parameters revealed significant inhibition of CYP3A by goldenseal (AUC(0-infinity), 107.9+/-43.3 vs 175.3+/-74.8 ng x h/ml; Cl/F/kg, 1.26+/-0.59 vs 0.81+/-0.45 l/h/kg; T(1/2), 2.01+/-0.42 vs 3.15+/-1.12 h; Cmax, 50.6+/-26.9 vs 71.2+/-50.5 ng/ml). MDZ disposition was not affected by kava kava supplementation. These findings suggest that significant herb-drug interactions may result from the concomitant ingestion of goldenseal and CYP3A substrates.

Hypercapnia during the first 3 days of life is associated with severe intraventricular hemorrhage in very low birth weight infants.

OBJECTIVE: To examine whether hypercapnia in very low birth weight (VLBW) infants during the first 3 days of life is associated with severe intraventricular hemorrhage (IVH). STUDY DESIGN: Retrospective cohort study of inborn VLBW infants between January 1999 and May 2004 with arterial access during the first 3 days of life. A multiple logistic regression analysis was used where IVH was dichotomized ((grades 0/1/2) = non-severe; (grades 3/4) = severe). Measures of hypercapnia were entered into the model to ascertain their association with severe IVH. RESULTS: In total, 574 VLBW infants met entry criteria. Worst IVH grade was 0 in 400; 1: 54; 2: 42; 3: 47; and 4: 31 infants. The logistic regression model consisted of the following predictors of severe IVH: gestational age, gender, 1 min Apgar score (dichotomized into two groups: >3 vs < or =3), multifetal gestation, vasopressor use, and maximum PaCO(2). CONCLUSION: In addition to traditional risk factors, it appears maximum PaCO(2) is a dose-dependent predictor of severe IVH during the permissive hypercapnia era.

Leucodysplasia, microcephaly, cerebral malformation (LMC): a novel recessive disorder linked to 2p16.

We report three related and one unrelated child with an apparently novel neurodevelopmental disorder. The clinical course was very similar in all the four patients: congenital microcephaly with severe failure of post-natal brain growth, neonatal onset of intractable seizures associated with lack of developmental progression and death within the first 3 years of life. The appearance on cerebral neuroimaging was almost identical, with simplified gyration associated with a non-thickened cortex, severe hypoplasia of the corpus callosum, a small flattened brain stem, and specific cystic lesions in the white matter around the temporal and occipital horns. To our knowledge these patients represent a previously unreported, autosomal recessive syndrome. Homozygosity mapping in the consanguineous family has identified a candidate region on the chromosome 2p16.

Effectiveness of payment for reduced carbon monoxide levels and noncontingent payments on smoking behaviors in cocaine-abusing outpatients wearing nicotine or placebo patches.

In a 2-week intervention to reduce cigarette smoking among outpatients in treatment for cocaine addiction, 20 subjects were randomly assigned to a contingent group, receiving monetary vouchers for breath samples with carbon monoxide (CO) levels of 8 ppm or less, or to a noncontingent group, receiving vouchers regardless of CO level. Subjects wore either nicotine or placebo patches in a randomized crossover design. Contingent subjects had significantly lower CO levels and met the 8 ppm target significantly more often than did noncontingent subjects; however, number of cigarettes reported smoked did not differ between groups. Use of nicotine patches resulted in CO levels significantly lower than did use of placebo patches, but levels still exceeded 8 ppm regardless of type of patch. Because contingent reward helped cocaine-dependent smokers achieve nonsmoking CO targets, behavioral antismoking interventions merit continued study in similar populations.

The P50 midlatency auditory evoked potential in patients with chronic low back pain (CLBP).

OBJECTIVE: Patients with Chronic Low Back Pain (CLBP) show arousal, attentional and cognitive disturbances. The sleep state-dependent P50 midlatency auditory evoked potential was used to determine if patients with CLBP [with and without co-morbid depression (DEP)] show quantitative disturbances in the manifestation of the P50 potential. METHODS: P50 potential latency, amplitude and habituation to repetitive stimuli at 250, 500 and 1000ms interstimulus intervals (ISIs) was recorded, along with the McGill Pain Questionnaire-Short Form (MPQ-SF). CLBP subjects (n=42) were compared with Controls (n=43), and with subjects with DEP only (n=6). Of the CLBP subjects, 20/42 had clinical depression (CLBP+DEP); 8/20 were taking anti-depressant medication (CLBP+DEP+med), the others were not (CLBP+DEP-med). RESULTS: There were no differences (ANOVA) in age, sex or P50 potential latency, although there was a trend towards increased latencies in CLBP groups. P50 potential amplitude was lower in CLBP groups, but not in sub-groups, again indicating a trend. P50 potential habituation was decreased in the DEP only subjects at the 250m ISI, and decreased in CLBP+DEP-med subjects at the 500ms ISI. This difference was not present in CLBP+DEP+med subjects. The MPQ-SF revealed that patients with CLBP and CLBP+DEP-med showed lower pain scores than CLBP+DEP+med patients. CONCLUSIONS: There is decreased habituation of the P50 potential habituation in unmedicated patients with CLBP+DEP compared to Controls. SIGNIFICANCE: Patients with CLBP+DEP-med may be less able to disregard incoming sensory information, including painful sensations, but anti-depressant medications help correct this deficit. However, their perception of pain may be increased by medication.

Increased intimal hyperplasia after carotid endarterectomy in spontaneously hypertensive rats.

This study evaluated the effects of hypertension on postoperative intimal hyperplasia using a rat carotid endarterectomy (CEA) model with spontaneously hypertensive rats (SHR) and normotensive Sprague-Dawley rats (SD). SHR and SD rats underwent left carotid exposure and CEA via an arteriotomy, scoring and removal of the intima, followed by arteriotomy closure. The rats were then sacrificed two weeks postoperatively. The left carotid artery was harvested and underwent elastin and double immunohistochemical staining. The percent of lumenal stenosis was calculated using morphometric measurements, and stained cells within the intimal hyperplasia were counted. The means and standard deviation of the means were calculated, and the two groups were compared using a 2-sample t test. The systolic blood pressure was 228 +/-35 mm Hg in the SHR group and 108 +/-8 mm Hg in the SD group (p<0.00001). The percent of lumenal stenosis was 82.6 +/-17.1% in the SHR group and 21.2 +/-13.7% in the SD rats (p value <0.0001). The percentage of cells staining for a-SM actin was equal in the SHR group and the SD group (> 91%) but the percentage of these cells staining for BrdU was 38.2 +/-8.4% in the SHR group and 10.7 +/-5.8% in the SD group (p< 0.00001). Hypertension in the SHR rats was associated with an increased lumenal stenosis due to increased intimal hyperplasia. The increased intimal hyperplasia was due to enhanced and accelerated replication of smooth muscle cells. Hypertension may be associated with increased restenosis rates after CEA.

Increasing levels of dietary homocystine with carotid endarterectomy produced proportionate increases in plasma homocysteine and intimal hyperplasia.

PURPOSE: The role that homocysteine may play in post-carotid endarterectomy (CEA) restenosis due to intimal hyperplasia is not well understood. This study was designed to investigate the effects of different levels of dietary homocystine on: (1) plasma homocysteine; (2) post-CEA intimal hyperplasia; and (3) levels of the methyl donor S-adenosylmethionine (SAM) and its counterpart S-adenosylhomocysteine (SAH) in the homocysteine pathway. METHODS: Male rats were fed specialized diets for 2 weeks pre- and post-CEA. Groups included control (0 homocystine added, n=9), 1.5 (1.5 g/kg homocystine added, n=10), 3.0 (3.0 g/kg homocystine added, n=9), and 4.5 (4.5 g/kg homocystine added, n=11). The rats underwent a surgical carotid endarterectomy. Endpoints included; plasma homocysteine, intimal hyperplasia, replicative index using with alpha-SM actin and BrdU, hepatic SAM levels, SAH levels, and the hepatic activities of methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta-synthase (CBS). RESULTS: Increasing dietary homocystine produced a proportionate increase in plasma homocysteine and an increase in intimal hyperplasia. Regression analysis of plasma homocysteine levels and intimal hyperplasia showed a significant correlation (r=0.71,P=0.003). Plasma homocysteine levels above 15 microM were associated with significant increases in intimal hyperplasia above 6.5% (P=0.04). Elevation of plasma homocysteine levels to moderate levels (5-25 microM) resulted in significant post-CEA intimal hyperplasia. Cellular analysis of the area of intimal hyperplasia in all diet groups showed comparable amounts of cells positive for alpha-SM actin. However, with increasing levels of dietary homocystine and plasma homocysteine there was an increase in replicative index (P<0.001) as determined by BrdU staining. Increasing dietary homocystine increased plasma homocysteine and was followed by increases in the replicative index thus producing increased intimal hyperplasia and lumenal stenosis. In hepatic measurements the 1.5 and 3.0 g/kg homocystine diets caused: increased liver activity of MTHFR (P=0.03) and decreased hepatic levels of SAM, SAH and SAM/SAH ratios compared to controls. Homocystine treatment did not cause significant alterations in CBS levels (P=0.992). These studies also showed no correlation of the MTHFR and CBS enzymes with plasma homocysteine levels or intimal hyperplasia. However, hepatic levels of SAM showed significant negative correlations with plasma homocysteine (r=-0.58; P=0.006) and with BrdU percentages of cellular proliferation (r=-0.69; P=0.06). CONCLUSION: The degree of post-CEA intimal hyperplasia in a rat model is directly related to the plasma level of homocysteine. The hyperplastic effects of homocysteine may be mediated in part by a physiological insufficiency of methyl donors as shown by decreases in SAM. Thus, increasing levels of plasma homocysteine enhanced and accelerated the smooth muscle cell response after CEA which led to increased intimal hyperplasia and lumenal stenosis.

Health-related quality-of-life measure enhances acute treatment response prediction in depressed inpatients.

BACKGROUND: Many nonbiological variables are reported to predict treatment response for major depression; however, there is little agreement about which variables are most predictive. METHOD: Inpatient subjects (N = 59) diagnosed with current DSM-IV major depressive disorder completed weekly depressive symptom ratings with the Hamilton Rating Scale for Depression (HAM-D-17) and Beck Depression Inventory (BDI), and weekly health-related quality-of-life (HRQL) ratings with the Quality of Well-Being Scale (QWB). Acute responders were identified by a 50% decrease in HAM-D-17 score from baseline within 4 weeks of medication treatment. Predictor variables were initially chosen from a literature review and then tested for their association with acute treatment response. RESULTS: An initial predictive model including age at first depression, admission BDI score, and melancholia predicted acute treatment response with 69% accuracy and was designated as the benchmark model. Adding the admission QWB index score to the benchmark model did not improve the prediction rate; however, adding the admission QWB subscales for physical and social activity to the benchmark model significantly improved acute treatment response prediction to 86% accuracy (p = .001). CONCLUSION: In addition to being designed for use in cost-effectiveness analyses, the QWB subscales appear to be useful HRQL variables for predicting acute inpatient depression treatment response.

The design, synthesis and physical chemical properties of novel human vasopressin V2-receptor antagonists optimized for parenteral delivery.

Ionizable groups were introduced onto the 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine scaffold of the vasopressin V2-antagonist WAY-VPA-985 in the search for molecules optimized for parenteral formulation. The synthesis and structure activity relationships (SAR) are presented together with solubility data in a model parenteral system. The amine, WAY-140288 (4f), was chosen for further development. p6