Intimate Partner Violence and Food Insecurity Predict Early Behavior Problems Among South African Children over 5-years Post-Birth

Households experiencing intimate partner violence (IPV) and food insecurity are at high risk of lifelong physical and behavioral difficulties. Longitudinal data from a perinatal home-visiting cluster-randomized controlled intervention trial in South Africa townships were used to examine the relationships between household settings and mothers’ histories of risk and children’s behavior problems at 3 and 5 years of age. IPV, food insecurity, maternal depressed mood, and geriatric pregnancy (at age of 35 or older) were consistently associated with children’s internalizing and externalizing behavior problems. Aggressive behavior was more prevalent among 3- and 5-year olds boys, and was associated with maternal alcohol use. The effects of these factors on child behavior were more prominent than maternal HIV status. There is a continuing need to reduce IPV and household food insecurity, as well as supporting older, depressed, alcohol using mothers in order to address children’s behavioral needs.

     

Synthesis of 3'- and 5'-nitrooxy pyrimidine nucleoside nitrate esters: "nitric oxide donor" agents for evaluation as anticancer and antiviral agents

A group of 3'-O-nitro-2'-deoxyuridines, 3'-O-nitro-2'-deoxycytidines, and 5'-O-nitro-2'-deoxyuridines possessing a variety of substituents (H, Me, F, I) at the C-5 position were synthesized for evaluation as anticancer/antiviral agents that have the ability to concomitantly release cytotoxic nitric oxide (*NO). Although these compounds generally released a greater percent of *NO than the reference drug isosorbide dinitrate upon incubation in the presence of l-cysteine, or serum, their cytotoxicity (CC(50) = 10(-3) to 10(-6) M range) was comparable to 5-iodo-2'-deoxyuridine, but weaker than 5-fluoro-2'-deoxyuridine, against a variety of cancer cell lines. No differences in cytotoxicity against nontransfected (KBALB, 143B), and the corresponding transfected (KBALB-STK, 143B-LTK) cancer cell lines possessing the herpes simplex virus type 1 (HSV-1) thymidine kinase gene (TK(+)) were observed, indicating that expression of the viral TK enzyme did not provide a gene therapeutic effect. These nitrate esters were inactive antiviral agents except for 5-iodo-3'-O-nitro-2'-deoxyuridine that showed modest activity against HSV-1, HSV-2, and vaccinia virus.     

Increased glutamate levels in the medial prefrontal cortex in patients with postpartum depression

The medial prefrontal cortex (MPFC) is a key brain area in depressive symptomatology; specifically, glutamate (Glu) has been reported to play a significant role in major depression (MD) in this area. MPFC Glu levels are sensitive to ovarian hormone fluctuations and pregnancy and the postpartum period are associated with the most substantial physiological alterations of female hormones. It is therefore logical to measure MPFC Glu levels in women with postpartum depression (PPD). Using in vivo magnetic resonance spectroscopy (MRS) at a field strength of 3?T, we acquired single-voxel spectra from the MPFC of 12 women with PPD and 12 healthy controls (HCs) matched for postpartum scan timing. Water-referenced MPFC Glu levels were measured using a MRS technique that allowed us to be specific for Glu with very little glutamine contamination. The concentrations of other water-quantified brain metabolites such as glycerophosphorylcholine plus phosphorylcholine, N-acetylaspartate (NAA), and creatine plus phosphocreatine were measured in the same MR spectra. MPFC Glu levels were higher in women with PPD (7.21±1.20) compared to matched HCs (6.04±1.21). There were no differences between groups for other brain metabolites measured. These findings suggest an association between Glu dysregulation in the MPFC and PPD. Whether the pathophysiology of PPD differs from the pathophysiology of MD remains to be determined. Further investigations are needed to determine the chronological associations between the occurrence of symptoms of PPD and the onset of changes in MPFC Glu levels.     

Stress-induced activation of nitric oxide-producing neurons in the rat brain

Nitric oxide (NO) is a gaseous neurotransmitter that may mediate a decrease in sympathetic output to the periphery. This implication predicts that NO-producing neurons in the brain are activated in animals experiencing increased levels of sympathetic activity. To test this prediction, we subjected three groups of experimental rats to differing levels of environmental stimulation for 1 hour: minimal stimulation, moderate stimulation, and restraint stress. NO-producing neurons were histochemically visualized in sections of the brain, and activation of these neurons was assessed according to the neuronal expression of the immediate early gene c-fos. Constitutive activation of NO-producing neurons was found in the hypothalamus (paraventricular and supraoptic nuclei), dorsal raphe nuclei, and spinal nucleus of the trigeminal nerve of minimally stimulated rats. When animals were subjected to a novel environment (moderate stimulation), additional NO-producing neurons were activated in the medial septum, medial amygdala, hypothalamic nuclei (lateral, periventricular, and posterior), colliculi, nucleus raphe obscurus, medial vestibular nucleus, nucleus of the tractus solitarius, and several components of the ventrolateral medulla. Restraint stress caused the activation of NO-producing neurons in all of these areas, often in increasing numbers, and the activation of additional NO-producing neurons in the diagonal band of Broca, lateral and medial preoptic areas, basomedial and basolateral amygdalar nuclei, hypothalamic nuclei (dorsomedial, retrochiasmatic supraoptic, and circularis), nucleus raphe pontus, lateral parabrachial nucleus, and pontine nuclei. Expressed as a proportion of NO-producing neurons per section, the largest percentages (>20%) of double-stained neurons were found in the basolateral amygdala (46%), hypothalamic paraventricular nucleus (35%), corpora quadrigemina (estimated at 40%), dorsal raphe (45%), nuclei raphe pontus (33%) and obscurus (63%), lateral parabrachial nucleus (22%), medial vestibular nucleus (25%), lateral division of the nucleus paragigantocellularis (26%), and lateral reticular nucleus (35%). Evidence from other studies increasingly supports the concept that NO plays a generalized role in autonomic regulation by decreasing sympathetic output. Our results show that more NO-producing neurons were activated during stress than during minimal or moderate levels of stimulation. Together, the evidence suggests that NO is a neurochemical messenger that is utilized by individual autonomic neurons as the organism responds to increased levels of sympathetic activity. J. Comp. Neurol. 377:509–519. © 1997 Wiley-Liss, Inc.     

Dose-dependent pharmacokinetics of 1-(2-deoxy-beta-D- ribofuranosyl)-2,4-difluoro-5-iodobenzene: a potential mimic of 5-iodo-2'-deoxyuridine

The dose-range pharmacokinetics of l-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-iodobenzene (5-IDFPdR), a C-aryl nucleoside mimic of IUdR, were studied in male Sprague-Dawley rats following single intravenous (i.v.) and oral doses. After i.v. administration, the blood clearance decreased from approximately 32 ml/min/kg at a dose of 15 mg/kg, to approximately 19 ml/min/kg when dosed at 54 mg/kg, and the elimination half-life increased from 8.4 min to 21.5 min, for the respective doses. While the dose-normalized area under the concentration-time curve (AUCnorm) remained practically unchanged (0.132 kg min ml(-1)) upon increasing the i.v. dose from 5 to 15 mg/kg, it increased by about 44% ( approximately 0.19 kg min ml(-1)) when the i.v. dose was increased from 15 to 54 mg/kg. Similarly, there was a dose-dependent increase in AUCnorm with increasing oral doses: AUCnorm increased by 49% as the oral dose increased from 20 to 40 mg/kg, and further by 55% as the oral dose was increased from 40 mg/kg to 54 mg/kg. For the respective oral doses, the elimination half-life increased from 24.5 min to 176 min, while blood clearance was reduced from approximately 37 ml/min/kg to approximately 17 ml/min/kg. The urinary recoveries of unchanged 5-IDFPdR and its glucuronides (as percent of the dose) were somewhat increased at higher doses. This increase was more pronounced following the highest oral dose. The total biliary recovery of 5-IDFPdR (as percent of the dose) was, however, decreased with increasing doses. The overall kinetic profile of 5-IDFPdR based on these data is suggestive of dose-dependent pharmacokinetics. Decreased elimination of 5-IDFPdR with increasing dose, as supported by longer elimination half-lives at higher doses, is one likely mechanism contributing to the dose-dependent behaviour of this compound. Saturable non-renal metabolism might explain the reduced total body clearance of 5-IDFPdR at higher doses, despite the unchanged or increased urinary clearance.For drugs exhibiting nonlinear kinetics, the dosage regimens may need to be carefully designed to avoid potential unpredictable toxicity and/or lack of pharmacological response associated with the disproportional changes in steady state drug concentrations on changing dose. Manifestation in the rat of nonlinear kinetics at doses of 5-IDFPdR, which may be of therapeutic relevance, warrants extended dose-range evaluations of this compound in future preclinical and clinical studies, to establish safe and efficacious dosage regimens.     

Gene Expression Profiles Can Predict Panitumumab Monotherapy Responsiveness in Human Tumor Xenograft Models

Background

Epidermal growth factor receptor (EGFR)-targeted agents have demonstrated clinical benefit in patients with cancer. Identifying tissue-of-origin-independent predictive biomarkers is important to optimally treat patients. We sought to identify a gene array profile that could predict responsiveness to panitumumab, a fully human EGFR-binding antibody, using preclinical models of human cancer.

Methods

Mice bearing 25 different xenograft models were treated twice weekly with panitumumab or immunoglobulin G2 control to determine their responsiveness to panitumumab. Samples from these xenografts and untreated xenografts were arrayed on the Affymetrix human U133A gene chip to identify gene sets predicting responsiveness to panitumumab using univariate and multivariate analyses. The predictive models were validated using the leave-one-group-out (LOO) method.

Results

Of the 25 xenograft models tested, 12 were responsive and 13 were resistant to panitumumab. Unsupervised analysis demonstrated that the xenograft models clustered by tissue type rather than responsiveness to panitumumab. After normalizing for tissue effects, samples clustered by responsiveness using an unsupervised multidimensional scaling. A multivariate selection algorithm was used to select 13 genes that could stratify xenograft models based on responsiveness after adjustment for tissue effects. The method was validated using the LOO method on a training set of 22 models and confirmed independently on three new models. In contrast, a univariate gene selection method resulted in higher misclassification rates.

Conclusion

A model was constructed from microarray data that prospectively predict responsiveness to panitumumab in xenograft models. This approach may help identify patients, independent of disease origin, likely to benefit from panitumumab.     

Pharmacokinetics and metabolism of the novel synthetic C-nucleoside, 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-iodobenzene: a potential mimic of 5-iodo-2'-deoxyuridine

1-(2-Deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-iodobenzene (5-IDFPdR) is one of the several unnatural 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-substituted-benzenes recently synthesized for evaluation as anticancer, antiviral and diagnostic imaging agents. This class of C-nucleosides was designed to exploit several potential advantages relative to classical 5-substituted-2'-deoxyuridines, including stability towards phosphorolysis by pyrimidine phosphorylase, increased lipophilicity that may alter their ability to cross the blood-brain-barrier, and a greater resistance towards catabolism and deiodination. The physiochemical evaluation of 5-IDFPdR showed high lipophilicity (log P = 2.8), moderately high protein binding (70-75%), stability towards phosphorolysis (e.g. no evidence of metabolic deglycosylation) by thymidine phosphorylase, and minimal microsomal metabolism in vitro. Pharmacokinetic studies of 5-IDFPdR in rat were characterized by a short elimination half-life (9-12 min), modest urinary elimination in pooled 0-24 h urine specimens (10-14%, including 2% as unconjugated drug) and high oral bioavailability (F = 0.96). Both glucuronide and sulfate metabolites were present in urine. Glucuronidation was the predominant conjugation pathway.     

Leptin increases cardiomyocyte hyperplasia via extracellular signal-regulated kinase- and phosphatidylinositol 3-kinase-dependent signaling pathways

Obesity is a major risk factor for the development of heart failure. Importantly, it is now appreciated that a change in the number of myocytes is one of multiple structural and functional alterations (remodeling) leading to heart failure. Here we investigate the effect of leptin, the product of the obese (ob) gene, on proliferation of human and murine cardiomyocytes. Leptin caused a time- and dose-dependent significant increase in proliferation of HL-1 cells that was inhibited by preincubation with PD98059 and LY294002, suggesting that leptin mediated proliferation via extracellular signal-regulated kinase-1/2- and phosphatidylinositol-3-kinase-dependent signaling pathways. We confirmed that leptin activates both extracellular signal-regulated kinase-1/2 phosphorylation and association of phosphatidylinositol-3-kinase (regulatory p85 subunit) with phosphotyrosine immunoprecipitates. We also examined bromodeoxyuridine incorporation as a measure of new DNA synthesis and demonstrated a stimulatory effect of leptin in both HL-1 cells and human cardiomyocytes. Bromodeoxyuridine incorporation in HL-1 cells was inhibited by PD98059 and LY294002. Our results establish a mitogenic effect of leptin in cardiomyocytes and provide additional evidence for a potential direct link between leptin and cardiac remodeling in obesity.     

Increased Glutamate Levels in the Medial Prefrontal Cortex in Patients with Postpartum Depression

The medial prefrontal cortex (MPFC) is a key brain area in depressive symptomatology; specifically, glutamate (Glu) has been reported to play a significant role in major depression (MD) in this area. MPFC Glu levels are sensitive to ovarian hormone fluctuations and pregnancy and the postpartum period are associated with the most substantial physiological alterations of female hormones. It is therefore logical to measure MPFC Glu levels in women with postpartum depression (PPD). Using in vivo magnetic resonance spectroscopy (MRS) at a field strength of 3 T, we acquired single-voxel spectra from the MPFC of 12 women with PPD and 12 healthy controls (HCs) matched for postpartum scan timing. Water-referenced MPFC Glu levels were measured using a MRS technique that allowed us to be specific for Glu with very little glutamine contamination. The concentrations of other water-quantified brain metabolites such as glycerophosphorylcholine plus phosphorylcholine, N-acetylaspartate (NAA), and creatine plus phosphocreatine were measured in the same MR spectra. MPFC Glu levels were higher in women with PPD (7.21±1.20) compared to matched HCs (6.04±1.21). There were no differences between groups for other brain metabolites measured. These findings suggest an association between Glu dysregulation in the MPFC and PPD. Whether the pathophysiology of PPD differs from the pathophysiology of MD remains to be determined. Further investigations are needed to determine the chronological associations between the occurrence of symptoms of PPD and the onset of changes in MPFC Glu levels.     

Parkinson’s disease-like midbrain hyperechogenicity is frequent in amyotrophic lateral sclerosis

Clinical and neuroimaging data suggest impairment of the nigrostriatal system in amyotrophic lateral sclerosis (ALS). We thus hypothesized whether Parkinson’s disease (PD)-like midbrain sonography findings are also present in ALS. Eighty-six patients with the diagnosis of possible or definite ALS according to revised El Escorial criteria were examined by transcranial B-mode sonography compared to 76 age- and gender-matched controls and 33 PD patients. Hyperechogenic areas of the midbrain representing the substantia nigra were measured planimetrically using standard protocols. In subjects with sufficient temporal acoustic bone windows, mean midbrain hyperechogenic areas were significantly higher in ALS (0.251 ± 0.104 cm²) and PD patients (0.286 ± 0.078 cm²) compared to controls (0.091 ± 0.054 cm²) with no significant difference between ALS and PD patients (one-way ANOVA: F value = 94.3; P < 0.0001). Sixty-seven percent (95 % CI 57–78 %) of ALS patients and 84 % (95 % CI 71–97 %) of PD patients displayed abnormal midbrain hyperechogenic areas (P = 0.383 for group comparison, χ² test). No correlations of hyperechogenic area sizes in ALS patients were found in regard to age, gender, ALS subtype (bulbar versus spinal form) or ALS-FRS-R score. In summary, we observed hyperechogenicity of the substantia nigra in patients with sporadic ALS with a frequency similar to that in PD and higher than in all other movement disorders. These findings are important for the diagnosis and differential diagnosis of PD and ALS alike.