Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson's disease.

Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson's disease (PD) by testing an expanded dose range of VEGF-B (1 and 10 µg) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 µg), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 µg VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p=1.9e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p=0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy controls and PD patients, in neuronal cells that show co-expression with neuromelanin. These results have demonstrated that VEGF-B has potential as a neuroprotective agent for PD therapy and should be further investigated.

Over-expression of the potassium channel Kir2.3 using the dopamine-1 receptor promoter selectively inhibits striatal neurons.

Dysfunction of basal ganglia circuits underlies a variety of movement disorders and neuropsychiatric conditions. Selective control of the electrical activity of striatal outflow pathways by manipulation of ion channel function presents a novel therapeutic approach. Toward this end, we have constructed and studied in vitro an adenoviral gene transfer vector that employs the promoter region of the dopamine-1 receptor to drive expression of the inward rectifier K(+) channel Kir2.3. The use of this neuronal promoter confers cell-type specificity and a physiological level of trans-gene expression in rat primary striatal cultures. The electrophysiological properties were confirmed in transfected human embryonic kidney cells, in which an inwardly-rectifying, Cs(+)-sensitive current was measured by voltage clamp. Current clamp studies of transduced striatal neurons demonstrated an increase in the firing threshold, latency to first action potential and decrease in neuronal excitability. Neurotoxin-induced activation of c-Fos, a marker of neuronal activity, was blocked in transduced neurons indicating that the decrease in electrical excitability was physiologically significant. When used in vivo, this strategy may have the potential to positively impact movement disorders by selectively changing activity of neurons belonging to the direct striatal pathway, characterized by the expression of dopamine-1 receptors.

Altered hippocampal-prefrontal activation in HIV patients during episodic memory encoding.

OBJECTIVE: To investigate the integrity of hippocampal-prefrontal circuitry during episodic encoding in patients with HIV. METHODS: Functional MRI was used to observe changes in blood oxygenation level-dependent (BOLD) signal in 14 HIV-positive participants and 14 age- and education-matched control subjects while performing an episodic encoding task. Subjects also completed neuropsychological measures of attention and memory. RESULTS: Behavioral results revealed no significant differences in neuropsychological performance. The fMRI results revealed that while both groups recruited brain regions known to be important for successful encoding, including bilateral medial temporal lobes and inferior prefrontal gyri, the HIV group demonstrated significantly reduced signal intensity changes in the right posterior hippocampus, right inferior frontal gyrus, and left lingual gyrus. Additionally, the HIV group exhibited more activity within lateral frontal and posterior parietal regions. CONCLUSIONS: This study demonstrates altered integrity of hippocampal-prefrontal regions during episodic encoding in HIV-positive patients. These results extend previous studies that have documented the effects of HIV on fronto-striatal circuits, and suggest the virus functionally impacts the hippocampal system as well.

Developmental regulation of the A-type potassium-channel current in hippocampal neurons: role of the Kvbeta 1.1 subunit.

The rapidly inactivating A-type K+ current (IA) is prominent in hippocampal neurons; and the speed of its inactivation may regulate electrical excitability. The auxiliary K+ channel subunit Kvbeta 1.1 confers fast inactivation to Shaker-related channels and is postulated to affect IA. Whole-cell patch clamp recordings of rat hippocampal pyramidal neurons in primary culture showed a developmental decrease in the time constant of inactivation (tau(in)) of voltage-gated K+ currents: 17.9+/-1.5 ms in young neurons (5-7 days in vitro; n=53, mean+/-S.E.M.); 9.9+/-1.0 ms in mature neurons (12-15 days in vitro; n=72, mean+/-S.E.M., P<0.01). During the same developmental time, the level of Kvbeta 1.1 transcript increased more than two-fold in vitro and in vivo, determined by semi-quantitative reverse transcriptase-polymerase chain reaction for hippocampus. The hypothesis that up-regulation of Kvbeta 1.1 led to the changes in tau(in) was tested in vitro, using antisense knockdown. Kvbeta 1.1-specific antisense DNA was introduced with a modified herpes virus co-expressing enhanced green fluorescent protein and knockdown of Kvbeta 1.1 was verified by immunocytochemistry. Following transduction with the antisense virus, mature neurons reverted to tau(in) values characteristic of young neurons: 18.3+/-2.4 ms (n=20). The effect of antisense knockdown on electrical excitability was tested using current-clamp protocols to induce repetitive firing. Treatment with the antisense virus increased the interspike interval over a range of membrane depolarization (baseline membrane potential=-40 to +20 mV). This effect was most pronounced at -40 mV, where the ISI of the first pair of action potentials was nearly doubled. These data indicate that Kvbeta 1.1 contributes to the developmental control of IA in hippocampal neurons and that the magnitude of effect is sufficient to regulate electrical excitability. Viral-mediated antisense knockdown of Kvbeta 1.1 is capable of decreasing the electrical excitability of post-mitotic hippocampal neurons, suggesting this approach has applicability to gene therapy of neurological diseases associated with hyperexcitability.

Viral vector-mediated expression of K+ channels regulates electrical excitability in skeletal muscle.

Modification of K+ currents by exogenous gene expression may lead to therapeutic interventions in skeletal muscle diseases characterized by alterations in electrical excitability. In order to study the specific effects of increasing outward K+ currents, we expressed a modified voltage-dependent K+ channel in primary cultured rat skeletal muscle cells. The rat Kv1.4 channel was expressed as an N-terminal fusion protein containing a bioluminescent marker (green fluorescent protein). Transgene expression was carried out using the helper-dependent herpes simplex 1 amplicon system. Transduced myoballs, identified using fluorescein optics and studied electrophysiologically with single-cell patch clamp, exhibited a greater than two-fold increase in K+ conductance by 20-30 h after infection. This increase in K+ current led to a decrease in membrane resistance and a 10-fold increase in the current threshold for action potential generation. Electrical hyperexcitability induced by the Na+ channel toxin anemone toxin II (1 microM) was effectively counteracted by overexpression of Kv1.4 at 30-32 h after transduction. Thus, virally induced overexpression of a voltage-gated K+ channel in skeletal muscle has a powerful effect in reducing electrical excitability.

Inferring traits from behaviors versus behaviors from traits: the induction-deduction asymmetry.

It is argued that inductive inferences from behaviors to traits are performed more frequently than deductive inferences from traits to behaviors-a phenomenon referred to as the induction-deduction asymmetry. Two experiments are reported in which behavior-to-trait inferences and trait-to-behavior inferences were compared within the same paradigm: Participants learned a series of descriptions of a target person, half of which were presented in trait form, half in behavior form. A subsequent recognition task was constructed so that some of the items (traits and behaviors) had actually been seen, some were entirely new, and some were new but had been implied by the information given. The 2 experiments provide clear evidence for the hypothesis that traits implied by a behavior are more frequently misidentified as already seen than behaviors implied by a trait. Response-time data in Experiment 2 further suggest that inferences from behaviors to traits are made on-line, whereas inferences from traits to behaviors appear to be memory based.

Medial temporal and prefrontal contributions to working memory tasks with novel and familiar stimuli.

Lesions of parahippocampal structures impair performance of delayed matching tasks in nonhuman primates, suggesting a role for these structures in the maintenance of items in working memory and short-term stimulus matching. However, most human functional imaging studies have not shown medial temporal activation during working memory tasks and have primarily focused on functional magnetic resonance imaging (fMRI) signal intensity changes in the prefrontal and posterior parietal cortex. The goal of this study was to test the hypothesis that the difference between the human and nonhuman primate data results from the use of highly familiar stimuli in human working memory studies and trial-unique stimuli in nonhuman primate studies. We used fMRI to examine prefrontal and temporal lobe activation during performance of a working memory (two-back) task, using blocks of novel and highly familiar complex pictures. Performance of the working memory task with novel complex pictures resulted in greater signal change within medial temporal lobe structures than performance of the task with familiar complex pictures. In contrast, the working memory task with highly familiar stimuli resulted in greater prefrontal activation. These results are consistent without hypothesis that the medial temporal lobe is recruited for the short-term maintenance of information that has no prior representation in the brain, whereas the prefrontal cortex is important for monitoring familiar stimuli that have a high degree of interference. A second set of tasks examined stimulus matching. Subjects performed a target-matching task, during which they identified a single target presented in blocks of novel or familiar stimuli. The results provide evidence of hippocampal and parahippocampal recruitment in the target-matching task with familiar stimuli. These results are consistent with prior animal studies and suggest that prefrontal regions may be important for the monitoring and matching of familiar stimuli which have a high potential for interference, whereas medial temporal regions may become proportionally more important for matching and maintenance of novel stimuli.

From adolescence to adulthood: age-related changes in beliefs about cigarette smoking in a midwestern community sample.

The current study used a cohort-sequential design to examine age-related changes in health-relevant beliefs from the middle school years through age 37 in a large, midwestern, community sample (N=8,556). Results suggest systematic age-related changes such that beliefs in the personalized risks of smoking declined in middle school and then increased, beliefs in generalized health risks increased beginning in the middle school years, and values placed on health as an outcome decreased in the high school years and then increased. These findings suggest that intervention programs must counter declining personalized risk perceptions among middle school students and declining values placed on health among high school age students.

Hyper-reflexia without spasticity after unilateral infarct of the medullary pyramid.

Whether or not a lesion confined to the pyramidal tract produces spasticity in humans remains an unresolved controversy. We have studied a patient with an ischemic lesion of the right medullary pyramid, using objective measures of hyper-reflexia, spasticity, and weakness. Electromyographic activity (EMG) of the biceps muscles was recorded under the following conditions: (1) in response to a tendon tap with an instrumental reflex hammer, (2) in response to imposed quick stretch with motion analysis, and (3) during an isometric holding task. Hyper-reflexia of the involved arm in response to tendon tap was shown to be due primarily to an increase in the gain of the reflex arc. No velocity-dependent increase in the response to quick stretch of the involved arm was present. This was consistent with the absence of detectable spasticity on the clinical exam. These findings suggest that a lesion confined to the medullary pyramid can give rise to weakness and hyper-reflexia without causing spasticity. Moreover, these findings suggest that different anatomical substrates may underlie the clinical phenomena of hyper-reflexia and spasticity.

The natural history of cigarette smoking from adolescence to adulthood in a midwestern community sample: multiple trajectories and their psychosocial correlates.

Previous research on the natural history of smoking has focused on overall group trajectories without considering the possibility of risk subgroup variation. To address this limitation, the authors of the present study aimed to identify subgroups with varying trajectories of smoking behavior. The authors accomplished this within a cohort-sequential study of a large community sample (N = 8,556) with measurements spanning ages 11-31. After removing 2 a priori groups (abstainers and erratics), the authors empirically identified 4 trajectory groups--early stable smokers, late stable smokers, experimenters, and quitters--and psychosocial variables from adolescence and young adulthood were significantly distinguished among them. Given recent advances in quantitative methods, it is now feasible to consider subgroups of trajectories within an overall longitudinal design.

Twin gestation in a woman with a uterus didelphys. A case report.

BACKGROUND: Twin gestation in a uterus didelphys is a rare condition, and the preferred labor course for these patients is unclear. CASE: A woman with a uterus didelphys presented at 14 weeks' gestational age. Serial ultrasound examinations demonstrated normally growing, diamniotic, dichorionic twins situated one in each uterine horn. The prenatal course was marked by intrauterine growth retardation, elevated liver functions and significant proteinuria. At 31 weeks' gestation, labor was induced; however, due to chorioamnionitis and arrest of cervical dilatation, cesarean section was performed 23 hours after rupture of membranes, and two viable female infants (1,480 and 1,421 g) were delivered. CONCLUSION: Twin gestation in a uterus didelphys is a rare condition, in which a trial of labor may be offered, with careful monitoring of both fetuses.

The clinical importance of sociocognitive models of hypnosis: response set theory and Milton Erickson's strategic interventions.

This article documents the contributions and clinical relevance of influential sociocognitive models of hypnosis. We argue that an appreciation of the influence and interplay of sociocognitive constructs, combined with a knowledge of basic research findings, can contribute to sound clinical practice. This article extends previous statements of response set theory (e.g., Kirsch & Lynn, 1998, 1999; Lynn, 1998) by further elucidating the social and cognitive underpinnings of how response sets are established, maintained, and strengthened. It does so by providing a scientific rationale for Milton H. Erickson's most prominent strategic interventions.

Varieties of groups and the perception of group entitativity.

Three studies examined perceptions of the entitativity of groups. In Study 1 (U.S.) and Study 2 (Poland), participants rated a sample of 40 groups on 8 properties of groups (e.g., size, duration, group member similarity) and perceived entitativity. Participants also completed a sorting task in which they sorted the groups according to their subjective perceptions of group similarity. Correlational and regression analyses were used to determine the group properties most strongly related to entitativity. Clustering and multidimensional scaling analyses in both studies identified 4 general types of groups (intimacy groups, task groups, social categories, and loose associations). In Study 3, participants rated the properties of groups to which they personally belonged. Study 3 replicated the results of Studies 1 and 2 and demonstrated that participants most strongly valued membership in groups that were perceived as high in entitativity.

Complications of gynecologic laparoscopy.

STUDY OBJECTIVE: To examine the frequency of gynecologic laparoscopy complications from January 1996 to June 1996. DESIGN: Prospective review (Canadian Task Force classification II-1). SETTING: Tertiary center teaching hospital with 607 beds. PATIENTS: Two hundred thirty-four patients (age 15-70 yrs). INTERVENTIONS: Gynecologic laparoscopy. MEASUREMENTS AND MAIN RESULTS: The overall number of complications was 23 (9.8%). They were principally infection, extraperitoneal insufflation, and injury to blood vessels. Complication rates were examined by service (private, clinic, staff) and by type of laparoscopy (operative, diagnostic, laparoscopic-assisted vaginal hysterectomy). Of 11 (47.8%) complications that occurred during laparoscopic-assisted vaginal hysterectomy, 5 involved postoperative infection. CONCLUSION: The complication rate in this review was similar to that published in the literature, with the exception of ileus and infection, which occurred at higher rates in our institution. (J Am Assoc Gynecol Laparosc 6(3):317-321, 1999)

Maternal socialization of adolescent smoking: the intergenerational transmission of parenting and smoking.

A longitudinal multigenerational design was used to examine the intergenerational transmission of smoking and the correlated transmission of parental support and control. Whether maternal socialization of adolescent smoking (both general parenting practices and smoking-specific strategies) would predict adolescent smoking both directly and indirectly by affecting peer affiliations was tested. There was strong evidence for the intergenerational transmission of cigarette smoking and for the relation between peer smoking and adolescent smoking. Both general parenting practices and smoking-specific discussion and punishment were significantly related to adolescents' smoking, especially for adolescent-reported parenting. Support for the intergenerational transmission of parenting practices emerged only in mothers' reports of support. Results suggest expanding current peer-focused prevention efforts to include parental socialization strategies.

The use and failure rates of protective equipment to prevent blood and bodily fluid contamination in the obstetric health care worker.

OBJECTIVE: To determine the frequency of use and the failure rate of protective equipment by obstetric staff during common obstetric procedures. METHODS: A prospective observational study was conducted of multiple obstetric procedures. The presence, area of specialty, level of training, and gender of each team member were recorded along with the use of protective equipment (cap, mask, eyewear, gown, gloves, and shoe protection). These observations were recorded by two trained observers. Blood and bodily fluid contamination of the protective equipment was quantified and recorded for each person. A forensic medicine reagent (Luminol; Cluefinders Inc., Tampa, FL) was used to detect trace amounts of blood on the inner surface of a selected subset of gowns that had gross external contamination but no obvious penetration. RESULTS: Two hundred forty-one obstetric procedures were observed involving 1022 medical personnel. The use of at least one piece of protective equipment was noted 88% of the time. Compliance with universal precautions by attending and resident physicians in all deliveries (vaginal, forceps, vacuum, cesarean) was observed in 65 (25.2%) medical personnel. The use of protective equipment varied by the type of procedure, area of specialty, and level of training of the team member. In the gowns examined with the forensic medicine reagent, 44% of the cases demonstrated laboratory evidence of penetration. The frequency of gown failure varied with the type of surgical gown used. CONCLUSION: Despite the mandate in the medical community for universal precautions, the rate of compliance remains low. However, even among the compliant medical staff, protective equipment labeled as impenetrable has a high failure rate.

Hydrogen peroxide poisoning causing brain infarction: neuroimaging findings.

OBJECTIVE: We describe the CT and MR imaging findings of the brain in patients who inadvertently poisoned themselves with concentrated hydrogen peroxide. Thirty-five percent hydrogen peroxide is commercially available as an oxidant and disinfectant. This solution is currently sold and promoted in health food stores in the United States as a means of "improving oxygenation" in people with coronary artery disease and other health problems. CONCLUSION: Our findings show the high toxicity of concentrated hydrogen peroxide. CNS damage and death are likely consequences after ingestion of this agent.

Within-target illusory correlations and the formation of context-dependent attitudes.

Two experiments explored the formation of context-dependent attitudes about a single social target. One such mechanism for the development of differential attitudes toward a target in different contexts is illusory correlation formation. It was proposed that within-target illusory correlations (i.e., perceiving unwarranted associations between salient target behaviors and distinctive domains in which the target is observed) can result in biased evaluations of a social target in different domains (e.g., home vs. work). When memory-based (vs. on-line) judgments were induced, perceivers formed context-dependent attitudes for both group (Experiment 1) and individual (Experiment 2) targets. These findings are consistent with theories regarding multiply categorizable attitude objects. Further, they suggest that some apparent discrepancies between attitudes and behavior may reflect holding multiple context-dependent attitudes about social targets.

Target entitativity: implications for information processing about individual and group targets.

It is hypothesized that perceptions of entitativity (i.e., seeing social targets as possessing unity and coherence) have important implications for how one organizes information about, and forms impressions of, individual and group targets. When perceivers expect entitativity, they should form an integrated impression of the target, resulting in on-line judgments. However, when perceivers expect little entitativity, they should not process target-relevant information in an integrative fashion, resulting in memory-based judgments. Although many factors affect perceptions of entitativity, the current study focused on expectations of similarity and behavioral consistency. It was predicted that in general, perceivers expect greater entitativity for individual than group targets. However, when explicitly provided with similar expectancies of entitativity, information processing would be similar for both individual and group targets. Two experiments supported these predictions, using recall, memory-judgment correlation, and illusory correlation measures.