bluuebunny/crossref_metadata_2025 huggingface dataset:
Experience‐Dependent Affective Learning and Risk for Psychopathology in Children
Authors: POLLAK SETH D.
Published: March 2004

Abstract: The influence of childhood affective experiences across development may be understood in terms of preparedness to learn about emotion, combined with general immaturity and neuro‐plasticity of perceptual systems. Early in development, processing resources are relatively immature and limited in capacity, thereby constraining how much information the young child can absorb. But it is clear that learning about emotions proceeds swiftly in nearly all children, suggesting biological preparedness to track associations between certain stimuli and outcomes. It is proposed here that limited processing capacity, in tandem with dispositions to filter or select key privileged stimuli in the environment, facilitates adaptive, rapid, affective learning. The developmental organization of affective systems is contingent upon those features of input that are most learnable, such as signals that are particularly salient, frequent, or predictable. Therefore, plasticity confers risk for maladaptation in that children's learning will be based upon these prominent features of the environment, however aberrant.
Applying Learning Principles to the Treatment of Post‐Trauma Reactions
Authors: ROTHBAUM BARBARA OLASOV , DAVIS MICHAEL
Published: March 2004

Abstract:Posttraumatic stress disorder (PTSD) can be characterized as a failure of recovery caused, in part, by a failure of fear extinction after trauma. By studying the process of extinction, we can be informed regarding the etiology and maintenance of PTSD. The normal response to trauma in humans includes a set of predictable reactions including reexperiencing, avoidance, and hyperarousal that typically extinguish in the days and weeks after the trauma. In the majority of people exposed to trauma, these responses extinguish over time. However, in a substantial minority, extinction fails and these persisting responses become the symptoms of PTSD. Therefore, one of our fundamental hypotheses is that PTSD is a disorder caused in part by the failure of extinction of predictable posttraumatic physiological and psychological reactions. The most empirically validated treatments for PTSD involve exposure of the patient to trauma‐related cues in the absence of danger that then lead to the extinction of these reexperiencing, avoidance, and arousal symptoms. There is also mounting evidence that individuals with PTSD are more resistant to extinction. Regarding early interventions with traumatized individuals, there is mounting evidence that some early one‐time interventions actually may impede extinction, whereas interventions delivered in more than one session, at least several weeks after the trauma, to individuals continuing to experience above average reactions, generally are effective in preventing the development of PTSD. Thus, there appears to be an interaction between timing of the intervention, number of intervention sessions, and either arousal level and/or risk status in determining whether the intervention will be helpful, harmful, or neutral.
Gene‐Environment Interactions and the Neurobiology of Social Conflict
Authors: SUOMI STEPHEN J.
Published: March 2004

Abstract:Recent research has disclosed marked individual differences in biobehavioral responses to social conflicts exhibited by rhesus monkeys across the life span. For example, approximately 5–10% of rhesus monkeys growing up in the wild consistently exhibit impulsive and/or inappropriately aggressive responses to mildly stressful situations throughout development; those same individuals also show chronic deficits in their central serotonin metabolism. These characteristic patterns of biobehavioral response emerge early in life and remain remarkably stable from infancy to adulthood. Laboratory studies have demonstrated that although these characteristics are highly heritable, they are also subject to major modification by specific early experiences, particularly those involving early social attachment relationships. Moreover, genetic and early experience factors can interact, often in dramatic fashion. For example, a specific polymorphism in the serotonin transporter gene is associated with deficits in early neurobehavioral functioning and serotonin metabolism, extreme aggression, and excessive alcohol consumption among monkeys who experienced insecure early attachment relationships, but not in monkeys who developed secure attachment relationships with their mothers during infancy. Because daughters tend to develop the same type of attachment relationships with their own offspring that they experienced with their mothers early in life, such early experiences provide a possible nongenetic mechanism for transmitting these patterns to subsequent generations.
The Policy Context for Child and Adolescent Mental Health Services: Implications for Systems Reform and Basic Science Development
Authors: HOAGWOOD KIMBERLY
Published: March 2004

Abstract: Significant state and national policy initiatives are focusing on strategies for financing and structuring the delivery of evidence‐based services for children. These initiatives reflect, in part, an increased awareness of and respect for scientific standards about effective treatments and services. At the same time, major studies of system reform and organizational behavior are calling into question the effectiveness of current practices and identifying the complexities of taking science‐based services to scale. Four major policy initiatives are described and the implications of scientific developments within the basic neurosciences for improving policy, practice, and service in children's mental health is discussed.
Neural Substrates Underlying Impulsivity
Authors: KING JEAN A. , TENNEY JEFFREY , ROSSI VICTORIA , COLAMUSSI LAURALEA , BURDICK STACY
Published: March 2004

Abstract: Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder whose three main symptoms are impulsiveness, inattention, and hyperactivity. Although ADHD is an early developmental disorder, it may persist into adulthood, resulting in deficits associated with poor academic performance, frequent job changes, poor and unstable marriages, and increases in motor vehicle accidents. Of the three primary symptoms of ADHD, deficits in impulse control are the most challenging to the social network and the judicial system. While the etiology of ADHD remains unknown, recent work suggests that the central deficits in ADHD may be due to poor response inhibition that is linked to monoamine and prefrontal lobe deficiencies. In the past, preclinical studies designed to understand the lack of impulse control have generally been relegated to studies linked to aggression and drug abuse. With the use of innovative noninvasive techniques, like anatomical and functional magnetic resonance imaging, selective neurochemical and behavioral paradigms have converged with preclinical reports and lend support to the premise that monoaminergic neurotransmitter systems and the cortio‐striatal circuitry are essential to impulse control. Furthermore, new emerging data on neural substrates underlying impulsivity have incorporated brain regions involved in reinforcement, reward, and decision making such as the nucleus accumbens, cerebellum, and amygdala. As noninvasive brain imaging, neurochemical, and behavioral approaches are combined, our knowledge of the neural networks underlying impulsivity will hopefully give rise to therapeutic approaches aimed at alleviating this disorder.
Response Inhibition and Disruptive Behaviors
Authors: NIGG JOEL T.
Published: March 2004

Abstract: Response disinhibition is one of several processes that may account for disruptive behavior problems. It is associated with both attention deficits/hyperactivity (ADHD‐C) and early onset, unsocialized conduct disorder (CD‐E). Response inhibition is not a unitary construct. It is best understood via a dual process model of regulatory control. Executive inhibition refers to deliberate suppression of immediate motor behavior in the service of a distal goal in working memory, with relatively low anxiety activation. It is instantiated in the same frontal‐striatal‐thalamic neural loops as executive function and corresponds in temperament theory to effortful control. Motivational or reactive inhibition refers to anxiety‐provoked interruption of behavior in the context of unexpected, novel, or punishment‐cue indicators. Along with reward‐response and hostile/angry response it corresponds to reactivity in temperament theory, and invokes limbic responsivity. With regard to these types of inhibitory control, ADHD‐combined type is predominantly associated with dysfunctional executive inhibition. CD‐E is predominantly associated with dysfunctions in the motivational inhibition process, with smaller, secondary effects in executive control. However, in both syndromes etiological heterogeneity is notable. For example, recent evidence indicates that executive inhibitory control is familial, but characterizes only a subset of children with ADHD‐C. Recent dual‐process models for both ADHD‐C and CD‐E are therefore important; they are noted and integrated. Examination of the correlates of behavioral inhibition in the subgroups with these inhibitory deficits may prove fruitful in clarifying the diverse routes to disruptive psychopathology in children.
Irritability in Pediatric Mania and Other Childhood Psychopathology
Authors: LEIBENLUFT ELLEN , BLAIR R JAMES R. , CHARNEY DENNIS S. , PINE DANIEL S.
Published: March 2004

Abstract:Irritability is an important symptom in childhood psychopathology that has received relatively little research attention. Recent controversy concerning the diagnosis of mania in children has focused attention on how little is known about how to assess irritability in a systematic way, and about its diagnostic associations. For example, subtyping irritability according to course (chronic vs. episodic), precipitants, and family history may facilitate the identification of psychopathology and the study of pathophysiology. While normative and pathologic irritability can be differentiated reliably, the validity of the distinction is unclear. In addition, there is a need for scales designed to measure the severity of irritability in children with mood and anxiety disorders. In order to facilitate research, we propose a definition of irritability from the perspective of affective neuroscience. Because reactive aggression may be a helpful animal model for irritability, we review the neural circuitry mediating this behavior. Behavioral paradigms that evoke frustration, as well as those that assess the ability to inhibit a prepotent motor response, maintain attentional focus, execute response reversal, recognize angry faces, and regulate emotional responses, may be useful in the study of irritability. Examples of such paradigms are described, and the pharmacology of irritability is reviewed briefly.
Brain Imaging Studies of the Anatomical and Functional Consequences of Preterm Birth for Human Brain Development
Authors: PETERSON BRADLEY S.
Published: March 2004

Abstract: Premature birth can have devastating effects on brain development and long‐term functional outcome. Rates of psychiatric illness and learning difficulties are high, and intelligence on average is lower than population means. Brain imaging studies of infants born prematurely have demonstrated reduced volumes of parietal and sensorimotor cortical gray matter regions. Studies of school‐aged children have demonstrated reduced volumes of these same regions, as well as in temporal and premotor regions, in both gray and white matter. The degrees of these anatomical abnormalities have been shown to correlate with cognitive outcome and with the degree of fetal immaturity at birth. Functional imaging studies have shown that these anatomical abnormalities are associated with severe disturbances in the organization and use of neural systems subserving language, particularly for school‐aged children who have low verbal IQs. Animal models suggest that hypoxia‐ischemia may be responsible at least in part for some of the anatomical and functional abnormalities. Increasing evidence suggests that a host of mediators for hypoxic‐ischemic insults likely contribute to the disturbances in brain development in preterm infants, including increased apoptosis, free‐radical formation, glutamatergic excitotoxicity, and alterations in the expression of a large number of genes that regulate brain maturation, particularly those involved in the development of postsynaptic neurons and the stabilization of synapses. The collaboration of both basic neuroscientists and clinical researchers is needed to understand how normal brain development is derailed by preterm birth and to develop effective prevention and early interventions for these often devastating conditions.
Integrating Neuroscience and Psychological Approaches in the Study of Early Experiences
Authors: GUNNAR MEGAN R.
Published: March 2004

Abstract: Rodent maternal separation and primate rearing environment paradigms demonstrate that early disturbances in caregiving that sensitize stress‐responsive neurocircuits may play a role in the etiology of mood disorders. Psychosocial studies document the importance of adverse early experiences in the risk for psychopathology. The time is ripe for integrating the animal neuroscience and human psychosocial research on early experiences and stress. Based on work by the National Institute of Mental Health Early Experience, Stress Neurobiology & Prevention Science research network, findings in the human literature that are consistent with those in animal models are reviewed. In addition, however, anomalous findings and the challenge they pose in translating the basic neuroscience findings to human development are also discussed.
The Serotonin Transporter Gene in Aggressive Children with and without ADHD and Nonaggressive Matched Controls
Authors: BEITCHMAN JOSEPH H. , DAVIDGE KRISTEN M. , KENNEDY JAMES L. , ATKINSON LESLIE , LEE VIVIEN , SHAPIRO SOLOMON , DOUGLAS LORI
Published: March 2004

Abstract: Using an ethnically homogeneous sample of highly aggressive Caucasian children and their matched controls, we report differential associations of the 5HTTLPR and VNTR polymorphisms with ADHD and aggression, respectively. Given the small sample size and the peliminary nature of our findings, replication is necessary.
Effortful Control, Attention, and Aggressive Behavior in Preschoolers at Risk for Conduct Problems
Authors: DENNIS TRACY A. , BROTMAN LAURIE MILLER
Published: March 2004

Abstract: This work examines distinct aspects of effortful control and attention predicted aggression in a group of children at elevated risk for the development of conduct problems. Results suggested that behavioral inhibition, rather than attentional control, best predicted maternal reports of child aggressive behaviors.
Hallucinations in Nonpsychotic Children
Authors: EDELSOHN GAIL A. , RABINOVICH HARRIS , PORTNOY RUBEN
Published: March 2004

Abstract: Sixty‐two cases of children with hallucinations but without psychosis were identified in a psychiatric emergency service. Auditory hallucinations were more frequent than visual ones. There were positive trends between the content of auditory hallucinations and diagnosis. Recognition of this clinical phenomenon of hallucinations in children in the absence of psychosis and awareness of underlying psychopathology and precipitating factors is necessary in evaluating hallucinations in nonpsychotic children. Children with such presentations run the risk of being misdiagnosed as having psychosis or schizophrenia and being subjected to the inherent risks of treatment with antipsychotics.
Subanalysis of the Location of White Matter Hyperintensities and Their Association with Suicidality in Children and Youth
Authors: EHRLICH STEFAN , NOAM GIL G. , IN KYOON LYOO  , KWON BAE J. , CLARK MEGAN A. , RENSHAW PERRY F.
Published: March 2004

Abstract: Our previous research with psychiatrically hospitalized children and youth indicates that white matter hyperintensities (WMH) on T2‐weighted MRI images are associated with a history of suicide attempt. This subanalysis of the specific locations of the WMH suggests that youth with deep WMH in the parietal lobe but not in the frontal lobe have a significantly higher prevalence of reported past suicide attempt.
Longitudinal Assessment of Callous/Impulsive Traits, Substance Abuse, and Symptoms of Depression in Adolescents
Authors: NEUMANN CRAIG S. , VITACCO MICHAEL , ROBERTSON ANGELA , SEWELL KENNETH
Published: March 2004

Abstract: Latent variable structural modeling was used to examine the associations among callous/impulsive personality traits, substance abuse, and symptoms of depression in a sample of 156 adjudicated male adolescents. Assessments were conducted at baseline and 6‐month follow‐up. The results highlight an unfolding of interrelationships among disturbances in personality, substance use, and mood over time.
Prenatal Nicotine Exposure and Behavior
Authors: ROSSI V , MESSENGER T , PETERS D , FERRIS C , KING J
Published: March 2004

Abstract: Prenatal exposure to nicotine has been associated with changes in behavioral indices in offspring. Flank marking, a scent‐marking behavior in golden hamsters, appears to be controlled by arginine vasopressin (AVP) neurons in the hypothalamus. The present study examines the effects of prenatal exposure to nicotine on the vasopressinergic system associated with flank marking behavior.
Familial Psychiatric Disorders in Child DSM‐IV ADHD: Moderation by Child Gender
Authors: STAWICKI JULIEANN , NIGG JOEL T.
Published: March 2004

Abstract: Examined selected psychiatric disorders in parents of boys and girls with DSM‐IV ADHD and control children. Excess parent psychopathology was observed for parents of boys—primarily due to psychopathology in fathers—score potential gender differences in development of ADHD.
Early Deprivation Alters the Vocalization Behavior of Neonates Directing Maternal Attention in a Rat Model of Child Neglect
Authors: ZIMMERBERG BETTY , KIM JU H. , DAVIDSON ABIGAIL N. , ROSENTHAL ABIGAIL J.
Published: March 2004

Abstract: Animal models of child neglect (known as maternal separation or early deprivation) have suggested a causal link to subsequent depression and/or anxiety in children. In this experiment, the acoustical features of the ultrasonic calls emitted by a rat pup when separated from its dam were analyzed as well as the maternal behavior when the dam was allowed to retrieve the pup. Bout structure and harmonic double shifts did differ between controls and “neglected” pups, as did maternal attention. This model will be used to determine neural mechanisms underlying deficits in attachment behavior.
Phase II Trial of Cetuximab in Patients With Refractory Colorectal Cancer That Expresses the Epidermal Growth Factor Receptor
Authors: Saltz Leonard B. , Meropol Neal J. , Loehrer Patrick J. , Needle Michael N. , Kopit Justin , Mayer Robert J.
Published: March 2004

Purpose

To evaluate the antitumor activity and toxicity of single-agent cetuximab in patients with chemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor.

Patients and Methods

Phase II, open-label clinical trial. Patients were required to have EGFr expression demonstrated on formalin-fixed paraffin-embedded tumor tissue by immunohistochemical staining before study participation. Patients were required to have received irinotecan, either alone or in a combination regimen, and to have demonstrated clinical failure on this regimen before study entry. Cetuximab was administered weekly by intravenous infusion. The first dose of 400 mg/m2 was given during the course of 2 hours. Subsequent weekly treatments were given at a dose of 250 mg/m2 during the course of 1 hour.

Results

Fifty-seven eligible patients were treated. All were assessable for toxicity and response. The most commonly encountered grade 3 to 4 adverse events, regardless of relationship to study drug, were an acne-like skin rash, predominantly on the face and upper torso (86% with any grade; 18% with grade 3), and a composite of asthenia, fatigue, malaise, or lethargy (56% with any grade, 9% with grade 3). Two patients (3.5%) experienced grade 3 allergic reactions requiring discontinuation of study treatment. A third patient experienced a grade 3 allergic reaction that resolved, and the patient continued on the study. Neither diarrhea nor neutropenia were dose limiting in any of the 57 patients treated. Five patients (9%; 95% CI, 3% to 19%) achieved a partial response. Twenty-one additional patients had stable disease or minor responses. The median survival in these previously treated patients with chemotherapy-refractory colorectal cancer is 6.4 months.

Conclusion

Cetuximab on this once-weekly schedule has modest activity and is well-tolerated as a single agent in patients with chemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor. Further studies of cetuximab will evaluate the use of cetuximab in conjunction with first-line and adjuvant treatments for this disease.
GATA-4 and GATA-6 Modulate Tissue-Specific Transcription of the Human Gene for P450c17 by Direct Interaction with Sp1
Authors: Flück Christa E. , Miller Walter L.
Published: March 2004

Cytochrome P450c17 catalyzes steroidogenic 17α-hydroxylase and 17,20 lyase activities. Expression of the gene for P450c17 is cAMP dependent, tissue specific, developmentally programmed, and varies among species. Binding of Sp1, Sp3, and NF1-C (nuclear factor 1-C) to the first 227 bp of 5′flanking DNA (−227/LUC) is crucial for basal transcription in human NCI-H295A adrenal cells. Human placental JEG-3 cells contain Sp1, Sp3, and NF1, but do not express −227/LUC, even when transfected with a vector expressing steroidogenic factor 1 (SF-1). Therefore, other factors are essential for basal expression of P450c17. Deoxyribonuclease I footprinting and EMSAs identified a GATA consensus site at −64/−58 and an SF-1 site at −58/−50. RT-PCR identified GATA-4, GATA-6, and SF-1 in NCI-H295A cells and GATA-2 and GATA-3, but not GATA-4, GATA-6, or SF-1 in JEG-3 cells. Cotransfection of either GATA-4 or GATA-6 without SF-1 activated −227/LUC in JEG-3 cells, but cotransfection of GATA-2 or GATA-3 with or without SF-1 did not. Surprisingly, mutation of the GATA binding site in −227/LUC increased GATA-4 or GATA-6 induced activity, whereas mutation of the Sp1/Sp3 site decreased it. Furthermore, promoter constructs including the GATA site, but excluding the Sp1/Sp3 site at −196/−188, were not activated by GATA-4 or GATA-6, suggesting an interaction between Sp1/Sp3 and GATA-4 or GATA-6. Glutathione-S-transferase pull-down experiments and coimmunoprecipitation demonstrated interaction between GATA-4 or GATA-6 and Sp1, but not Sp3. Chromatin immunoprecipitation assays confirmed that this GATA-4/6 interaction with Sp1 occurred at the Sp site in the P450c17 promoter in NCI-H295A cells. Demethylation with 5-aza-2-deoxycytidine permitted JEG-3 cells to express endogenous P450c17, SF-1, GATA-4, GATA-6, and transfected −227/LUC. Thus, GATA-4 or GATA-6 and Sp1 together regulate expression of P450c17 in adrenal NCI-H295A cells and methylation of P450c17, GATA-4 and GATA-6 silence the expression of P450c17 in placental JEG-3 cells.
Generation of Thyrotropin-Releasing Hormone Receptor 1-Deficient Mice as an Animal Model of Central Hypothyroidism
Authors: Rabeler Roland , Mittag Jens , Geffers Lars , Rüther Ulrich , Leitges Michael , Parlow Albert F. , Visser Theo J. , Bauer Karl
Published: March 2004

To provide an animal model of central hypothyroidism, mice deficient in the TRH-receptor 1 (TRH-R1) gene were generated by homologous recombination. The pituitaries of TRH-R1−/− mice are devoid of any TRH-binding capacity, demonstrating that TRH-R1 is the only receptor localized on TRH target cells of the pituitary. With the exception of some retardation in growth rate, TRH-R1−/− mice appear normal, but compared with control animals they exhibit a considerable decrease in serum T3, T4, and prolactin (PRL) levels but not in serum TSH levels. In situ hybridization histochemistry and real-time RT-PCR analysis revealed that in adult TRH-R1−/− animals TSHβ-mRNA expression is not impaired whereas PRL mRNA and GH mRNA levels are considerably reduced compared with control mice. The numbers of thyrotropes, somatotropes, and lactotropes, however, are not affected by the deletion of the TRH-R1 gene. The mutant mice are fertile, and the dams nourish their pups well, indicating that TRH is not a decisive factor for suckling-induced PRL release. In situ hybridization and quantitative RT-PCR analysis, furthermore, revealed that, as in control animals, pituitary PRL-mRNA expression in TRH-R1−/− is considerably increased during lactation, albeit strongly reduced as compared with lactating control animals.
Blocking actions of glibenclamide on ATP-sensitive K+ channels in pig urethral myocytes
Authors: Teramoto Noriyoshi , Zhu Hai-Lei , Ito Yushi
Published: March 2004

The inhibitory effects of glibenclamide on the levcromakalim-induced ATP-sensitive K+ (KATP) channels were investigated with cell-attached configuration in pig proximal urethra. Application of 10 μm glibenclamide reversibly inhibited the activity of the 100 μm levcromakalim-induced KATP channel, decreasing not only the channel open probability but also the amplitude of unitary current. The inhibitory concentration-response curve of the glibenclamide-induced sublevel conductance of KATP channel was shifted to the right (IC50=4.7 μm), compared with the levcromakalim-induced KATP channel (full conductance, IC50=0.5 μm). Glibenclamide is the first reported sulphonylurea to selectively block KATP channel, not only by decreasing the channel activity but also by reducing the unitary amplitude in smooth muscle.
Inhibition of acetylcholinesterase by Tea Tree oil
Authors: Mills Clive , Cleary Brian V , Walsh John J , Gilmer John F
Published: March 2004

Pediculosis is a widespread condition reported in schoolchildren. Treatment most commonly involves the physical removal of nits using fine-toothcombs and the chemical treatment of adult lice and eggs with topical preparations. The active constituents of these preparations frequently exert their effects through inhibition of acetylcholinesterase (AChE, EC 3.1.1.7). Increasing resistance to many preparations has led to the search for more effective treatments. Tea Tree oil, otherwise known as Melaleuca oil, has been added to several preparations as an alternative treatment of head lice infestations. In this study two major constituents of Tea Tree oil, 1,8-cineole and terpinen-4-ol, were shown to inhibit acetylcholinesterase at IC50 values (inhibitor concentrations required to give 50% inhibition) of 0.04 and 10.30 mm, respectively. Four samples of Tea Tree oil tested (Tisserand, Body Treats, Main Camp and Irish Health Culture Association Pure Undiluted) showed anticholinesterase activity at IC50 values of 0.05, 0.10, 0.08 and 0.11 μL mL−1, respectively. The results supported the hypothesis that the insecticidal activity of Tea Tree oil was attributable, in part, to the anticholinesterase activity of Tea Tree oil.
Human skin permeation of Δ8-tetrahydrocannabinol, cannabidiol and cannabinol
Authors: Stinchcomb Audra L , Valiveti Satyanarayana , Hammell Dana C , Ramsey Diana R
Published: March 2004

The purpose of this study was to quantify the in-vitro human skin transdermal flux of Δ8-tetrahydrocannabinol (Δ8-THC), cannabidiol (CBD) and cannabinol (CBN). These cannabinoids are of interest because they are likely candidates for transdermal combination therapy. Differential thermal analysis and in-vitro diffusion studies with human tissue were completed for the compounds. Heats of fusion, melting points and relative thermodynamic activities were determined for the crystalline compounds, CBD and CBN. Flux, permeability, tissue concentration and lag times were measured in the diffusion experiments. CBN had a lower heat of fusion and corresponding higher calculated relative thermodynamic activity than CBD. Ethanol concentrations of 30 to 33% significantly increased the transdermal flux of Δ8-THC and CBD. Tissue concentrations of Δ8-THC were significantly higher than for CBN. Lag times for CBD were significantly smaller than for CBN. The permeabilities of CBD and CBN were 10-fold higher than for Δ8-THC. Combinations of these cannabinoids with ethanol will be further studied in transdermal patch formulations in vitro and in vivo, as significant flux levels of all the drugs were obtained. CBD, the most polar of the three drugs, and other more polar cannabinoids will also be the focus of future drug design studies for improved transdermal delivery rates.
Pharmacokinetic interaction of ibuprofen enantiomers in rabbits
Authors: Lin Wenhui , Hayakawa Toru , Yanaguimoto Hitomi , Kuzuba Mamoru , Obara Takako , Inotsume Nobuo , Lin Wenhui , Cui Fude , Ding Guohua
Published: March 2004

The potential interaction between two ibuprofen enantiomers was studied after intravenous administration of R-(–)-, S-(+)- and racemic ibuprofen to rabbits. The total body clearance values calculated by compartmental model analysis (0.65+0.21 for R-(–)-ibuprofen and 0.63+0.34 for S-(+)-ibuprofen) after intravenous administration of the racemate of ibuprofen were significantly smaller than those of individual enantiomers (0.95+0.23 for R-(–)-ibuprofen and 1.03+0.23 for S-(+)-ibuprofen), indicating that the enantiomer–enantiomer interaction results in a mutual inhibition. The enantiomeric interaction in the pharmacokinetic behaviour of ibuprofen after racemic administration is considered to be a result of an alteration in the metabolic or excretion phase (or both) rather than stereoselective protein binding in the systemic distribution.
Pharmacokinetics and distribution of sodium 3,4-diaminonaphthalene-1-sulfonate, a Congo Red derivative active in inhibiting PrPres replication
Authors: Gervasoni M , Pirola R , Mantegazza P , Bareggi S R , Pollera C , Poli G , Villa S , Cignarella G , Gervasoni M , Pirola R , Pollera C , Villa S , Cignarella C , Mantegazza P , Poli G , Bareggi S R
Published: March 2004

Sodium 3,4-diaminonaphthalene-1-sulfonate (CRA) is a compound, synthesised by our group from Congo Red (CR), that is active in preventing the pathological conversion of normal prion protein (PrP). As the precise mechanisms controlling the ways in which prions are distributed and infect the brain and other organs are not fully understood, studying the pharmacokinetics of drugs that are active against prions may clarify their targets and their means of inhibiting prion infection. This paper describes the pharmacokinetics of CRA in plasma, spleen and brain after single or repeated intraperitoneal or subcutaneous administration, as determined by means of specific and sensitive fluorimetric HPLC. A single intraperitoneal administration led to peak plasma CRA concentrations after 15 min, followed by biphasic decay with an apparent half-life of 4.3 h. After subcutaneous administration, Tmax was reached after 30 min, and was followed by a similar process of decay: Cmax and the AUC0-last were 25% those recorded after intraperitoneal administration. The mean peak concentrations and AUCs of CRA after a single intraperitoneal or subcutaneous administration in peripheral tissue (spleen) were similar to those observed in blood, whereas brain concentrations were about 2% those in plasma. After repeated intraperitoneal or subcutaneous doses, the Cmax values in plasma, brain and spleen were similar to those observed at the same times after a single dose. After repeated intraperitoneal doses, CRA was also found in the ventricular cerebrospinal fluid at concentrations of 1.8 + 0.2 μg mL−1, which is similar to, or slightly higher than, those found in brain. Brain concentrations may be sufficient to explain the activity of CRA on PrP reproduction in the CNS. However, peripheral involvement cannot be excluded because the effects of CRA are more pronounced after intraperitoneal than after intracerebral infection.
Small intestinal glucose absorption in cystic fibrosis: a study in human and transgenic ΔF508 cystic fibrosis mouse tissues
Authors: Hardcastle J , Harwood M D , Taylor C J
Published: March 2004

Intestinal transport is disturbed in cystic fibrosis (CF), with both defective Cl− secretion and changes in absorption being reported. We have examined the effects of the disease on Na+-dependent glucose absorption by the small intestine. Active glucose absorption was monitored as changes in short-circuit current (SCC) in intact and stripped intestinal sheets from normal (Swiss) and transgenic CF (Cftrtm 1 Eur and Cftrtm 2 Cam) mice with the ΔF508 mutation, and in jejunal biopsies from children with CF and normal controls. Na+-dependent glucose uptake at the luminal membrane was measured in brush-border membrane vesicles (BBMVs). Intact and stripped sheets of jejunum and midintestine from Swiss mice exhibited a concentration-dependent increase in SCC with glucose. Apparent Km values were similar in the two preparations, but the apparent Vmax was greater in stripped sheets. This difference was not due to a loss of neural activity in stripped sheets as tetrodotoxin did not influence the glucose-induced SCC in intact sheets. Similar results were observed in stripped sheets of jejunum and mid-intestine from wild-type Cftrtm 1 Eur mice, but in tissues from CF mice the apparent Vmax value was reduced significantly. A lower Vmax was also obtained in intact sheets of mid-intestine from CF (Cftrtm 2 Cam) mice. Jejunal biopsies from CF patients however, exhibited an enhanced glucose-dependent rise in SCC. Na+-dependent uptake by BBMVs from CF (Cftrtm 1 Eur) mice was not reduced compared with wild-type and Swiss BBMVs. It was concluded that, in contrast to human intestine, intestinal glucose absorption was reduced in transgenic mouse models of CF with the ΔF508 mutation, but that this could not be detected in an isolated preparation of brush-border membranes. Transgenic mouse models of CF may not accurately reflect all aspects of intestinal dysfunction in the human disease.
The emulsification and solubilisation properties of polyglycolysed oils in self-emulsifying formulations
Authors: Devani Manisha , Ashford Marianne , Craig Duncan Q M
Published: March 2004

Self-emulsifying drug delivery systems (SEDDS), whereby drugs are dispersed in an oil–surfactant mix that emulsifies on contact with water, represent a highly promising approach for enhancing oral bioavailability. However, the choice of formulation is, at present, largely empirical both in terms of the composition dependence of the emulsification process and the solubilisation of the drug in the initial oil–surfactant mixture. In this investigation, a range of chemically related self-emulsifying systems have been studied, based on the Labrafil family of polyglycolysed oils, using Tween 80 and Tween 20 as surfactants. The ease of emulsification, the particle size distribution and the appearance of the emulsion droplets were studied as a function of composition, while the solubility of danazol and mefenamic acid in the various oil–surfactant mixes was measured. It was noted that dilution of the emulsions led to apparent change in particle size distribution. The more hydrophilic oil–surfactant mixes showed a greater ease of emulsification and a lower particle size. It was also noted that multiple emulsions could be formed using systems of lower polarity. A linear relationship was observed between the hydrophile–lipophile balance (HLB) of the mix and the solubility of both danazol and mefenamic acid, with more hydrophilic mixes showing greater drug solubility values. The study has indicated that, within the range studied, more hydrophilic mixes tend to result in superior emulsification properties and greater drug solubility.
Histatins: antimicrobial peptides with therapeutic potential
Authors: Kavanagh Kevin , Dowd Susan
Published: March 2004

Histatins are a group of antimicrobial peptides, found in the saliva of man and some higher primates, which possess antifungal properties. Histatins bind to a receptor on the fungal cell membrane and enter the cytoplasm where they target the mitochondrion. They induce the non-lytic loss of ATP from actively respiring cells, which can induce cell death. In addition, they have been shown to disrupt the cell cycle and lead to the generation of reactive oxygen species. Their mode of action is distinct from those exhibited by the conventional azole and polyene drugs, hence histatins may have applications in controlling drug-resistant fungal infections. The possibility of utilising histatins for the control of fungal infections of the oral cavity is being actively pursued with the antifungal properties of topical histatin preparations and histatin-impregnated denture acrylic being evaluated. Initial clinical studies are encouraging, having demonstrated the safety and efficacy of histatin preparations in blocking the adherence of the yeast Candida albicans to denture acrylic, retarding plaque formation and reducing the severity of gingivitis. Histatins may represent a new generation of antimicrobial compounds for the treatment of oral fungal infections and have the advantage, compared with conventional antifungal agents, of being a normal component of human saliva with no apparent adverse effects on host tissues and having a mode of action distinct to azole and polyene antifungals.
polyhomeoticis required for somatic cell proliferation and differentiation during ovarian follicle formation inDrosophila
Authors: Narbonne Karine , Besse Florence , Brissard-Zahraoui Jeanine , Pret Anne-Marie , Busson Denise
Published: March 2004

The polyhomeotic (ph) gene of Drosophila is a member of the Polycomb group (Pc-G) genes, which are required for maintenance of a repressed state of homeotic gene transcription, which stabilizes cell identity throughout development. The ph gene was recovered in the course of a gain-of-function screen aimed at identifying genes with a role during ovarian follicle formation in Drosophila, a process that involves coordinated proliferation and differentiation of two cell lineages, somatic and germline. Subsequent analysis revealed that ph loss-of-function mutations lead to production of follicles with greater or fewer than the normal number of germ cells associated with reduced proliferation of somatic prefollicular cells, abnormal prefollicular cell encapsulation of germline cysts and an excess of both interfollicular stalk cells and polar cells. Clonal analysis showed that ph function for follicle formation resides specifically in somatic cells and not in the germline. This is thus the first time that a role has been shown for a Pc-G gene during Drosophila folliculogenesis. In addition,we tested mutations in a number of other Pc-G genes, and two of them, Sex combs extra (Sce) and Sex comb on midleg(Scm), also displayed ovarian defects similar to those observed for ph. Our results provide a new model system, the Drosophilaovary, in which the function of Pc-G genes, distinct from that of control of homeotic gene expression, can be explored.
Genetic disruptions ofO/E2andO/E3genes reveal involvement in olfactory receptor neuron projection
Authors: Wang Song S. , Lewcock Joseph W. , Feinstein Paul , Mombaerts Peter , Reed Randall R.
Published: March 2004

The mammalian Olf1/EBF (O/E) family of repeated helix-loop-helix (rHLH)transcription factors has been implicated in olfactory system gene regulation,nervous system development and B-cell differentiation. Ebf(O/E1) mutant animals showed defects in B-cell lineage and brain regions where it is the only O/E family member expressed, but the olfactory epithelium appeared unaffected and olfactory marker expression was grossly normal in these animals. In order to further study the mammalian O/E proteins,we disrupted O/E2 and O/E3 genes in mouse and placed tau-lacZ and tau-GFP reporter genes under the control of the respective endogenous O/E promoters. Mice mutant for each of these genes display reduced viability and other gene-specific phenotypes. Interestingly, both O/E2 and O/E3 knockout mice as well as O/E2/O/E3 double heterozygous animals share a common phenotype:olfactory neurons (ORN) fail to project to dorsal olfactory bulb. We suggest that a decreased dose of O/E protein may alter expression of O/E target genes and underlie the ORN projection defect.
A forkhead protein controls sexual identity of theC. elegansmale somatic gonad
Authors: Chang Weiru , Tilmann Christopher , Thoemke Kara , Markussen Finn-Hugo , Mathies Laura D. , Kimble Judith , Zarkower David
Published: March 2004

In sex determination, globally acting genes control a spectrum of tissue-specific regulators to coordinate the overall development of an animal into one sex or the other. In mammals, primary sex determination initially occurs in the gonad, with the sex of other tissues specified as a secondary event. In insects and nematodes, globally acting regulatory pathways have been elucidated, but the more tissue- and organ-specific downstream effectors of these pathways remain largely unknown. We focus on the control of sexual dimorphism in the C. elegans gonad. We find that the forkhead transcription factor FKH-6 promotes male gonadal cell fates in XO animals. Loss-of-function fkh-6 mutant males have feminized gonads and often develop a vulva. In these mutant males, sex-specific cell divisions and migrations in the early gonad occur in the hermaphrodite mode, and hermaphrodite-specific gonadal markers are expressed. However, sexual transformation is not complete and the male gonad is malformed. By contrast, fkh-6 mutant hermaphrodites exhibit no sign of sex reversal. Most fkh-6 hermaphrodites form a two-armed symmetrical gonad resembling that of the wild type, but differentiation of the spermatheca and uterus is variably abnormal. The function of fkh-6 appears to be restricted to the gonad: fkh-6 mutants have no detectable defects in extra-gonadal tissues, and expression of a rescuing fkh-6 reporter is gonad-specific. Genetic and molecular analyses place fkh-6 downstream of tra-1, the terminal regulator of the global sex determination pathway, with respect to the first gonadal cell division. We conclude that fkh-6 regulates gonadogenesis in both sexes, but is male specific in establishing sexual dimorphism in the early gonad.
Synergistic interaction of three ERECTA-family receptor-like kinases controlsArabidopsisorgan growth and flower development by promoting cell proliferation
Authors: Shpak Elena D. , Berthiaume Chris T. , Hill Emi J. , Torii Keiko U.
Published: March 2004

Growth of plant organs relies on coordinated cell proliferation followed by cell growth, but the nature of the cell-cell signal that specifies organ size remains elusive. The Arabidopsis receptor-like kinase (RLK) ERECTA regulates inflorescence architecture. Our previous study using a dominant-negative fragment of ERECTA revealed the presence of redundancy in the ERECTA-mediated signal transduction pathway. Here, we report that Arabidopsis ERL1 and ERL2, two functional paralogs of ERECTA, play redundant but unique roles in a part of the ERECTA signaling pathway, and that synergistic interaction of three ERECTA-family RLKs define aerial organ size. Although erl1 and erl2 mutations conferred no detectable phenotype, they enhanced erecta defects in a unique manner. Overlapping but distinct roles of ERL1 and ERL2 can be ascribed largely to their intricate expression patterns rather than their functions as receptor kinases. Loss of the entire ERECTA family genes led to striking dwarfism, reduced lateral organ size and abnormal flower development,including defects in petal polar expansion, carpel elongation, and anther and ovule differentiation. These defects are due to severely reduced cell proliferation. Our findings place ERECTA-family RLKs as redundant receptors that link cell proliferation to organ growth and patterning.
Disruption of gradient expression of Zic3 resulted in abnormal intra-retinal axon projection
Authors: Zhang Jinhua , Jin Zhe , Bao Zheng-Zheng
Published: March 2004

The targeting of retinal ganglion axons toward the optic disc is the first step in axon pathfinding in the visual system. The molecular mechanisms involved in guiding the retinal axons to project towards the optic disc are not well understood. We report that a gene encoding a zinc-finger transcription factor, Zic3, is expressed in a periphery-high and center-low gradient in the retina at the stages of active axon extension inside the retina. The gradient expression of Zic3 recedes towards the periphery over the course of development, correlating with the progression of retinal cell differentiation and axonogenesis. Disruption of gradient expression of Zic3 by retroviral overexpression resulted in mis-targeting of retinal axons and some axons misrouted to the sub-retinal space at the photoreceptor side of the retina. Misexpression of Zic3 did not affect neurogenesis or differentiation inside the retina, or grossly alter retinal lamination. By stripe assay, we show that misexpression of Zic3 may induce the expression of an inhibitory factor to the retinal axons. Zic3 appears to play a role in intra-retinal axon targeting, possibly through regulation of the expression of specific downstream genes involved in axon guidance.
Maspin plays an essential role in early embryonic development
Authors: Gao Fei , Shi Heidi Y. , Daughty Cathy , Cella Nathalie , Zhang Ming
Published: March 2004

Maspin (Mp) is a member of the serpin family with inhibitory functions against cell migration, metastasis and angiogenesis. To identify its role in embryonic development in vivo, we generated maspin knockout mice by gene targeting. In this study, we showed that homozygous loss of maspin expression was lethal at the peri-implantation stage. Maspin was specifically expressed in the visceral endoderm after implantation; deletion of maspin interfered with the formation of the endodermal cell layer, thereby disrupting the morphogenesis of the epiblast. In vitro, the ICM of the Mp–/– blastocysts failed to grow out appropriately. Data from embryoid body formation studies indicated that the Mp–/– EBs had a disorganized, endodermal cell mass and lacked a basement membrane layer. We showed that the embryonic ectoderm lineage was lost in the Mp–/– EBs,compared with that of the Mp+/+ EBs. Re-expression of maspin partially rescued the defects observed in the Mp–/– EBs, as evidenced by the appearance of ectoderm cells and a layer of endoderm cells surrounding the ectoderm. In addition, a maspin antibody specifically blocked normal EB formation,indicating that maspin controls the process through a cell surface event. Furthermore, we showed that maspin directly increased endodermal cell adhesion to laminin matrix but not to fibronectin. Mp+/–endodermal cells grew significantly slower than Mp+/+endodermal cells on laminin substrate. We conclude that deletion of maspin affects VE function by reducing cell proliferation and adhesion, thereby controlling early embryonic development.