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Biomedical subjects

A D Hershey

Publications and source records attributed to A D Hershey.

At least 19 recordsLinked to original sources
PubMed2004

Valproic acid blood genomic expression patterns in children with epilepsy - a pilot study.

OBJECTIVE: Valproic acid (VPA) is a commonly used anticonvulsant with multiple systemic effects. The purpose of this pilot study is to examine the blood genomic expression pattern associated with VPA therapy in general and secondly VPA efficacy in children with epilepsy. MATERIALS AND METHODS: Using oligonucleotide microarrays, gene expression in whole blood was assessed in pediatric epilepsy patients following treatment with VPA compared with children with epilepsy prior to initiation of anticonvulsant therapy (drug free patients). RESULTS: The expression of 461 genes was altered in VPA patients (n = 11) compared with drug free patients (n = 7), among which a significant number of serine threonine kinases were down-regulated. Expression patterns in children seizure free on VPA therapy (n = 8) demonstrated 434 up-regulated genes, many in mitochondria, compared with VPA children with continuing seizures (n = 3) and drug free seizure patients (n = 7). CONCLUSION: VPA therapy is associated with two significant and unique blood gene expression patterns: chronic VPA monotherapy in general and a separate blood genomic profile correlated with seizure freedom. These expression patterns provide new insight into previously undetected mechanisms of VPA anticonvulsant activity.

Adolescent↗
PubMed2004

Quality of life in paediatric migraine: characterization of age-related effects using PedsQL 4.0.

The aim of this study was to measure quality of life (QOL) across a broad age range of paediatric migraine patients. Children and adolescents (n=686) with migraine completed the Pediatric Quality of Life Inventory, version 4.0 (PedsQL 4.0) and a standardized headache assessment at an initial clinic visit. The sample size for each PedsQL age group was: age 2-4=21, age 5-7=86, age 8-12=298, and age 13-18=281. Mean total score was 72.7 +/- 14.8, significantly less than healthy norms (P<0.01). Teens reported lower School Functioning than older and young children (P<0.05) and young children reported lower Social Functioning than older children and teens (P<0.001). A moderate relation was found between self and parent report. Age-related effects on QOL have implications for the evaluation and management of migraine in paediatric practice. The self and parent report forms of the PedsQL can be used in a practice setting.

Adolescent↗
PubMed2004

Development of a patient-based grading scale for PedMIDAS.

The objective was to develop and validate a patient-based grading scale for PedMIDAS. PedMIDAS was administered to 329 children, who rated their overall disability based on the adult MIDAS grades. This patient-based rating and PedMIDAS scores were compared to develop the grading scale. Headache disability was rated little to none, 49.5%; mild, 26.7%; moderate, 15.8%; and severe, 7.9%, with PedMIDAS raw scores of 4.9 +/- 6.3, 17.8 +/- 14.9, 40.6 +/- 34.2, and 91.4 +/- 69.8. Convergence of these results yielded an empirically derived grading system: Grade I, 0-10; II, 11-30; III, 31-50 and IV, > 50. Higher grades corresponded to an increased need for prophylactic treatment. A patient-based grading scale further increases the utility of PedMIDAS in assessing migraine disability in children, so that it can be widely used in routine clinical evaluation and management.

Adolescent↗
PubMed2003

Migraine headaches and sleep disturbances in children.

OBJECTIVE: The aim of the present study was to investigate the prevalence of sleep disturbances in children with migraine headaches and to describe individual differences in sleep behaviors based on headache features (eg, frequency, duration, intensity). BACKGROUND: A relationship between migraine headaches and sleep disturbances has been suggested in both children and adults, but there is a lack of research examining the relationship between specific headache features and the range of sleep behaviors in children. METHODS: One hundred eighteen children, aged 2 to 12 years (mean, 9.1; standard deviation, 2.3) were evaluated for headaches at two pediatric neurology departments. Parents completed the Children's Sleep Habits Questionnaire and a standardized questionnaire regarding headache characteristics. RESULTS: Parents reported a high rate of sleep disturbances in children, including sleeping too little (42%), bruxism (29%), child co-sleeping with parents (25%), and snoring (23%). Children with migraine headaches experienced more sleep disturbances compared to published healthy control norms. After controlling for child demographics, we found that the frequency and duration of migraine headaches predicted specific sleep disturbances, including sleep anxiety, parasomnias, and bedtime resistance. CONCLUSIONS: Children with migraine headaches have a high prevalence of sleep disturbances. The direction of the relationship between headaches and sleep is unknown. Regardless, interventions targeting sleep habits may improve headache symptoms, and effective treatment of headaches in children may positively impact sleep.

Child↗
PubMed2001

PedMIDAS: development of a questionnaire to assess disability of migraines in children.

BACKGROUND: For adults, disability produced by migraines has been assessed with a migraine-specific disability tool-MIDAS. The objective of this study was to develop and validate a similar tool that accurately depicts the disability of headaches in school-age children and adolescents. METHODS: A six-question tool (PedMIDAS) was developed and administered to patients attending a tertiary referral center for pediatric headaches. Internal consistency and test/retest reliability were assessed. Validity was assessed by correlating scores with headache frequency, severity, and duration. Changes in the total score in response to treatment were assessed in a portion of the patients. RESULTS: The PedMIDAS questionnaire was administered to 441 patients for a total of 724 trials. The mean score at the initial visit was 44.3 +/- 47.9, whereas the overall mean score was 25.1 +/- 36.5. A 2-week test/retest reliability assessment for 56 patients confirmed the stability of the instrument with a Pearson coefficient of 0.80. The correlation of the PedMIDAS score with frequency, severity, and duration had Pearson's coefficient values of 0.58, 0.27, and 0.23. The PedMIDAS score was reduced to 20.0 +/- 32.3 (p < 0.0001) at the first follow-up assessment with subsequent continued reduction. CONCLUSIONS: The PedMIDAS questionnaire provided a developmentally sensitive, reliable, and valid assessment of the disability of childhood and adolescent headaches. This questionnaire provides a tool to assess the impact of migraines in children and to monitor response to treatment. Further research should focus on additional validation of the PedMIDAS using a larger population and sampling from other populations (e.g., primary care and community samples).

Adolescent↗
PubMed2001

Characterization of chronic daily headaches in children in a multidisciplinary headache center.

BACKGROUND: Chronic daily headaches (CDH) occur in >4% of the adult population. The criteria for CDH, however, are controversial. In children, the characterization of frequent headaches and CDH is limited. METHODS: A Headache Center to characterize headaches in children (3 to 18 years old) was established. Over 34 months, 577 children have been evaluated. With use of a definition of > or =15 headaches per month, 200 (34.6%) children had CDH. RESULTS: The average age at the first headache in these children was 9.3 +/- 3.6 years, whereas the average age at presentation to the Headache Center was 12.5 +/- 3.1 years. Sixty-eight percent were girls, 88% were Caucasian, and 11% were African American. Ninety-two percent clinically had migraine headaches, whereas 60.5% met the International Headache Society migraine criteria. The pain was pulsatile in 79%, 63.5% had nausea with or without vomiting, and 59.5% had photophobia and phonophobia. Three subcategories emerged, with 37% having frequent headaches but not daily, 43.5% having episodic daily headaches, and 19.5% having a continuous headache. CONCLUSION: The features of CDH in children most closely match those of migraine. A clear division of these children using frequency identifies three groups: frequent headaches (15 to 29), daily intermittent, and daily continuous. The daily continuous group is the most unique; however, the nature of these headaches continues to remain migrainous.

Adolescent↗
PubMed2001

Depression and functional disability in chronic pediatric pain.

OBJECTIVES: The primary aim of this study was to describe pain characteristics, coping strategies, depression, and functional disability in children and adolescents with chronic pain and to examine potential factors that are associated with functional disability in a pediatric pain population. The secondary aim of this study was to compare functional disability in two chronic pain conditions: localized musculoskeletal pain and chronic daily headaches. SUBJECTS: The participants in this study were 73 pediatric pain patients with a variety of chronic pain conditions. Subjects in the second part of the study were a subset of patients (N = 44) from the pain clinic sample with chronic localized musculoskeletal pain and a subset of patients (N = 38) from the headache center of the same hospital who had chronic daily headaches. DESIGN: Patients completed self-report measures of pain intensity, depression, coping strategies, coping efficacy, and functional disability. RESULTS: Results indicated that chronic pain had a substantial impact on the children's lives and that depression was strongly associated with functional disability. Maladaptive coping was correlated with depression and disability; however, maladaptive coping was not independently associated with functional disability. A comparison between the two groups found significant differences in pain intensity and functional disability. The localized musculoskeletal pain group reported higher levels of disability and more difficulty coping than the chronic daily headache group. CONCLUSIONS: The implications for treatment of chronic pain in children are discussed with an emphasis on greater attention to developmental issues and their relation to coping, emotional functioning, and disability in pediatric pain. Further research examining differences in coping and disability between different pediatric pain groups is also warranted.

Adaptation, Psychological↗
PubMed2001

Tolerability and effectiveness of prochlorperazine for intractable migraine in children.

OBJECTIVE: To study the effectiveness of prochlorperazine in aborting severe, intractable migraines in children. STUDY DESIGN: Patients for this study were drawn from the population seen and evaluated in the Headache Center at Cincinnati Children's Hospital Medical Center. All patients were diagnosed with migraine headache by both clinical and International Headache Society criteria. The effectiveness of intravenous prochlorperazine in 20 consecutive patients referred to the emergency department for severe, prolonged migraines was retrospectively reviewed. RESULTS: Patients evaluated in this study presented with a mean headache severity of 8.4 on a 0- to 10-point scale and an average duration of 54 hours. At 1 hour, 90% of the patients reported feeling better with 50% becoming pain-free. A 50% or greater reduction in severity occurred in 75% of patients at 1 hour and in 95% at 3 hours. At 3 hours, 95% of the patients reported feeling better, and 60% were pain-free. Only 1 patient failed to respond to prochlorperazine. CONCLUSION: Prochlorperzaine was shown to be highly effective in aborting intractable migraines in children. It was well tolerated with no significant side effects. Additional large, double-blinded, randomized, placebo-controlled studies are needed to further investigate its effectiveness.

Adolescent↗
PubMed1995

Characterization of the substance P (NK-1) receptor in tunicamycin-treated transfected cells using a photoaffinity analogue of substance P.

Chinese hamster ovary cells expressing the N-glycosylated substance P (NK-1) receptor were treated with the glycosylation inhibitor tunicamycin and photolabeled with 125I-Bolton-Hunter-p-benzoyl-L-phenylalanine8-substance P. Two radioactive proteins of M(r) 80,000 and 46,000, representing the glycosylated and nonglycosylated substance P (NK-1) receptor, respectively, were observed. The IC50 for the inhibition of photolabeling of both receptor forms was 0.3 +/- 0.1 nM for substance P and 30 +/- 5 nM for neurokinin A (substance K). Thus, glycosylation of the substance P (NK-1) receptor has no detectable effect on the affinity of the substance P (NK-1) receptor for substance P or neurokinin A (substance K).

Animals↗
PubMed1994

Crystallization and preliminary crystallographic studies of Saccharomyces cerevisiae alcohol dehydrogenase I.

The cytoplasmic yeast alcohol dehydrogenase I crystallized at 5 degrees C as hexagonal plates or short columns in the presence of NAD+ and 2,2,2-trifluoroethanol, in sodium N-tris(hydroxymethyl)methyl-3-aminopropanesulfonate buffer at pH 8.2 to 8.6, using polyethylene glycol 4000 as precipitant. X-ray diffraction data to 3.2 A resolution show that the crystals are hexagonal in space group P622 with unit cell dimensions a = b = 147.9 A, c = 69.1 A. There is one subunit of the tetrameric enzyme per asymmetric unit, giving a packing density of 2.9 A3/Da.

Alcohol Dehydrogenase↗
PubMed1992

Structure, functions, and mechanisms of substance P receptor action.

Substance P is a member of a family of structurally related peptides, called tachykinins, that are involved in the regulation of many biologic processes. Diversity in the generation of multiple tachykinin peptides arises due to multiple genes encoding these peptides as well as by mechanisms of alternative RNA processing and differential posttranslational processing. The multiple peptides are neurotransmitters and/or neuromodulator substances, and they bring about their actions mainly by activating three primary types of receptors, NK-1, NK-2, and NK-3. The pharmacology and tissue locations of these receptor sites are discussed, as is their involvement in certain biologic responses. These three receptor sites have been molecularly characterized by cDNA cloning and functional expression, and all are members of the superfamily of receptors coupled to G-regulatory proteins. Second messenger systems established to be activated by tachykinin receptor stimulation include the hydrolysis of inositol containing phospholipids by a phospholipase C mechanism. The role of substance P in neurogenic inflammation and plasma extravasation is briefly discussed. The generation of new research tools recently in the tachykinin field should allow for a detailed examination of the mechanisms of peptide action, including a focus on receptor structure-function relations and regulation of receptor sensitivity.

Amino Acid Sequence↗
PubMed1992

Ligand binding kinetics of substance P and neurokinin A receptors stably expressed in Chinese hamster ovary cells and evidence for differential stimulation of inositol 1,4,5-trisphosphate and cyclic AMP second messenger responses.

Stably transfected Chinese hamster ovary cells expressing either the substance P receptor or neurokinin A receptor were constructed, isolated, and characterized. Equilibrium ligand binding studies performed on whole cells demonstrated that cell lines expressing either of these receptors contained a single class of high-affinity binding sites with an apparent KD of 0.16 nM for the substance P receptor and an apparent KD of 2.1 nM for the neurokinin A receptor. The higher affinity of substance P for its receptor was accounted for by both a greater association rate constant and a lesser dissociation rate constant. The time course and extent of ligand-stimulated inositol 1,4,5-trisphosphate mass increases in both cell lines were similar and displayed rapid and transient kinetics. Ligand-stimulated cyclic AMP accumulation was also apparent in the cell lines, although the time course and magnitude of the responses were substantially different, with the neurokinin A receptor mediating a greater and more prolonged response. These studies establish the presence of functional substance P receptors and neurokinin A receptors in the stably transfected cell lines and provide evidence for agonist-dependent differential stimulation of second messenger responses.

Animals↗
PubMed1991

Amyloid-beta peptide, substance P, and bombesin bind to the serpin-enzyme complex receptor.

During the formation of an inhibitory complex with neutrophil elastase, alpha 1 antitrypsin (alpha 1 AT) undergoes a structural rearrangement and the resulting alpha 1 AT-elastase complex becomes endowed with chemoattractant activities, mediates an increase in synthesis of alpha 1 AT, and is rapidly cleared from the circulation. In previous studies we have provided evidence that these biological activities involve the recognition of a conformation-specific domain in the alpha 1 AT molecule by a cell surface receptor on human hepatoma HepG2 cells and human monocytes. The receptor has been termed the serpin-enzyme complex (SEC) receptor because it also recognizes complex of serpins antithrombin III, alpha 1 anti-chymotrypsin, and C1 inhibitor with their cognate enzymes. Because a pentapeptide domain of alpha 1 AT (amino acids 370-374, Phe-Val-Phe-Leu-Met) is sufficient for binding to the SEC receptor and the sequence of this domain is remarkably similar to those of substance P, several other tachykinins, bombesin, and the amyloid-beta peptide, we have examined the possibility that these other ligands bind to the SEC receptor. The results indicate that substance P, several other tachykinins, and bombesin compete for binding to, and cross-linking of, the SEC receptor. The SEC receptor is distinct from the substance P receptor by several criteria. There is no substance P receptor mRNA in HepG2 cells; the SEC receptor is present in much higher density on receptor-bearing cells and binds its ligands at lower affinity than the substance P receptor; the SEC receptor is much less restricted in the specificity with which it recognizes ligand; ligands for the SEC receptor including peptide 105Y (based on alpha 1 AT sequence 359-374), alpha 1 AT-protease complexes, and bombesin do not compete for binding of substance P to a stable transfected cell line expressing the substance P receptor. Finally, we show here that the amyloid-beta peptide competes for binding to the SEC receptor but does not bind to the substance P receptor, therein raising the possibility that the SEC receptor is involved in certain biological activities, including the recently described neurotrophic and neurotoxic effects ascribed to the amyloid-beta peptide.

Amino Acid Sequence↗
PubMed1991

Organization, structure, and expression of the gene encoding the rat substance P receptor.

The gene for the rat substance P receptor has been cloned, its genomic structure determined, and the patterns of mRNA expression extensively analyzed. Unlike many genes encoding G protein-coupled receptors, the protein-coding region of this gene is divided into five exons consisting of 965, 195, 151, 197, and 2,010 base pairs. The substance P receptor gene extends more than 45 kilobases in length, and the splice sites for the exons occur at the borders of the sequences encoding putative membrane-spanning domains. The transcription initiation site has been defined by solution hybridization-nuclease protection and nucleotide sequence analyses, and lies downstream of a conventional TATA sequence. Substance P receptor mRNA levels in various tissues have been quantitated using solution hybridization-nuclease protection assays and were found to comprise from 0.00008 to 0.0016% of total RNA levels. Relatively high levels of substance P receptor mRNA are seen in the urinary bladder and the sublingual salivary gland, whereas moderate levels are observed for the submandibular salivary gland, striatum, hippocampus, midbrain, and olfactory bulb with lower levels in the remainder of the central nervous system and alimentary canal. These results are discussed in relation to the evolutionary role of multiple exons for a G protein-coupled receptor and with regard to the locations and mechanisms of substance P receptor gene expression.

Amino Acid Sequence↗
PubMed1990

Molecular characterization of a functional cDNA encoding the rat substance P receptor.

Substance P is a member of the tachykinin peptide family and participates in the regulation of diverse biological processes. The polymerase chain reaction and conventional library screening were used to isolate a complementary DNA (cDNA) encoding the rat substance P receptor from brain and submandibular gland. By homology analysis, this receptor belongs to the G protein-coupled receptor superfamily. The receptor cDNA was expressed in a mammalian cell line and the ligand binding properties of the encoded receptor were pharmacologically defined by Scatchard analysis and tachykinin peptide displacement as those of a substance P receptor. The distribution of the messenger RNA for this receptor is highest in urinary bladder, submandibular gland, striatum, and spinal cord, which is consistent with the known distribution of substance P receptor binding sites. Thus, this receptor appears to mediate the primary actions of substance P in various brain regions and peripheral tissues.

Amino Acid Sequence↗