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Biomedical subjects

W B Young

Publications and source records attributed to W B Young.

At least 37 records · Page 2Linked to original sources
PubMed2001

Hemicrania continua is not that rare.

BACKGROUND: Hemicrania continua is an indomethacin-responsive headache disorder characterized by a continuous, moderate to severe, unilateral headache. More than 90 cases of hemicrania continua have been reported, but there is still uncertainty about its clinical features. METHODS: The authors compared 34 new cases (24 women, 10 men) with previously reported cases. All the patients met Goadsby and Lipton's proposed criteria. The authors compared baseline (continuous background headache) and exacerbation (attacks of severe periods of headaches). RESULTS: The baseline headache was typically mild to moderate in intensity and usually not associated with severe disability. In contrast, the headache exacerbations were severe and associated with photophobia, phonophobia, nausea, and disability. At least one autonomic symptom was present in 25 patients (74%). Jabs and jolts were present in 14 patients (41%). The mean indomethacin dose was 136.7 +/- 60 mg (range 25 to 225 mg). Twenty-four patients (70.6%) met International Headache Society criteria for migraine in their exacerbation period. Occipital tenderness was observed in 23 patients (67.6%). The temporal pattern was remitting in four patients (11.8%), continuous from onset in 18 (52.9%), and continuous evolving from remitting in 12 (35.3%). CONCLUSION: Hemicrania continua is not a rare disorder. All cases of chronic unilateral daily headaches should receive an indomethacin trial early if not first in treatment.

Adult↗
PubMed2001

Development of serine protease inhibitors displaying a multicentered short (<2.3 A) hydrogen bond binding mode: inhibitors of urokinase-type plasminogen activator and factor Xa.

Novel scaffolds that bind to serine proteases through a unique network of short hydrogen bonds to the catalytic Ser195 have been developed. The resulting potent serine protease inhibitors were designed from lead molecule 2-(2-hydroxyphenyl)1H-benzoimidazole-5-carboxamidine, 6b, which is known to display several modes of binding. For instance, 6b can recruit zinc and bind in a manner similar to that reported by bis(5-amidino-2-benzimidazolyl)methane (BABIM) (Nature 1998, 391, 608-612).(1) Alternatively, 6b can bind in the absence of zinc through a multicentered network of short (<2.3 A) hydrogen bonds. The lead structure was optimized in the zinc-independent binding mode toward a panel of six human serine proteases to yield optimized inhibitors such as 2-(3-bromo-2-hydroxy-5-methylphenyl)-1H-indole-5-carboxamidine, 22a, and 2-(2-hydroxybiphenyl-3-yl)-1H-indole-5-carboxamidine, 22f. Structure-activity relationships determined that, apart from the amidine function, an indole or benzimidazole and an ortho substituted phenol group were also essential components for optimal potency. The affinities (K(i)) of 22a and 22f, for example, bearing these groups ranged from 8 to 600 nM toward a panel of six human serine proteases. High-resolution crystal structures revealed that the binding mode of these molecules in several of the enzymes was identical to that of 6b and involved short (<2.3 A) hydrogen bonds among the inhibitor hydroxyl oxygen, Ser195, and a water molecule trapped in the oxyanion hole. In summation, novel and potent trypsin-like serine protease inhibitors possessing a unique mode of binding have been discovered.

Amidines↗
PubMed2001

Neutral inhibitors of the serine protease factor Xa.

A neutral inhibitor of the serine protease factor Xa was identified via a high-throughput screen of a commercial library. The initial lead 1 demonstrated reversible and competitive inhibition kinetics for factor Xa and possessed a high degree of selectivity versus other related serine proteases. Initial modeling efforts and the generation of a series of analogues of 1 are described.

Aniline Compounds↗
PubMed2001

Korean American health insurance and health services utilization.

The purpose of this ethnic group study was to describe the unique pattern of Korean Americans, as compared with the aggregate of Asian Americans, for: (a) the predisposing, enabling, and need factors for health service utilization, focusing specifically on the role of health insurance coverage; and (b) predictors of health insurance coverage. Using the behavioral model for health service utilization, data were selected from the 1992 National Health Insurance Survey (NHIS, 1994) for Korean Americans (n = 345) and Asian Americans (n = 3,059). Results differed between the Korean American group and the Asian American group. Health insurance coverage was the strongest predictor of Korean American utilization, and need factors lacked significance, suggesting that uninsured Korean Americans have less access regardless of need. For the aggregate Asian American group, need factors tempered the influence of health insurance on utilization. Results of this type of study may be helpful for designing and implementing health care services tailored for specific ethnic at-risk markets.

Adolescent↗
PubMed2001

Modular headache theory.

Many people experience headaches that do not fulfil the International Headache Society's criteria for a specific headache disorder yet behave biologically like that disorder. Others fulfil criteria for one headache disorder and yet have features of another disorder. To explain these observations, we propose that groups of neurones called modules become activated to produce each symptom of a primary headache disorder, and that each module is linked to other modules that together produce an individual's headache. This theory has implications for the classification, research and treatment of primary and secondary headache patients.

Headache↗
PubMed2001

Quality-of-life differences between patients with episodic and transformed migraine.

OBJECTIVE: To determine whether there are any differences in health-related quality of life between patients with migraine and those with transformed migraine. BACKGROUND: There are no published reports comparing the health-related quality of life between patients with migraine and patients with transformed migraine. METHODS: We conducted a retrospective analysis examining the health-related quality of life of patients with transformed migraine and migraine seen at a specialty headache clinic. Data collected included the Short Form-36 (SF-36) and the Migraine Disability Assessment questionnaires as well as demographic information. Both of these forms are part of the initial evaluation at the headache clinic. A t test with Bonferroni correction was used to test for significant differences in the SF-36 domains between the groups. RESULTS: Data were collected for 90 patients, 46 with transformed migraine and 44 with migraine. There were no significant differences between groups with respect to sex, race, or age. Over the last 90 days prior to their first visit, patients with transformed migraine reported having a headache an average of 69 days compared with patients with migraine who averaged 18 days with headache (P<.05). Compared with patients with migraine, patients with transformed migraine had statistically (P<.05) and clinically significant (difference >5 points) lower mean scores on seven of the eight SF-36 domains and both the mental and physical summary scores of the SF-36. CONCLUSIONS: The results of this study suggest that patients with transformed migraine have a lower health-related quality of life than patients with migraine. These findings indicate that the headache chronicity associated with transformed migraine has a significant influence on quality of life. The results highlight the importance of effective management of headaches to avoid the progression of migraine to the more disabling transformed migraine.

Adult↗
PubMed2001

Cluster headache in women: clinical characteristics and comparison with cluster headache in men.

OBJECTIVE: To study the clinical characteristics of cluster headache in women. Cluster headache is a disorder of men (male to female ratio 6-7:1). METHODS: Retrospective chart review to identify all women diagnosed with cluster headache at an academic headache centre from January 1995 through July 1998. RESULTS: Thirty two women and 69 men were identified. The mean age of onset of cluster headache was 29.4 years in women versus 31.3 years in men. Two peaks of onset in women (2nd and 5th decade) were identified compared with one in men (3rd decade). Episodic cluster headache was present in 75% of women and 77% of men. Women and men had on average 3 attacks a day, but attack duration was shorter in women (67.2 minutes v 88.2 minutes). Cluster headache period duration (11.1 weeks v 10 weeks) and remission periods (21.1 months v 23.1 months) were similar in women and men. Miosis and ptosis seemed to be less common in women (miosis 13.3% v 24.6%, ptosis 41.9% v 58.1%) whereas lacrimation and nasal congestion/rhinorrhoea were almost equally prevalent in women and men. Women had more nausea than men (62.5% v 43.5%, p=0.09) and significantly more vomiting (46.9% v 17.4%, p=0.003). Photophobia occurred in 75% of women and 81.2% of men, and phonophobia occurred in 50% of women and 47.8% of men. CONCLUSIONS: The clinical characteristics of cluster headache in women are very similar to those in men. Women develop the disorder at an earlier age of onset and experience more "migrainous symptoms" with cluster headache, especially vomiting. Both men and women have frequent photophobia and phonophobia with cluster headache attacks. These symptoms are not included in the International Headache Society cluster headache criteria, suggesting the need for possible criteria revision.

Adult↗
PubMed2001

Perspectives on factor Xa inhibition.

Blood coagulation involves a complex cascade of enzymatic reactions, ultimately generating fibrin, the basis of all blood clots. This cascade is comprised of two arms, the intrinsic and extrinsic pathways which converge at factor Xa to form the common pathway. Factor Xa activates prothrombin to thrombin, which in turn catalyzes the conversion of fibrinogen to fibrin. Recently, both natural and synthetic factor Xa inhibitors have shown promising pharmacological effects in animal models of thrombosis. Accordingly, factor Xa has emerged as a compelling target for pharmacological intervention and much recent effort has focused on selective and potent inhibition of this key enzyme. Factor Xa and other enzymes in the coagulation cascade belong to the trypsin-like serine protease family, the various members of which are involved in numerous physiological functions in the body. Hence, to avoid toxicity and adverse side effects, it is important to selectively inhibit the target enzyme. Achieving the needed selectivity has proved challenging due to the high degree of structural homology around the active site of this class of enzymes. This article provides a brief review of the strategies currently being employed to develop oral anticoagulants and, more specifically, the structural features of protein-ligand binding that have been utilized to achieve potency and selectivity toward factor Xa. Additionally, selected lead molecules will be discussed to highlight binding motifs used to attain both potency and selectivity in drug candidates.

Animals↗
PubMed2001

Validity of double- and single-leg vertical jumps as tests of leg extensor muscle function.

The purpose of this research was to determine if 5 weeks of resistance training for the shoulder and hip flexor muscles produces improvements in vertical jumping (VJ) performance. Twenty-eight men were assessed on tests of shoulder power, leg extensor muscle function, and VJ performance using jumps performed from a standing position, a 3-stride run-up, and double- and single-leg takeoffs. A shoulder and hip flexor training group (n = 14) improved significantly more than a nontraining control group (n = 12) in shoulder power and 2 VJ performance tests, but not in the tests of leg extensor muscle function. It was concluded that the arm swing and free-leg drive significantly influence VJ performance and, therefore, VJ tests are not valid for assessment of leg extensor muscle function.

Adolescent↗
PubMed2001

Specificity of sprint and agility training methods.

The purpose of this study was to determine if straight sprint training transferred to agility performance tests that involved various change-of-direction complexities and if agility training transferred to straight sprinting speed. Thirty-six males were tested on a 30-m straight sprint and 6 agility tests with 2-5 changes of direction at various angles. The subjects participated in 2 training sessions per week for 6 weeks using 20-40-m straight sprints (speed) or 20-40-m change-of-direction sprints (3-5 changes of 100 degrees) (agility). After the training period, the subjects were retested, and the speed training resulted in significant improvements (p < 0.05) in straight sprinting speed but limited gains in the agility tests. Generally, the more complex the agility task, the less the transfer from the speed training to the agility task. Conversely, the agility training resulted in significant improvements in the change-of-direction tests (p < 0.05) but no significant improvement (p > 0.05) in straight sprint performance. We concluded that straight speed and agility training methods are specific and produce limited transfer to the other. These findings have implications for the design of speed and agility training and testing protocols.

Adult↗
PubMed2000

Dibasic inhibitors of human mast cell tryptase. Part 2: structure-activity relationships and requirements for potent activity.

Detailed structure activity relationships (SARs) for a series of dibasic human tryptase inhibitors are presented. The structural requirements for potent inhibitory activity are remarkably broad with a range of core template modifications being well tolerated. Optimized inhibitors demonstrate potent anti-asthmatic activity in a sheep model of allergic asthma. APC-2059, a dibasic tryptase inhibitor with subnanomolar activity, has been advanced to phase II clinical trials for the treatment of both psoriasis and ulcerative colitis.

Animals↗
PubMed2000

Cluster headache with aura.

Cluster headache with aura is rare. The authors retrospectively reviewed 101 cluster headache patient charts at the Jefferson Headache Center. Six patients had an associated aura, five visual and one olfactory, lasting 5 to 120 minutes. Only one had migraine (without aura). Auras always occurred with or were followed by a severe cluster headache. Two patients were related.

Adult↗
PubMed2000

Chimeric retroviral helper virus and picornavirus IRES sequence to eliminate DNA methylation for improved retroviral packaging cells.

Most retroviral packaging cell lines were established by a helper virus plasmid cotransfected with a separate plasmid encoding a selection marker. Since this selection marker coexisted in trans with the helper virus sequence, helper virus gene expression could be inactivated by host DNA methylation despite selection for the cotransfected selection marker. We have reported that DNA methylation could occur in the long terminal repeat (LTR) region of helper virus in vector producer cells (VPC) in up to 2% of the population per day (W. B. Young, G. L. Lindberg, and C. J. Link, Jr., J. Virol. 74:3177-3187, 2000). To overcome host cell DNA methylation that suppresses viral gene expression, we constructed a chimeric retroviral helper virus, pAM3-IRES-Zeo, that contains Moloney murine leukemia virus as a helper virus and a picornavirus internal ribosome entry site (IRES) sequence followed by a Zeocin selection marker at the 3' end of the env sequence. This pAM3-IRES-Zeo permitted selection for intact and functional helper virus in transfected cells without subcloning. By selection with Zeocin, a mixed population of pAM3-IRES-Zeo-transfected NIH3T3 cells (AMIZ cells) was maintained with little or no DNA methylation of the helper virus 5' LTR. The high level of pAM3-IRES-Zeo gene expression resulted in no detectable vector superinfection and in high vector titers (2 x 10(6) to 1.5 x 10(7) CFU/ml) after introduction of a retroviral vector. When Zeocin selection was withdrawn from AMIZ cells, methylation of the 5' LTR increased from 17 to 36% of the population during 67 days of continuous culture and the cells became susceptible to superinfection. During this period, gene expression of pAM3-IRES-Zeo decreased and vector titer production was reduced to 2 x 10(4) CFU/ml. These data demonstrate an important role of DNA methylation in the genetic instability of VPC. The chimeric helper virus allows the establishment of a mixed population of packaging cells capable of high-level and sustained vector production without cloning procedures.

3T3 Cells↗