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Biomedical subjects

R Young

Publications and source records attributed to R Young.

At least 73 records · Page 4Linked to original sources
PubMed1999

Uniparental isodisomy resulting from 46,XX,i(1p),i(1q) in a woman with short stature, ptosis, micro/retrognathia, myopathy, deafness, and sterility.

We report on a 43-year-old woman who was referred for evaluation because of minor facial anomalies, myopathy, sterility, short stature, hearing loss, downward slant of palpebral fissures, bilateral ptosis, severe micro/retrognathia, high arched palate, and scoliosis. Cytogenetic analyses utilizing GTG/CBG bandings showed presence of one i(1p) and one i(1q) without normal chromosome 1 homologues. Fluorescence in situ hybridization analysis showed hybridization to only two chromosomes, consistent with the G-banded interpretation of i(1p) and i(1q). To the best of our knowledge, this is the first case of isochromosomes 1p and 1q replacing the two normal chromosome 1s. Molecular investigations using markers for chromosome 1 showed inheritance of only one set of paternal alleles and absence of any maternal alleles in the patient. The adverse phenotype of the patient may be due to one or more recessive mutations, genomic imprinting, or a combination of both.

Abnormalities, Multiple↗
PubMed1999

Myosin I heavy chain kinase: cloning of the full-length gene and acidic lipid-dependent activation by Rac and Cdc42.

Acanthamoeba myosin I heavy chain kinase (MIHCK) phosphorylates the heavy chains of amoeba myosins I, increasing their actin-activated ATPase activities. The activity of MIHCK is increased by binding to acidic phospholipids or membranes and by autophosphorylation at multiple sites. Phosphorylation at a single site is necessary and sufficient for full activation of the expressed catalytic domain. The rate of autophosphorylation of native MIHCK is controlled by a region N-terminal to the catalytic domain. By its substrate specificity and the sequence of its C-terminal catalytic domain, MIHCK was identified as a p21-activated kinase (PAK). We have now cloned the full-length genomic DNA and cDNA of MIHCK and have shown it to contain the conserved p21-binding site common to many members of the PAK family. Like some mammalian PAKs, MIHCK is activated by Rac and Cdc42, and this activation is GTP-dependent and accompanied by autophosphorylation. In contrast to mammalian PAKs, activation of MIHCK by Rac and Cdc42 requires the presence of acidic lipids. Also unlike mammalian PAK, MIHCK is not activated by sphingosine or other non-negatively charged lipids. The acidic lipid-binding site is near the N terminus followed by the p21-binding region. The N-terminal regulatory domain of MIHCK contains alternating strongly positive and strongly negative regions. and the extremely Pro-rich middle region of MIHCK has a strongly acidic N-terminal segment and a strongly basic C-terminal segment. We propose that autophosphorylation activates MIHCK by neutralizing the basic segment of the Pro-rich region, thus unfolding the regulatory domain and abolishing its inhibition of the catalytic domain.

Acanthamoeba↗
PubMed1999

Complementation and characterization of the nested Rz and Rz1 reading frames in the genome of bacteriophage lambda.

Transposon insertions in the Rz gene of bacteriophage lambda block lysis if the medium contains divalent cations at concentrations greater than 5 mM, but otherwise cause no change in phenotype. The Rz protein is thought to have an endopeptidase activity, previously reported in lambda lysates, which might be involved in cleavage of oligopeptide crosslinks between glycosidic strands in the peptidoglycan and the Lpp lipoproteins of the outer bacterial membrane. Recently, a small lipoprotein has been reported as the product of a short reading frame, designated Rz1, in the +1 register within Rz. This protein has been detected in membranes of induced lambda lysogens. To determine whether Rz1 has a function in the lambda vegetative cycle, amber nonsense alleles of Rz and Rz1 have been constructed by site-directed mutagenesis and used for complementation and suppression analysis. Both Rzam and Rz1am alleles have phenotypes identical to those of the original Rz insertion alleles, and complement and are fully suppressed in a supE host, indicating that the two genes are independent, trans-acting genes encoding proteins required for lysis in the presence of cations. Moreover, supF suppresses Rzam but not the Rz1am mutation, and the defective Rz1am product in the supF host shows a partially dominant character and significantly retards lysis even in the absence of additional cations in the medium. Rz and Rz1 represent a unique example of two genes located in different reading frames in the same nucleotide sequence, which encode different proteins that are both required in the same physiological pathway.

Amino Acid Sequence↗
PubMed1999

Development of neural crest in Xenopus.

The neural crest is a unique cell population among embryonic cell types, displaying properties of both ectodermal and mesodermal lineages. Most of the recent studies examining the neural crest have been performed in avian embryos. Only in the first half of this century were amphibians extensively used. We first summarize this important older source of information, reviewing studies made since the turn of the century. Due to the increasingly detailed in cellular and molecular knowledge of the early development of Xenopus laevis, the remainder of the review focuses on this species. We describe the route of migration and fate of the neural crest and propose a new model of neural crest induction in which prospective cells are induced independently of the neural plate by a double gradient of a morphogen that patterns the entire ectoderm. This model is also discussed in a more general context in connection with the dorsoventral patterning of the neural tube. Finally, we discuss some ideas concerning neural crest evolution and propose a novel hypothesis about its phylogenetic origin.

Amphibians↗
PubMed1999

Stimulus properties of PMMA: effect of optical isomers and conformational restriction.

para-Methoxymethamphetamine (PMMA), a structural hybrid of two central stimulants, lacks stimulant properties but behaves in a manner similar to that of MDMA [N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane]. PMMA has been established as a training drug in drug discrimination studies, and in the present investigation we sought to determine which optical isomer of PMMA is primarily responsible for its stimulus effects. Because PMMA is a conformationally flexible molecule, it was also of interest to determine what conformation is most important for its actions. Accordingly, we prepared and examined S(+)PMMA, R(-)PMMA, and conformationally restricted forms of PMMA: PMMA-AT, TIQ-1, and TIQ-2. S(+)PMMA (ED50 = 0.32 mg/kg) was found to be at least as potent as PMMA (ED50 = 0.41 mg/kg), whereas R(-)PMMA failed to result in complete stimulus generalization. An aminotetralin-like conformation, as found in PMMA-AT (ED50 = 0.29 mg/kg), seems to better account for the actions of PMMA than a tetrahydroisoquinoline-like conformation because TIQ-1 and TIQ-2 failed to result in stimulus generalization. The results of the present study further support the concept that PMMA and MDMA share considerable similarity with respect to their stimulus properties in animals except that PMMA lacks the amphetaminergic stimulant component of action associated with MDMA.

Animals↗
PubMed1999

Prioritising family health needs: a time--space analysis of women's health-related behaviours.

Much has been made over the years of the view that health-related geographical research has failed fully to explore the complex and mutually reinforcing impact of social and spatial relations on individual health-related behaviours. At the same time, there is a growing awareness elsewhere in the social sciences and in health services research of the generally inadequate exploration of the role of place particularly at the scale of the local community--in the social construction of health, illness and health care use. This paper aims to contribute to the debate by offering a clear framework within which to analyse the impact of spatially configured social relations at the micro-level. In-depth interview evidence from Liverpool shows that, looking at the problem from the perspective of the opportunity-costs of time-space constraints, is a useful means to understand the distinct ways in which health services are used, when and why, across different social groups and geographical areas. Particular attention is drawn to the different thresholds for decision-making depending upon whose health-related needs are being negotiated within the family. The paper concludes with the latest policy developments in UK primary care which offer professionals the clear opportunity to develop much more sophisticated understandings of what constitutes locally-sensitive health service provision. The argument is that such developments must be based on a firm sense of how individual time-space circumstances interact with conditions in the local area if the best possible use of increasingly scarce and valuable resources is to be achieved--particularly in communities characterised by poverty and social exclusion such as those in Liverpool.

Adult↗
PubMed1999

Characterization of the dual start motif of a class II holin gene.

Holins are small membrane proteins that, at a genetically programmed time in a bacteriophage infective cycle, allow bacteriolytic enzymes, or endolysins, to escape to the periplasm and to attack the cell wall. Most holins fall into two sequence classes, I and II, based on the number of potential transmembrane domains (three for class I and two for class II). The prototype class I holin gene, S lambda, has a dual start motif and encodes not only the effector holin, Slambda105, but also an inhibitor, Slambda107, with a Met-Lys ...extension at the terminus. The prototype class II holin gene of phage 21, S 21, begins with the motif Met-Lys-Ser-Met ..., and a potential RNA secondary structure overlaps the Shine-Dalgarno sequence. Here, we demonstrate that (i) two protein products are elaborated from S 21, S2171 and S2168; (ii) the shorter product is required for lysis; (iii) the longer product, S2171, inhibits S 21 function; and (iv) the Lys-2 residue is important for the inhibitor function. Moreover, the RNA stem-loop structure is involved in the downregulation of S2171 synthesis. However, our results suggest that, in S 21, different segments of the single consensus Shine-Dalgarno sequence serve the two translational starts. These results show that the dual start motifs of class II holin genes are functionally homologous to those of class I holin genes.

Alleles↗
PubMed1999

A systematic review of foot ulcer in patients with Type 2 diabetes mellitus. II: treatment.

AIM: To assess the value of treatments for foot ulcers in patients with Type 2 diabetes mellitus. METHODS: A systematic review of interventions to treat diabetic foot ulcers. RESULTS: The evidence base for treating infections and dressing wounds is poor. A number of new and potentially promising treatments are being developed but currently available studies are often small, inadequately powered and use different methods and outcomes. CONCLUSIONS: Given the prevalence, morbidity and healthcare costs of diabetic foot disease, it is surprising that available trials provide inadequate evidence to improve upon current empirically based treatment approaches. Substantial effort and resources should be deployed in order to investigate both new and existing treatments in a co-ordinated, systematic and consistent manner, so that a proper evidence base can be established for this important disease area.

Diabetes Mellitus, Type 2↗
PubMed1999

Intravascular extraction of problematic or infected permanent pacemaker leads: 1994-1996. U.S. Extraction Database, MED Institute.

Of the 400,000-500,000 permanent pacemaker leads implanted worldwide each year, around 10% may eventually fail or become infected, becoming potential candidates for removal. Intravascular techniques for removing problematic or infected leads evolved over a 5-year period (1989-1993). This article analyzes results from January 1994 through April 1996, a period during which techniques were fairly stable. Extraction of 3,540 leads from 2,338 patients was attempted at 226 centers. Indications were: infection (27%), nonfunctional or incompatible leads (25%), Accufix or Encore leads (46%), or other causes (2%). Patients were 64+/-17 years of age (range 5-96); 59% were men, 41% women. Leads were implanted 47+/-41 months (maximum 26 years), in the atrium (53%), ventricle (46%), or SVC (1%). Extraction was attempted via the implant vein using locking stylets and dilator sheaths, and/or transfemorally using snares, retrieval baskets, and sheaths. Complete removal was achieved for 93% of leads, partial for 5%, and 2% were not removed. Risk of incomplete or failed extraction increased with implant duration (P<0.0001), less experienced physicians (P<0.0001), ventricular leads (P<0.005), noninfected patients (P<0.0005), and younger patients (P<0.0001). Major complications were reported for 1.4% of patients (<1% at centers with >300 cases), minor for 1.7%. Risk of complications increased with number of leads removed (P<0.005) and with less experienced physicians (P<0.005); risk of major complications was higher for women (P<0.01). Given physician experience, appropriate precautions, and appropriate patient selection, contemporary lead removal techniques allow success with low complication rates.

Adolescent↗
PubMed1999

The C-terminal sequence of the lambda holin constitutes a cytoplasmic regulatory domain.

The C-terminal domains of holins are highly hydrophilic and contain clusters of consecutive basic and acidic residues, with the overall net charge predicted to be positive. The C-terminal domain of lambda S was found to be cytoplasmic, as defined by protease accessibility in spheroplasts and inverted membrane vesicles. C-terminal nonsense mutations were constructed in S and found to be lysis proficient, as long as at least one basic residue is retained at the C terminus. In general, the normal intrinsic scheduling of S function is deranged, resulting in early lysis. However, the capacity of each truncated lytic allele for inhibition by the S107 inhibitor product of S is retained. The K97am allele, when incorporated into the phage context, confers a plaque-forming defect because its early lysis significantly reduces the burst size. Finally, a C-terminal frameshift mutation was isolated as a suppressor of the even more severe early lysis defect of the mutant SA52G, which causes lysis at or before the time when the first phage particle is assembled in the cell. This mutation scrambles the C-terminal sequence of S, resulting in a predicted net charge increase of +4, and retards lysis by about 30 min, thus permitting a viable quantity of progeny to accumulate. Thus, the C-terminal domain is not involved in the formation of the lethal membrane lesion nor in the "dual-start" regulation conserved in lambdoid holins. Instead, the C-terminal sequence defines a cytoplasmic regulatory domain which affects the timing of lysis. Comparison of the C-terminal sequences of within holin families suggests that these domains have little or no structure but act as reservoirs of charged residues that interact with the membrane to effect proper lysis timing.

Amino Acid Sequence↗
PubMed1999

A comparison of single fraction radiosurgery tumor control and toxicity in the treatment of basal and nonbasal meningiomas.

Between July 1993 and October 1997, 107 patients with 118 meningiomas were treated with Gamma Knife radiosurgery (GKRS). The most frequent site of tumor origin was the skull base (54%). The mean tumor diameter and volume were 2.5 cm and 9.4 cm3, respectively. The mean dose to the tumor periphery was 17 Gy, prescribed to a mean iso-dose of 47%. At a mean follow-up of 28 months, tumor control for basal and nonbasal meningiomas was 80%. Deteriorating peritumoral edema associated with symptoms was observed in 1 of 49 (2%) skull-base tumors and in 4 of 39 (10%) non-basal tumors, without associated tumor growth. (p=0.l5 and 0.234 respectively, z-test). Stereotactic radiosurgery can achieve acceptable tumor control with low morbidity in the treatment of most meningiomas. However, when the tumor is nonbasal, the potential morbidity from peritumoral edema should be recognized and other treatment options considered, such as adjuvant surgery, partial fractionated irradiation or stereotactic radiotherapy.

Adolescent↗
PubMed1999

Ugly stepchildren?

Explore the source record for details and available documents.

Family Practice↗
PubMed1999

Tissue-specific mutant frequencies and mutational spectra in cyclophosphamide-treated lacI transgenic mice.

The induction and nature of mutations in the lacI transgene were evaluated in multiple tissues after exposure of adult male B6C3F1 lacI transgenic mice to cyclophosphamide (CP). Mice were given a single i.p. injection of 25 mg CP/kg, 100 mg CP/kg, or vehicle (PBS) and then necropsied 6 weeks after treatment to allow DNA extraction and lacI mutant recovery. Tissues evaluated included target tissues for tumorigenesis (lung, urinary bladder) and sites not susceptible to tumor formation in B6C3F1 mice (kidney, bone marrow, splenic T-lymphocytes). After exposure to the high dose of CP, a significant increase in the mutant frequency (Mf) was detected in the lungs and urinary bladders, compared to the respective tissues from vehicle-treated controls. In contrast, the Mfs in kidney, bone marrow, and splenic T cells from CP-treated mice were not significantly different from controls. The spectra of mutations in lacI from lung and urinary bladder were significantly changed after high-dose CP treatment, with a significant increase in the frequency of A. T --> T. A transversions found in both tissues and a significantly elevated frequency of deletions in the lungs. Conversely, in vehicle-treated mice, the two predominant classes of lacI mutations recovered in lung and urinary bladder were G. C --> A. T transitions at CpG sites and G. C --> T. A transversions. These CP exposures were also genotoxic as measured by the significant induction of micronuclei in peripheral blood 48 hr after exposure. These data indicate that under these study conditions, CP-induced mutations are detectable in the lacI transgene in the target tissues, but not in nontarget tissues for CP-induced cancer. With the lacI assay it is possible to study mutagenicity in a variety of critical tissues to provide mechanistic information related to genotoxicity and carcinogenicity in vivo.

Animals↗
PubMed1999

A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. Effects on bone mineral density, symptoms and lipid profiles.

OBJECTIVE: To compare the effects of two doses of conjugated equine estrogen (CEE) and two of esterified estrogen plus methyltestosterone (E + A) in surgically menopausal women. STUDY DESIGN: A two-year, parallel-group, double-blind study of 311 women who were randomly assigned to one of four regimens: (1) CEE, 0.625 mg/d; (2) CEE, 1.25 mg/d; (3) esterified estrogens, 0.625 mg, + methyltestosterone, 1.25 mg/d; or (4) esterified estrogens, 1.25, + methyltestosterone, 2.5 mg/d. Study parameters were symptoms, lipids, bone mineral density, side effects and safety. RESULTS: All treatments prevented loss of bone in the spine and hip. The higher E + A dose increased spine and hip BMD more than other treatments (P < .002). All treatments improved menopausal symptoms, with non-significantly greater improvements in well-being and sexual interest in the E + A groups. Similar and significant decreases in low-density lipoprotein were observed in all groups, but high-density lipoprotein and triglycerides were increased only in the unopposed estrogen groups (P < .05). Hirsutism was uncommon and similar in all groups at two years. Discontinuation rates and reasons for withdrawal from the study were similar in both groups. No clinically significant side effects or laboratory test abnormalities were seen. CONCLUSION: As compared to estrogen alone, E + A significantly improved BMD and was well tolerated in surgically menopausal women.

Administration, Oral↗
PubMed1999

Recruitment and retention of general practitioners in the UK: what are the problems and solutions?

Recruitment and retention of general practitioners (GPs) has become an issue of major concern in recent years. However, much of the evidence is anecdotal and some commentators continue to question the scale of workforce problems. Hence, there is a need to establish a clear picture of those instabilities (i.e. imbalances between demand and supply) that do exist in the GP labour market in the UK. Based on a review of the published literature, we identify problems that stem from: (i) the changing social composition of the workforce and the fact that a large proportion of qualified GPs are significantly underutilized within traditional career structures; and (ii) the considerable differences in the ability of local areas to match labour demand and supply. We argue that one way to address these problems would be to encourage greater flexibility in a number of areas highlighted in the literature: (i) time commitment across the working day and week; (ii) long-term career paths; (iii) training and education; and (iv) remuneration and contract conditions. Overall, although the evidence suggests that the predicted 'crisis' has not yet occurred in the GP labour market as a whole, there is no room for lack of imagination in planning terms. Workforce planners continue to emphasize national changes to the medical school intake as the means to balance labour demand and supply between the specialities; however, better retention and deployment of existing GP labour would arguably produce more effective supply-side solutions. In this context, current policy and practice developments (e.g. Primary Care Groups and Primary Care Act Pilot Sites) offer a unique learning base upon which to move forward.

Attitude of Health Personnel↗
PubMed1998

Investigation of hallucinogenic and related beta-carbolines.

Certain beta-carbolines are known to be hallucinogenic in humans, and several produce stimulus effects in animals similar to those of the classical hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM). Classical hallucinogens bind at 5-HT2 serotonin receptors and these receptors are thought to play a role in their mechanism of action. In the present study, we examined the binding of 15 beta-carbolines at rat 5-HT2A and 5-HT2C receptors. Affinities (Ki values) of the beta-carbolines ranged from about 100 nM to greater than 10,000 nM depending upon the degree of saturation of the pyridyl ring, and upon the presence and location of methoxy substituents in the benzenoid ring. In a further study, six rats were trained to discriminate the hallucinogenic beta-carboline harmaline (3.0 mg/kg, i.p.) from vehicle using a VI-15s schedule of reinforcement. This represents the first time a hallucinogenic beta-carboline has been used as a training drug in a drug discrimination study. Administration of DOM to the harmaline-trained animals resulted in 76% harmaline-appropriate responding at 1.25 mg/kg DOM and disruption of behavior at a higher dose. Taken together, the results of the present investigation demonstrate that: (a) certain beta-carbolines bind at 5-HT2 receptors; (b) that harmaline serves as a training drug at 3.0 mg/kg in drug discrimination studies with rats as subjects; and that (c) there is some similarity between the stimulus effects produced by harmaline and DOM.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1998

Comparison of the use of standardized diagnostic criteria and intuitive clinical diagnosis in the diagnosis of common viral warts (verrucae vulgaris).

OBJECTIVE: To assess the diagnostic value of standardized diagnostic criteria compared with the clinical intuitive diagnosis for verrucae vulgaris. DESIGN: A blind comparison with cross-over of experienced dermatologists using either intuitive clinical diagnosis or else recording the presence of standardized diagnostic criteria in verrucae vulgaris. SETTING: Clinical outpatient department in a major teaching hospital. PATIENTS: Fifteen patients aged 6 to 60 years with 21 verrucae vulgaris and 24 control lesions. INTERVENTION: Dermatologists examined the lesions and recorded either the diagnosis by the usual clinical intuitive method or else whether standardized diagnostic criteria were present in the lesion of each patient. Each dermatologist did 1 only of the 2 methods for each lesion with the other doing the alternative method for the same lesion, neither of them having previously been aware of any of the diagnoses. MAIN OUTCOME MEASURE: The sensitivity, specificity, and positive predictive, negative predictive, and relative values for each diagnostic approach were compared. RESULTS: Use of intuitive clinical diagnosis resulted in 100% specificity, sensitivity, and positive predictive, negative predictive, and relative values for both the verrucae vulgaris and the control lesions. Recording the presence of the diagnostic criteria reduced to a varying extent all the parameters of diagnostic accuracy with site--fingers and hands, elbows, and knees--being the most efficacious of the criteria. CONCLUSIONS: These data indicate that care is required in relying too much on standardized criteria as the basis for clinical diagnosis, even for a lesion as simple as a wart. They also reinforce the value of clinical experience obtained from repeated exposure to multiple variants of a disease in the traditional bedside teaching model.

Adolescent↗