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P Young

Publications and source records attributed to P Young.

At least 73 records · Page 4Linked to original sources
PubMed2001

[Histological and clinical forms of the eosinophilic cellulitis].

BACKGROUND: Wells' syndrome is characterized by clinical features of cellulitis and a histological picture of eosinophilic infiltrate of the dermis with some "flame" figures. PATIENTS AND METHODS: The clinical and histological features of nine patients with Wells' syndrome seen from 1988 to 1998 were retrospectively reviewed. RESULTS: The clinical features of the nine patients (five men and four women) were urticaria (n=1), cellulitis (n=2), annular plaques (n=3), vesiculo-bullous lesions (n=2) and edema of the face with nodules of the conjunctiva (n=1). Histological examination of skin biopsies showed an eosinophilic infiltrate of the dermis associated with some "flame" figures in all cases. The infiltrate was located in the superficial or deep dermis in accordance with the different clinical features. One patient developed a non Hodgkin lymphoma and presented successively: a Wells' syndrome, a leucocytoklastic vasculitis and a Sweet's syndrome. Numerous treatment were used: topical corticosteroids, H1-antihistamines, dapsone and systemic corticosteroids. Two patients relapsed after treatment withdrawal. DISCUSSION: This study demonstrated a wide polymorphism of the clinical and histological features of Wells' syndrome. The clinical features seem to depend on the location of the dermal infiltrate, suggesting the existence of a spectrum of eosinophilic dermatoses, like in neutrophilic dermatoses. The successive occurrence of vasculitis, Wells' syndrome and Sweet'syndrome in a patient suggests an overlap between these diseases. Systemic corticosteroids are the most effective treatment, but may lead to a corticosteroid dependence.

Adolescent↗
PubMed2001

Cellular and humoral immune response in progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a fatal, demyelinating disease caused by JC virus (JCV) in patients with severe immunosuppression. We studied the JCV-specific cellular and humoral immune response in 7 healthy donors (HD), 6 human immunodeficiency virus-1 (HIV-1)-infected patients without PML (HIV), 4 HIV-1-negative patients with PML (PML), and 8 HIV-1-positive patients with PML (HIV/PML). As antigens, recombinant virus-like particles of the major structural protein VP1 (VP1-VLP) of JCV, tetanus toxoid (TT), or the mitogen phytohemagglutinin (PHA) were used. Proliferation of peripheral blood mononuclear cells (PBMC) after stimulation with the VP1-VLP was significantly suppressed in PML and HIV/PML patients compared to HD. After antigen stimulation the production of interferon-gamma (IFN-gamma) was reduced in PML, in HIV/PML, and in HIV patients. The production of interleukin-10 (IL-10), however, was elevated in HIV/PML patients. Neither proliferation nor cytokine production correlated with the presence of JCV DNA in PBMC. The immunoglobulin G serum antibody titer to the VP1-VLP was slightly elevated in HIV, elevated in PML, and highly elevated in HIV/PML patients compared to HD. The development of PML appears to coincide with a general impairment of the Th1-type T-helper cell function of cell-mediated immunity.

Cytokines↗
PubMed2001

DNA microarray analysis of differential gene expression of 6-year-old rat neural striatal progenitor cells during early differentiation.

EGF-responsive striatal progenitor cells from rat brain have been maintained in culture in the form of neurospheres for six years without exhausting their renewal capacity. The events surrounding differentiation of stem cells in the brain after a long progenitorship remain a mystery. Using DNA microarray analysis we investigated differential gene expression, comparing progenitor cells in their neurosphere state with the cells 24 hours after induction of differentiation. Eighty-one genes showed increased expression in the differentiated condition. Genes associated with cellular growth, neurite outgrowth, and synaptogenesis were activated, including both anti-apoptotic and pro-apoptotic genes. Two transmitter- related genes, acetylcholine receptor-beta and glutamate receptor-beta-unit were also elevated-, these genes not only fit the profile of early neural development, but also reflect the characteristics of striatal neurons. In addition, there are approximately 30 expressed sequence tags (ES7) increased during neural differentiation. Forty-seven genes showed decreased expression; half of them are known genes related to the cell cycle, cell adhesion, transcription, and signaling. Tbe signaling and cell cycle genes may be responsible for the life-long self-renewal. These data demonstrate for the first time that life-long quiescent stem cells retain the potential to become activated and develop into specific types of brain cells. The six-year long-term neural stem cells are an excellent model for studying developmental neurobiological processes and aging.

Animals↗
PubMed2000

The interaction of titin and alpha-actinin is controlled by a phospholipid-regulated intramolecular pseudoligand mechanism.

The assembly of stable cytoskeletal structures from dynamically recycled molecules requires developmental and spatial regulation of protein interactions. In muscle, titin acts as a molecular ruler organizing the actin cytoskeleton via interactions with many sarcomeric proteins, including the crosslinking protein alpha-actinin. An interaction between the C-terminal domain of alpha-actinin and titin Z-repeat motifs targets alpha-actinin to the Z-disk. Here we investigate the cellular regulation of this interaction. alpha-actinin is a rod shaped head-to-tail homodimer. In contrast to C-terminal fragments, full-length alpha-actinin does not bind Z-repeats. We identify a 30-residue Z-repeat homologous sequence between the actin-binding and rod regions of alpha-actinin that binds the C-terminal domain with nanomolar affinity. Thus, Z-repeat binding is prevented by this 'pseudoligand' interaction between the subunits of the alpha-actinin dimer. This autoinhibition is relieved upon binding of the Z-disk lipid phosphatidylinositol-bisphosphate to the actin-binding domain. We suggest that this novel mechanism is relevant to control the site-specific interactions of alpha-actinin during sarcomere assembly and turnover. The intramolecular contacts defined here also constrain a structural model for intrasterical regulation of all alpha-actinin isoforms.

Actinin↗
PubMed2000

Safety and costs of initiating angiotensin converting enzyme inhibitors for heart failure in primary care: analysis of individual patient data from studies of left ventricular dysfunction.

OBJECTIVE: To estimate the costs and consequences of diagnosing symptomatic heart failure with left ventricular systolic dysfunction and initiating angiotensin converting enzyme inhibitors in primary care. DESIGN: Analysis of individual patient data from studies of left ventricular dysfunction (SOLVD) to identify complications during test dose and titration phases. SETTING: Two randomised controlled trials in secondary care. PARTICIPANTS: 7487 patients taking a test dose of enalapril at enrolment to the treatment and prevention trials; 2569 patients with clinical signs of heart failure and established left ventricular dysfunction entered the treatment trial. MAIN OUTCOME MEASURES: Discontinuation during the test dose period. Discontinuation or reduction of dose during the first year of treatment for heart failure. Costs of diagnosis and titration of treatment. RESULTS: During the test dose phase, 585 patients (7.8%) reported side effects; 136 (1.8%) of these discontinued because of severe side effects. During the titration phase, compared with placebo, enalapril was associated with an increased risk of dose reduction due to hypotension (odds ratio 2.09, 95% confidence interval 1.15 to 3.82). However, overall, there was no difference in the rates of side effects leading to dose reduction or withdrawal between the enalapril and placebo groups. The costs of diagnosing heart failure with left ventricular systolic dysfunction and initiating and titrating an angiotensin converting enzyme inhibitor in primary care are pound300 to pound400. CONCLUSIONS: Treatment with angiotensin converting enzyme inhibitors can be safely started for patients with heart failure and left ventricular systolic dysfunction in primary care.

Adult↗
PubMed2000

Sex hormone-induced carcinogenesis in Rb-deficient prostate tissue.

The retinoblastoma (Rb) gene product is a prototypic tumor suppressor. Mice lacking the Rb gene are not viable and die in utero at approximately 13 days of gestation. In this study, we have rescued Rb-/- prostates by grafting pelvic organ rudiments from Rb-/- mouse embryos under the renal capsule of adult male nude mouse hosts. Grafts of embryonic pelvic organs developed into functional prostatic tissue. Some of the prostatic tissue generated was further used to construct chimeric prostatic tissue recombinants by combining wild-type rat urogenital mesenchyme (rUGM) with Rb-/- and Rb+/+ prostatic epithelium (PRE). The tissue recombinants were grown as subcapsular renal grafts and treated from the time of grafting with Silastic capsules containing 25 mg of testosterone plus 2.5 mg of estradiol. During 5-8 weeks of hormone treatment, rUGM+Rb+/+PRE tissue recombinants developed prostatic hyperplasia, whereas PRE in rUGM+Rb-/-PRE tissue recombinants developed hyperplasia, atypical hyperplasia, and carcinoma. During carcinogenesis in rUGM+Rb-/-PRE tissue recombinants, prostatic epithelial cells of the basal lineage disappeared, whereas the luminal cells underwent carcinogenesis. Epithelial E-cadherin almost totally disappeared. In all cases, epithelial PCNA labeling was elevated in tissue recombinants containing Rb-/- versus Rb+/+ epithelium. These epithelial changes were associated with almost total loss of smooth muscle cells in the stroma. In contrast, in untreated hosts rUGM+Rb+/+PRE tissue recombinants developed normally, and rUGM+Rb-/-PRE tissue recombinants developed mild epithelial hyperplasia. The results of this study demonstrate that Rb-/- prostatic tissue can be rescued from embryonic lethal mice and used to test its susceptibility to hormonal carcinogenesis. Deletion of the Rb gene predisposes prostatic epithelium to hyperplasia and increases proliferative activity Susceptibility to hormonal carcinogenesis in response to exogenous testosterone + estradiol is manifested in the progression from atypica hyperplasia to carcinoma. Thus, these findings demonstrate that the absence of the Rb tumor suppressor gene may predispose prostatic epithelial cells to carcinogenesis. Rescue of organs from Rb-/- embryos not only provides an opportunity to analyze the Rb gene pathway in the development and progression of prostate cancer but also provides an opportunity for specifically evaluating the role of the Rb pathway in development and carcinogenesis in other organs, such as the mammary gland and colon. Because rUGM greatly stimulates prostatic epithelial proliferation, the tissue recombinant model is a particularly useful tool for assessing the functional role of other genes in prostatic carcinogenesis through use of the appropriate transgenic or gene knockout mice.

Animals↗
PubMed2000

Hereditary recurrent focal neuropathies: clinical and molecular features.

The authors review the molecular genetics and pathophysiology of hereditary recurrent focal neuropathies: hereditary neuropathy with liability to pressure palsies (HNPP) and hereditary neuralgic amyotrophy (HNA). Significant progress in the understanding of HNPP and HNA has been achieved. HNPP and HNA are distinct clinical and pathologic disease entities with autosomal dominant inheritance. Molecular genetic studies have shown that HNPP and HNA are located on chromosome 17 but at distinct genetic loci (17p11.2 for HNPP, 17q25 for HNA). The 1.5 megabase deletion in 17p11.2 is the major cause of HNPP. This interstitial deletion causes the complete loss of one allele of the peripheral myelin protein 22 (PMP22) gene. Interestingly, rare HNPP patients are found without the 1.5 megabase deletion. However, these patients have distinct mutations in the PMP22 gene resulting in altered expression of the PMP22 protein. Current molecular genetic tests and clinical guidelines allow improved diagnosis, prognosis, and genetic counseling for patients with HNPP. Such tests are not available for HNA, because the disease-causing gene remains unknown. Molecular genetic advances in HNPP and HNA, as well as the study of transgenic animal and cellular models, will provide a more precise understanding of the disease mechanisms and will lead to the development of effective therapeutic tools for patients with inherited and sporadic recurrent peripheral neuropathies.

Charcot-Marie-Tooth Disease↗
PubMed2000

Topical treatments for fungal infections of the skin and nails of the foot.

OBJECTIVES: The objective of this review is to identify and evaluate the evidence of efficacy for topical treatments for fungal infections of the skin and nails of the human foot. To establish the effectiveness of topical treatments in achieving a cured condition and in preventing recurrence SEARCH STRATEGY: Randomised controlled trials were identified from the MEDLINE, EMBASE and CINHAL databases, from the beginning of these databases to December 1997. Also we screened the Cochrane Controlled Trials Register, the Science Citation Index BIOSIS, CAB - Health, Healthstar and Economic databases. References and unpublished studies were searched, podiatry journals handsearched and the pharmaceutical industry contacted. SELECTION CRITERIA: Only randomised controlled trials (RCTs) using participants who have mycologically diagnosed fungal infections of the skin and nails of the human foot are included in the analysis. DATA COLLECTION AND ANALYSIS: Two reviewers independently summarised the included trials and appraised their quality of reporting using a structured data extraction tool which assessed 12 quality criteria. MAIN RESULTS: Of 126 trials identified in 121 papers, 72 met the inclusion criteria. Placebo-controlled trials yielded the following pooled relative risks of failure to cure (RRFC) for skin infections: allylamines 0.30 (95% confidence interval 0.23 to 0.37); azoles 0.53 (0.42 to 0.68); undecenoic acid 0.28 (0.11 to 0.74); tolnaftate 0.46 (0.17 to 1.22). Though meta-analysis of 11 trials comparing allylamines and azoles showed an RRFC of 0.88 (0.78 to 0.99) in favour of allylamines, there was evidence of language bias. Seven English language reports favoured allylamines (RRFC = 0.79; 0.68 to 0.93) but four foreign language reports showed no difference between the two drugs (RRFC = 1.00; 0.90 to 1.12). The two trials of nail infections did not provide any evidence of benefit for topical treatments compared with placebo. REVIEWER'S CONCLUSIONS CONCLUSIONS: In placebo-controlled trials allylamines, azoles and undecenoic acid were efficacious. There are sufficient comparative trials to judge relative efficacy only between allylamines and azoles. Allylamines cure slightly more infections than azoles but are much more expensive. The most cost-effective strategy is first to treat with azoles or undecenoic acid and to use allylamines only if that fails.

Administration, Topical↗
PubMed2000

Echoplanar imaging in GI clinical practice: assessment of gastric emptying and antral motility in four patients.

Gastric emptying, frequency of antral contractions, and speed of antral contraction propagation were assessed in four patients using echoplanar imaging techniques. The results obtained and their impact on the diagnosis and management of the patients are presented and discussed. This shows that echoplanar evaluation of gastric function is noninvasive, well-tolerated by patients, detects clinically relevant abnormalities, and has the potential of becoming a valuable examination in the clinical gastrointestinal practice.

Adult↗
PubMed2000

Three to four-year-old nonpassaged EGF-responsive neural progenitor cells: proliferation, apoptosis, and DNA repair.

Epidermal growth factor responsive (EGFr) neural progenitor (NP) cells have been shown to be a potential alternative tissue source for neural transplantation and for developmental study. We have shown that nonpassaged EGFr NP cells can self-renew for 2 years in neurospheres and can robustly differentiate into glia and a number of neuronal cell types. We are now attempting to investigate if the EGFr NP cells will die or continue to live beyond the life span of the donor. In addition, we and other investigators have also found that EGFr NP cells, after transplant, retain only a small number of cells in the transplant site. In this study, we investigate the plasticity and fate of the EGFr NP cells. Using the nonpassaged method, we found EGFr NP cells live in the EGF supplement medium for over 4 years-the longest-lived EGFr NP cells ever reported. The 4-year-old striatal or cortical EGFr neurospheres, when subplated with substrate coating, migrate out of neurospheres and have robust growth with many processes. Furthermore, when nucleotide marker bromodeoxyuridine (BrdU) was added 3 days prior to the subplating, the EGFr NP cells were labeled positively with BrdU in the nucleus, indicating active proliferation activity. Meanwhile two other events were also found in the long-term EGFr NP cells. In the midst of the proliferation, apoptosis occurred. A subpopulation of EGFr NP cells are undergoing programmed cell death as indicated by the cell morphology and the TUNEL staining for DNA strand breaks. The TUNEL fluorescein-staining indicates that over 50% of EGFr NP cells are positive in the nuclei. On the other hand, we have also found that the major base excision repair enzyme, APE/ref-1, which is responsible for recognizing and repairing baseless sites in DNA, was present in the progenitor cells. However, in those cells undergoing apoptosis, APE/ref-1 levels were dramatically reduced or missing, and only a small percentage of cells were TUNEL and APE/ref-1 positive. These observations indicate that EGFr neural progenitor cells can live beyond the life span of the donor animal. The longevity of these cells in culture may be enhanced due to decreased apoptosis and the retention of normal DNA repair capacity.

Animals↗
PubMed2000

Paracrine mechanisms of mouse mammary ductal growth.

Ductal growth during puberty is stimulated by estrogens, which elicit their effects via specific estrogen receptors, ER alpha and ER beta. Analysis of mice with targeted disruption of ER alpha or ER beta has emphasized the importance of ER alpha in mammary gland development. In the mouse mammary gland, ER alpha are expressed in both epithelial and stromal cells (Kurita and Cunha, unpublished), which raises the possibility that the growth and morphogenetic effects of estrogen could be mediated via either epithelial or stromal ER. The aim of this paper is to review the role of epithelial versus stromal ER in mammary ductal-alveolar growth to assess the importance of paracrine mechanisms.

Aging↗
PubMed2000

PMP22 Thr118Met is not a clinically relevant CMT1 marker.

It is controversial if peripheral myelin protein 22 gene (PMP22) Thr118Met represents a functionally irrelevant polymorphism or, since hemizygosity for this variant has been found in two patients with Charcot-Marie-Tooth disease type 1 (CMT1 patients), it can act as a recessive CMT1 mutation. To shed further light on this variant and its diagnostic value we searched for carriers in 1018 individuals from the German general population, in 104 probands with hereditary neuropathy with liability to pressure palsies (HNPP) who were carriers of the 1.5-Mb deletion frequently associated with this disorder, in 187 patients with the 1.5-Mb duplication, and in 22 patients with a CMT1 phenotype who did not have any detectable anomaly in the PMP22 gene. Using allele-specific PCR we identified 14 [allele frequency (AF)=0.007] in the German general population, one (AF=0.01) in the HNPP group and six (AF=0.016) and two (AF=0.05) carriers of the PMP22 Thr118Met mutation in the CMT1 groups with and without gene defect. Carriers from all groups showed nerve conduction velocities which did not differ from typical values for these groups. We conclude that the hemizygous occurrence of the 118Met allele does not usually cause CMT1. Because of previous reports on its association with disease, and because its allele product shows abnormalities in in vitro expression systems, it seems possible that this mutation, together with yet unidentified factors, predisposes to CMT1. Alternatively, previously reported disease associations occurred by chance, and the 118Met allele causes biochemical abnormalities irrelevant for CMT1 formation. In either case this mutation is not a clinically relevant disease marker.

Biomarkers↗
PubMed2000

Treatment of an acyclovir and foscarnet-resistant herpes simplex virus infection with cidofovir in a child after an unrelated bone marrow transplant.

Herpes simplex virus (HSV) causes serious problems in immuno-compromised patients such as those receiving a bone marrow transplant (BMT) for a hematological malignancy. Resistance to acyclovir (ACV) is a growing major concern. Foscarnet is a non-thymidine kinase-dependent agent, but the emergence of ACV and foscarnet-resistant HSV requires a new therapeutic approach. We describe a girl treated with cidofovir for a life-threatening ACV-resistant HSV infection after an unrelated BMT for a relapse of an acute myeloblastic leukemia (AML).

Acyclovir↗
PubMed2000

Gastric response to increased meal viscosity assessed by echo-planar magnetic resonance imaging in humans.

Normal meals are highly viscous, and viscosity is a key factor in influencing gastric emptying of food. However, the process of meal dilution and mixing is difficult to assess with the use of conventional methods. The aim of this study was to validate an in vivo, novel, noninvasive, echo-planar magnetic resonance imaging (EPI) technique, capable of monitoring the viscosity of a model meal, and to use this to investigate the effects of viscosity on gastric emptying, meal dilution and satiety. Healthy volunteers (n = 8) ingested 500 mL of locust bean gum (0.25, 0.5, 1.0 or 1.5 g/100 g), nonnutrient, liquid meals of varying viscosities, and labeled with a nonabsorbable marker, phenol red. Meal viscosity was calibrated against the water proton transverse relaxation rate (T(2)(-1)) in vitro before ingestion, thus viscosity was measured in vivo via EPI measurements of T(2)(-1). Viscosity and dilution were also measured directly using nasogastric aspirates. Gastric volumes as measured by EPI, fullness, appetite and hunger were also assessed serially. Before ingestion, the log of initial meal viscosity was linearly related to T(2)(-1) (n = 8, r(2) = 0.95). Similarly, T(2)(-1) measured in vivo was also linearly related to the viscosity of the aspirates (r(2) = 0.88). All meals underwent rapid dilution, leading to a reduction in viscosity, which was greatest for the most viscous meal (P < 0.01). Surprisingly, despite the fact that the initial meal viscosity varied 1000-fold, there was only a small delay in gastric emptying (P for trend < 0.05). The area under the curve for satiety increased with initial meal viscosity, whereas that for hunger decreased (P < 0.05). In conclusion, the viscosity of a meal in vivo can be measured noninvasively using EPI. The stomach responds to meal ingestion by rapid intragastric dilution, causing a reduction of meal viscosity, and gastric emptying is minimally delayed. However, increased viscosity is associated with more prolonged satiety.

Adult↗