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Biomedical subjects

P Young

Publications and source records attributed to P Young.

At least 145 records · Page 8Linked to original sources
PubMed1997

Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium.

Estradiol-17beta (E2) acts through the estrogen receptor (ER) to regulate uterine growth and functional differentiation. To determine whether E2 elicits epithelial mitogenesis through epithelial ER versus indirectly via ER-positive stromal cells, uteri from adult ER-deficient ER knockout (ko) mice and neonatal ER-positive wild-type (wt) BALB/c mice were used to produce the following tissue recombinants containing ER in epithelium (E) and/or stroma (S), or lacking ER altogether: wt-S + wt-E, wt-S + ko-E, ko-S + ko-E, and ko-S + wt-E. Tissue recombinants were grown for 4 weeks as subrenal capsule grafts in intact female nude mice, then the hosts were treated with either E2 or oil a week after ovariectomy. Epithelial labeling index and ER expression were determined by [3H]thymidine autoradiography and immunohistochemistry, respectively. In tissue recombinants containing wt-S (wt-S + wt-E, wt-S + ko-E), E2 induced a similar large increase in epithelial labeling index compared with oil-treated controls in both types of tissue recombinants despite the absence of epithelial ER in wt-S + ko-E tissue recombinants. This proliferative effect was blocked by an ER antagonist, indicating it was mediated through ER. In contrast, in tissue recombinants prepared with ko-S (ko-S + ko-E and ko-S + wt-E), epithelial labeling index was low and not stimulated by E2 despite epithelial ER expression in ko-S + wt-E grafts. In conclusion, these data demonstrate that epithelial ER is neither necessary nor sufficient for E2-induced uterine epithelial proliferation. Instead, E2 induction of epithelial proliferation appears to be a paracrine event mediated by ER-positive stroma. These data in the uterus and similar studies in the prostate suggest that epithelial mitogenesis in both estrogen and androgen target organs are stromally mediated events.

Aging↗
PubMed1997

Refinement of the hereditary neuralgic amyotrophy (HNA) locus to chromosome 17q24-q25.

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant, recurrent focal neuropathy characterized by episodes of painful brachial plexus neuropathy with muscle weakness and atrophy, as well as sensory disturbances. Single episodes are commonly preceded by unspecific infections or immunization, or are associated with parturition. Minor facial dysmorphic features are present in some pedigrees but do not clearly segregate with the disease. To confirm the recently described HNA locus on distal chromosome 17q, we performed a genetic linkage study in an extended Turkish pedigree. We were able to refine the HNA locus on chromosome 17q24-q25 in a 16-cM region.

Brachial Plexus Neuritis↗
PubMed1997

Indomethacin treatment of eighteen patients with Sweet's syndrome.

BACKGROUND: The standard treatment for Sweet's syndrome (acute febrile neutrophilic dermatosis) is oral corticosteroids. Despite a good initial response, the disease is characterized by frequent relapses. OBJECTIVE: Our purpose was to test the therapeutic effect of the nonsteroidal antiinflammatory drug indomethacin on Sweet's syndrome. METHODS: All patients with Sweet's syndrome observed during a 4-year period were given indomethacin, 150 mg/day for the first week and 100 mg/day for two additional weeks. The therapeutic response was assessed on days 4, 7, 14, 30, and 180. RESULTS: Seventeen of 18 patients had a good initial response; fever and arthralgias were markedly attenuated within 48 hours and eruptions cleared between 7 and 14 days. The remaining patient's cutaneous lesions continued to develop and were successfully treated with prednisone (1 mg/kg/day). The only side effect of indomethacin treatment was epigastric pain in two patients. No patient had a relapse after discontinuation of indomethacin (mean followup, 20.1 months). CONCLUSION: Indomethacin is a safe and effective treatment for Sweet's syndrome.

Adult↗
PubMed1997

Elucidation of a role for stromal steroid hormone receptors in mammary gland growth and development using tissue recombinants.

The use of tissue recombinants in conjunction with steroid receptor deficient mice is described as a tool to dissect the complex paracrine pathways of sex-hormone-regulated epithelial growth and ductal morphogenesis in the mammary gland and other hormone target organs. The basic methodology involves the construction of the four possible tissue recombinants composed of epithelium (E) and stroma (S) from wild-type (wt) and knock-out (KO) mice: wt-S + wt-S, wt-S + KO-E, KO-S + KO-E, and KO-S + wt-E. All tissue recombinants are grown as subrenal capsule grafts in nude mice. Following appropriate hormonal challenge epithelial growth can be studied in the four types of tissue recombinants. Such studies using estrogen receptor, androgen receptor and progesterone receptor knockout mice demonstrate that epithelial steroid receptors are neither necessary nor sufficient for hormonal regulation of epithelial proliferation. Instead, hormonal regulation of epithelial proliferation is a paracrine event mediated by hormone-receptor-positive stromal cells.

Animals↗
PubMed1997

Substrate induction and glucose repression of maltose utilization by Streptomyces coelicolor A3(2) is controlled by malR, a member of the lacl-galR family of regulatory genes.

malR of Streptomyces coelicolor A3(2) encodes a homologue of the Lacl/GalR family of repressor proteins, and is divergently transcribed from the malEFG gene cluster, which encodes components of an ATP-dependent transport system that is required for maltose utilization. Transcription of malE was induced by maltose and repressed by glucose. Disruption or deletion of malR resulted in constitutive, glucose-insensitive malE transcription at a level markedly above that observed in the parental malR+ strain, and overproduction of MalR prevented growth on maltose as carbon source. Consequently, MalR plays a crucial role in both substrate induction and glucose repression of maltose utilization. malR is expressed from a single promoter with transcription initiating at the first G of the predicted GTG translation start codon.

Amino Acid Sequence↗
PubMed1997

The effect of maternal glycemic control on fetal growth in diabetic pregnancies.

In this prospective study, we examined the effect of maternal glycemic control on fetal growth in pregnancies complicated by pregestational diabetes. One hundred and sixty-five pregestational diabetic pregnancies were studied with serial ultrasound scans and fetal growth was examined as a function of maternal glycemic control. There was a significant, although small, reduction in fetal biparietal diameter growth rate in the presence of poor maternal glycemic control during the first half of the pregnancy. In the second half of pregnancy, maternal hyperglycemia contributed to fetal macrosomia. We conclude that in pregnancies with pregestational diabetes, maternal hyperglycemia affects fetal growth in a biphasic manner. As a result of that, although babies born to diabetic mothers appear of relatively overall normal size and weight, they may have smaller heads than their potential and more fat.

Adult↗
PubMed1997

A novel frameshift mutation in PMP22 accounts for hereditary neuropathy with liability to pressure palsies.

Peripheral myelin protein PMP22 deficiency is associated with hereditary neuropathy with liability to pressure palsies (HNPP). Most HNPP cases are caused by a 1.5-megabase deletion in chromosome 17p11.2-12, a region that contains the PMP22 gene, whereas point mutations leading to HNPP are extremely rare. We have identified a family with clinical and electrophysiologic features of HNPP,in which all affected members are heterozygous carriers of a single base insertion in codon 94. This mutation is predicted to alter the reading frame and to result in a delayed termination signal. We conclude that the functional consequences of the frameshift are equivalent to those of the PMP22 deletion allele.

Adult↗
PubMed1997

Constitutive and variable regions of Z-disk titin/connectin in myofibril formation: a dominant-negative screen.

The giant muscle protein titin (connectin) is assumed to play a crucial role in the control of Z-disk assembly. Analysis of the Z-disk region of titin/connectin revealed a novel 45 residue repeat that is spliced in variable copy numbers. The repeat region is coexpressed in normal human myocardium in size variants corresponding to between 5 and 7 repeats. Smaller isoforms can be detected in muscles with thinner Z-disks like M. psoas. Sequence analysis of chicken breast muscle titin/connectin reveals that in this tissue, where Z-disks are thin, only two Z-repeats are expressed. The greatly variable thickness of Z-disks is therefore correlated to a region of variable length in titin/connectin, constructed from a novel protein building block. Transfection experiments in myogenic cell lines demonstrate that overexpression of the entire integral Z-disk region of titin leads to a disruption of sarcomere assembly. The differentially expressed titin/connectin regions, however, show no dominant-negative effects on myofibril assembly and are not targeted to Z-disks. This supports the idea that the Z-repeat region of titin/connectin is responsible for the control Z-disk thickness as an element of highly variable length, due to extensive differential splicing.

Actins↗
PubMed1997

Effect of chronic food restriction on pulsatile luteinizing hormone secretion and hypothalamic neuropeptide Y gene expression in castrate male sheep.

Castrate male sheep (wethers, average liveweight 38 +/- 0.6 kg) were given one of the following diets for 10 weeks followed by euthanasia (n = 8/group): high-energy high-protein providing 1-5 times the energy required to maintain liveweight (maintenance) (group 1.5 M), low-energy low-protein at 0.5 maintenance (0.5 M), or low-energy high-protein at 0.5 maintenance (0.5 M + P). 1.5 M wethers gained 22% liveweight whereas 0.5 M and 0.5 M + P wethers lost 18 and 13% liveweight respectively. Relative to the 1.5 M group, the 0.5 M and 0.5 M + P groups had similar plasma concentrations of glucose and cortisol throughout, but elevated non-esterified fatty acids (P < 0.001) and reduced IGF-I and insulin (P < 0.05, 0.01 or 0.001) from 1 week onwards. Each week blood samples were taken every 12 min for 4 h and plasma assayed for LH. Mean concentration over 4 h, LH pulse frequency and LH pulse amplitude showed no progressive change in 1.5 M sheep. However, in both 0.5 M and 0.5 M + P groups mean LH increased (P < 0.001 and P < 0.01 respectively), pulse frequency decreased (P < 0.01 and P < 0.01) and pulse amplitude increased (P < 0.001 and P < 0.01) over the 10-week period. Anterior pituitary. LH content was greater in 0.5 M (P < 0.01) and 0.5 M + P (P < 0.05) than in 1.5 M sheep. Coronal sections (20 microns) of hypothalamic brain tissue were subjected to in situ hybridisation to determine gene expression for neuropeptide Y (NPY). NPY mRNA was concentrated in the arcuate nucleus and median eminence, with total amounts greater in both 0.5 M (310%, P < 0.001) and 0.5 M + P (333%, P < 0.01) groups than in 1.5 M sheep (100%). These data reveal that chronic low dietary energy intake by long-term castrates, with high or low protein intake, reduces LH pulse frequency but increases the circulating levels of LH by virtue of an increase in pulse amplitude, and concomitantly increases hypothalamic NPY gene expression.

Animals↗
PubMed1997

Relationship between the in vivo localization and the immunoblotting pattern of anti-basement membrane zone antibodies in patients with bullous pemphigoid.

OBJECTIVE: To compare the localization of anti-basement membrane zone (BMZ) antibodies bound in vivo with the antigenic specificities of circulating anti-BMZ antibodies in patients with bullous pemphigoid (BP). DESIGN: Comparison of the results of an examination of the skin specimens of the patients using direct immunoelectron microscopy and direct immunofluorescence on 1-mol/L sodium chloride-split skin with the results of an analysis of the corresponding serum samples using the immunoblot technique. SETTING: Immunodermatology department in a teaching hospital. PATIENTS: Thirty-six patients with typical BP and circulating anti-BMZ antibodies. RESULTS: Serum samples from 22 patients with BP indicated only BP antigen 1 in the results of immunoblot analysis. Using direct immunofluorescence, an analysis of the peribullous skin samples obtained from these 22 patients showed deposits of IgG exclusively located along the epidermal side of sodium chloride-split skin; the results of direct immunoelectron microscopic examination showed deposits of IgG located on the intracellular portion of hemidesmosomes in 18 (82%) of these 22 specimens, whereas 4 biopsy specimens had linear IgG deposits located both intracellularly and extracellularly along the keratinocyte plasma membrane. The results of immunoblot analysis of the serum samples from 5 patients with BP indicated BP antigen 2 alone; the results of direct immunoelectron microscopic examination of peribullous skin samples from these 5 patients showed linear intracellular and extracellular deposits along the keratinocyte membrane, corresponding to an epidermal fluorescence labeling pattern of peribullous sodium chloride-split skin in 2 patients and a combined (dermal and epidermal) pattern in 3 patients. CONCLUSION: The 2 different patterns of reactivity of anti-BMZ antibody deposits bound in vivo closely corresponded to the antigenic specificities indicated in the corresponding serum samples of the patients. These results are in accordance with those previously obtained in vitro and argue for identical binding profiles of circulating antibodies that are bound in vivo in BP.

Autoantibodies↗
PubMed1997

Jarman underprivileged area scores, tooth decay and the effect of water fluoridation.

OBJECTIVE: To examine the association between dental caries and Jarman underprivileged area scores at regional, district and electoral ward level and explore any possible relationship with water fluoridation. DESIGN: An ecological study using the English results from the NHS dental surveys on 5-year-old children in 1991/2 and 1993/4, and the survey of 12-year-old children in 1992/3. Jarman underprivileged area scores were used from the 1991 census. SETTING: The study used former English health authority regions and districts. The electoral wards were in non-fluoridated Salford and Trafford and Liverpool, and fluoridated Newcastle and North Tyneside. SUBJECTS: The random sample of 5-year-old children examined in 1991/2 and 1993/4, and 12-year-old children in 1992/3, in studies coordinated by the British Association for the Study of Community Dentistry. OUTCOME MEASURES: Correlations between regional, district and electoral ward mean dmft/DMFT and Jarman underprivileged area scores. RESULTS: Significant correlations were demonstrated at a regional level in 5-year-old children in 1991/2, district level in 5-year-old children in 1991/2 and 1993/4 and at electoral ward level in both age groups in 1992/3 and 1993/4. Correlation coefficients varied between r = 0.88 to r = 0.46. Multiple linear regression at electoral ward level showed significant interactions between Jarman scores and water fluoridation. There was an average 44 per cent and 43 per cent reduction in caries in fluoridated electoral wards in 5- and 12-year-old children respectively. In deprived electoral wards, with a Jarman score of 40, the reduction in caries increased to 54 per cent and 56 per cent for 5- and 12-year-old children respectively. CONCLUSIONS: Dental caries was associated with Jarman underprivileged area scores. The differential efficacy of fluoridation to deprived areas was demonstrated at electoral ward level. Water fluoridation was confirmed as an evidence based intervention which has halved the amount of tooth decay in 5- and 12-year-old children.

Child↗
PubMed1996

Bacteriophage T4 anaerobic ribonucleotide reductase contains a stable glycyl radical at position 580.

It has been recently recognized that the class III anaerobic ribonucleotide reductase requires the presence of a second activating gene product, NrdG. We have proposed that the role for NrdG involves the generation of an oxygen sensitive glycyl free radical within the NrdD enzyme. In this article we present the generation of such a glycyl free radical within the T4 NrdD subunit and its dependence upon the phage NrdG subunit. Initially, an overexpression system was created that allowed the joint production of T4 NrdD and T4 NrdG. With this system and in the presence of T4 NrdG, an oxygen-sensitive cleavage of NrdD was observed that mimicked the cleavage observed in phage infected Escherichia coli extracts. Under anaerobic conditions the presence of T4 NrdD with NrdG revealed a strong doublet EPR signal (g = 2.0039). Isotope labeling of the NrdD with [2H]glycine and [13C]glycine, respectively, confirmed the presence of a stabilized glycine radical. The unpaired electron is strongly coupled to C-2 in glycine and the doublet splitting originates from one of the alpha-protons. The glycine residue at position 580 was determined to be the radical containing residue through site-directed mutagenesis studies involving a G580A NrdD mutant. The glycyl radical generation was specific for the T4 NrdG, and the host E. coli NrdG was found to be unable to activate the phage reductase. Finally, anaerobic purification revealed the holoenzyme complex to contain iron, whereas the NrdD polypeptide was found to lack the metal. Our results suggest a tetrameric structure for the T4 anaerobic ribonucleotide reductase containing one homodimer each of NrdD and NrdG, with a single glycyl radical present.

Anaerobiosis↗
PubMed1996

[Molecular biology and genetics of hereditary motor and sensory neuropathies].

Hereditary neuropathies (HMSN) are among the most common genetic diseases in neurology. Various mutations in different genes are known which lead to the most frequent hereditary neuropathies. These mutations concern proteins of the myelin of the peripheral nervous system, as well as a gap-junction protein expressed in peripheral nerves. The molecular mechanisms leading from gene mutation to disease phenotypes are not fully understood. Nowadays, we are able to use DNA analysis for symptomatic, presymptomatic, and prenatal screening. The latter is of questionable value because of the variability in disease severity and outcome. Deeper insights into the molecular pathophysiology will, however, yield new therapeutic strategies in individual patients.

Connexins↗
PubMed1996

Urothelial transformation into functional glandular tissue in situ by instructive mesenchymal induction.

It is generally believed that adult tissue is terminally differentiated. The ureter is derived from the metanephric diverticulum which, along with the derivatives of the metanephric mesoderm, forms the kidney. In our experiments, the left ureters of adult male athymic mouse hosts were severed below the kidney, and mesenchyme from neonatal rat seminal vesicles (SVM) was grafted to the cut end of the ureter, thus bringing adult mouse ureter epithelium (URE) in contact with neonatal rat SVM. After four to eight weeks, the in situ tissue recombinants were harvested, and the epithelial secretory proteins recovered. In 5 of 11 cases, an induction occurred, resulting in an in situ transformation of the non-glandular transitional epithelium of the adult mouse ureter into the simple columnar epithelium of the seminal vesicle (SV). Functional cytodifferentiation was examined in these neonatal rat SVM + adult mouse URE tissue recombinants using antibodies against SV-specific secretory (SVS) proteins of the mouse and rat. From the cut end of the ureter, the adult URE was induced to undergo SV morphogenesis, to express SV cytodifferentiation, and to produce the complete spectrum of major SVS proteins characteristic of the mouse. The induced seminal vesicle epithelium (SVE) also expressed androgen receptors (AR) which are not seen in urothelial tissue. Staining with Hoechst dye 33258, which can distinguish cells of mouse and rat origin, further demonstrated that the induced SVE was indeed of mouse origin and not a contaminant of the inducing rat SVM. in addition, neonatal mouse vaginal mesenchyme was grafted in situ beneath the bladder mucosa of adult male mice, and the host animals were killed after three months. The vaginal mesenchyme implanted into the bladders induced prostate-like acini, indicating that the above reprogramming of adult organs in situ is not an isolate occurrence. These results set a precedent for the "recreation" of new vital organs, such as the kidney, in situ by demonstrating that adult epithelial cells retain a developmental plasticity equivalent to their undifferentiated fetal counterparts and are capable of being reprogrammed in situ to express a completely new morphological, biochemical, and functional phenotype.

Animals↗