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L Houghton

Publications and source records attributed to L Houghton.

15 recordsLinked to original sources
PubMed2001

Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle.

Aging skeletal muscles suffer a steady decline in mass and functional performance, and compromised muscle integrity as fibrotic invasions replace contractile tissue, accompanied by a characteristic loss in the fastest, most powerful muscle fibers. The same programmed deficits in muscle structure and function are found in numerous neurodegenerative syndromes and disease-related cachexia. We have generated a model of persistent, functional myocyte hypertrophy using a tissue-restricted transgene encoding a locally acting isoform of insulin-like growth factor-1 that is expressed in skeletal muscle (mIgf-1). Transgenic embryos developed normally, and postnatal increases in muscle mass and strength were not accompanied by the additional pathological changes seen in other Igf-1 transgenic models. Expression of GATA-2, a transcription factor normally undetected in skeletal muscle, marked hypertrophic myocytes that escaped age-related muscle atrophy and retained the proliferative response to muscle injury characteristic of younger animals. The preservation of muscle architecture and age-independent regenerative capacity through localized mIgf-1 transgene expression suggests clinical strategies for the treatment of age or disease-related muscle frailty.

Animals↗
PubMed2000

Sequential programs of retinoic acid synthesis in the myocardial and epicardial layers of the developing avian heart.

Endogenous patterns of retinoic acid (RA) signaling in avian cardiac morphogenesis were characterized by localized expression of a key RA-synthetic enzyme, RALDH2, which displayed a biphasic pattern during heart development. RALDH2 immunoreactivity was initially apparent posterior to Hensen's node of stage 5-6 embryos and subsequently in somites and unsegmented paraxial and lateral plate mesoderm overlapping atrial precursors in the cardiogenic plate of stage 9- embryos. Initial RALDH2 synthesis in the posterior myocardium coincided with activation of the AMHC1 gene, a RA-responsive marker of inflow heart segments. A wave of RALDH2 synthesis then swept the myocardium in a posterior-to-anterior direction, reaching the outflow tract by stage 13, then fading from the myocardial layer. The second phase of RALDH2 expression, initiated at stage 18 in the proepicardial organ, persisted in migratory epicardial cells that completely enveloped the heart by stage 24. Early restriction of RALDH2 expression to the posterior cardiogenic plate, overlapping RA-inducible gene activation, provides evidence for commitment of posterior avian heart segments by localized production of RA, whereas subsequent RALDH2 expression exclusively in the migratory epicardium suggests a role for the morphogen in ventricular expansion and morphogenesis of underlying myocardial tissues.

Aldehyde Oxidoreductases↗
PubMed1999

Regulation of a muscle-specific transgene by persistent expression of Hox genes in postnatal murine limb muscle.

Homeobox genes are necessary for the generation of the embryonic body plan in both invertebrate and vertebrate organisms. To investigate the potential function of homeodomain proteins in normal and regenerating skeletal muscle, we analyzed patterns of clustered homeobox gene expression in neonatal and adult muscle tissue. Transcripts encoding 5' genes in the HoxA cluster were detected in muscles from both the fore- and hindlimbs of neonatal and adult mice, whereas expression of HoxC gene transcripts was generally restricted to the muscles of the hindlimb. In contrast, transcripts encoding genes of the HoxB or HoxD clusters were not detected in muscles from either fore- or hindlimbs. Although ectopic expression of select HOX proteins in muscle cell cultures had modest effects upon the activity of a co-transfected myosin light chain (MLC) enhancer, mutation of a Hox binding site in this enhancer elicited increased linked reporter gene expression. Induction of muscle damage and regeneration was accompanied by the down-regulation of at least one Hox gene, concurrent with the activation of the regenerative program. Moreover, targeted ablation of the Hoxc-8 gene, normally expressed in mature fore- and hindlimb muscles, resulted in reduced expression of an MLC enhancer-driven transgene only in specific leg muscles. These results indicate that members of the HoxA and C clusters may, in combination, mediate various aspects of differentiation and patterning in adult musculature.

Aging↗
PubMed1999

Is surveillance for stage 1 germ cell tumours of the testis appropriate outside a specialist centre?

OBJECTIVE: To assess the results of treatment for stage 1 germ cell tumours of the testis, outside a specialist centre. PATIENTS AND METHODS: From May 1984 until March 1996, 123 patients with stage 1 disease were treated at our institution. Sixty patients with seminoma and 31 with teratoma were treated with orchidectomy only and surveillance; 32 patients with stage 1 seminoma elected for orchidectomy and adjuvant radiotherapy. The mean ages were 40, 31 and 35 years, and the median follow-up 52, 47 and 49 months, respectively. RESULTS: There were no disease- or treatment-related deaths. However, 18 (30%) patients with seminoma treated by orchidectomy only relapsed (median time 8 months, range 3-19); 14 of these responded to radiotherapy, three to radiotherapy and chemotherapy for second relapses outside the irradiated fields, and one to chemotherapy initially, for large-volume relapse. Fifteen (48%) patients with teratoma relapsed (median time 3 months, range 1-12); all responded to 4-6 courses of bleomycin/etoposide/cisplatin chemotherapy. One patient had a second relapse and is currently disease-free 3 years after surgical excision of a lung metastasis. CONCLUSION: These results show that stage 1 testis tumours can be managed successfully in a district general hospital. However, we are concerned about the high relapse rates and are now attempting to identify patients at greater risk of recurrence, to consider adjuvant therapy in this group.

Adult↗
PubMed1999

A retinoic acid-inducible transgenic marker of sino-atrial development in the mouse heart.

To study the specification of inflow structures in the heart we generated transgenic animals harboring the human alkaline phosphatase (HAP) gene driven by the proximal 840 bp of a quail SMyHC3 promoter. In transgenic mice, the SMyHC3-HAP reporter was expressed in posterior heart precursors at 8.25 dpc, in sinus venosa and in the atrium at 8.5 and 9.0 dpc, and in the atria from 10.5 dpc onwards. SMyHC3-HAP transgene expression overlapped synthesis and endogenous response to retinoic acid (RA) in the heart, as determined by antibodies directed against a key RA synthetic enzyme and by staining of RAREhsplacZ transgenic animals. A single pulse of all-trans RA administered to pregnant mice at 7.5, but not after 8.5, dpc induced cardiac dismorphology, ranging from complete absence of outflow tract and ventricles to hearts with reduced ventricles expressing both SMyHC3-HAP and ventricular markers. Blockade of RA synthesis with disulfiram inhibited RA-induced transcription and produced hearts lacking the atrial chamber. This study defines a novel marker for atrial-restricted transcription in the developing mouse heart. It also suggests that atrial-specific gene expression is controlled by localized synthesis of RA, and that exclusion of RA from ventricular precursors is essential for correct specification of the ventricles.

Alkaline Phosphatase↗
PubMed1996

Modular elements of the MLC 1f/3f locus confer fiber-specific transcription regulation in transgenic mice.

The two proteins encoded by the fast alkali myosin light chain (MLC) 1f/3f locus are developmentally regulated, muscle specific, and expressed exclusively in fast-twitch fibers. Their expression is independently regulated by two separate promoters and a downstream enhancer. Previous studies showed a reporter gene directed by the rat MLC If promoter and MLC enhancer to exhibit correct skeletal muscle-specific expression in transgenic mice during development and to be preferentially expressed in fast-twitch Type IIB fibers [Donoghue et al., (1991) J. Cell B.ol. 115:423-434]. The MLC 3f promoter also directed muscle-specific expression of a CAT reporter gene in adult transgenic mice and showed little dependence upon the enhancer. Here, we show that the MLC 3f promoter also directs transgene expression in the fast-twitch fibers of adult skeletal muscle, but almost exclusively to fiber Types IIA and IIX. MLC 3f transgene expression occurs in only a subset of the fiber types that express the endogenous locus, indicating modular elements included in the transgene confer fiber-specific transcription regulation. MyoD protein was also found to be restricted to fiber Types IIA and IIX, providing evidence for its possible role in mediating fiber-specific gene expression.

Animals↗
PubMed1993

Unusual organization of the human T-cell receptor beta-chain gene complex is linked to recombination hotspots.

Two rare Sfi I polymorphisms of 360 kb and 280 kb present within the human T-cell antigen receptor beta-chain gene complex were revealed by pulsed-field gel electrophoresis. They represent allelic variants of the polymorphic 330- and 300-kb Sfi I fragments previously described. The 360-kb polymorphism results from duplication of the 30-kb DNA fragment responsible for the 330/300-kb insertion/deletion-related polymorphism. The 280-kb polymorphism results from a 20-kb deletion from the 300-kb SfiI allele. The rare polymorphisms also map on either side of a Sal I site located near a recombination hotspot, suggesting that germline duplications and deletions arose from nonhomologous crossover events.

Chromosomes, Human, Pair 7↗
PubMed1991

Associations between breast cancer, plasma triglycerides, and cholesterol.

A case-control study investigating the association between plasma lipids and breast cancer was conducted among women aged 30-80 in Buffalo, NY. All eligible women from a large breast clinic and two area physicians' offices were requested to participate over a one-year period. Subjects completed a health questionnaire and donated a fasting blood sample prior to diagnostic breast biopsies. The 83 women found to have breast cancer (cases) had significantly higher plasma triglyceride values than did the 113 women found not to have breast cancer (controls). Lower plasma beta-carotene values were associated with breast cancer, but only in those women with elevated triglyceride or cholesterol. Plasma cholesterol values were lower in those breast cancer cases presenting with more advanced stages of cancer, suggesting that metabolic effects of clinical and preclinical breast cancer may lower cholesterol levels. Although the limitations of case-control studies are well-recognized, these data suggest an etiologic role for plasma triglycerides and beta-carotene or for related dietary factors.

Adult↗
PubMed1977

Subcapsular orchidectomy for carcinoma of the prostate.

Our results suggest that subcapsular orchidectomy is at least as effective as oestrogen therapy in producing long-lasting suppression of plasma testosterone. It has many advantages over oestrogen therapy, so that, like Huggins, we believe it to be the hormonal treatment of choice for patients who develop symptoms from carcinoma of the prostate.

Castration↗
PubMedDate not supplied

Effects of breast cancer treatments on plasma nutrient levels: implications for epidemiological studies.

The interpretation of case-control studies in which blood nutrient levels are examined as etiological factors in cancer is complicated by the possibility that either the disease or its treatment may alter these levels. Circulating levels of selected nutrients were examined prior to diagnostic biopsy and compared with levels 3 to 4 months after diagnosis among 71 women with breast cancer and 95 women with benign breast disease. Among women with benign breast disease or women with breast cancer who were not given postsurgical adjuvant drug therapy, levels of alpha-carotene, lycopene, alpha-tocopherol, cholesterol, and triglycerides did not change over time. In contrast, women who received chemotherapy had increased levels of cholesterol, retinol, and alpha- and gamma-tocopherol, and women on antiestrogen therapy showed increased levels of triglycerides and alpha-tocopherol. Overall, the concentrations of carotenoids (lycopene, alpha-carotene, and beta-carotene) did not change in breast cancer cases, although subgroup analyses showed increased levels of beta-carotene among cases not receiving drug treatment and decreased levels among those receiving antiestrogens. In summary, blood levels of some nutrients did not appear to be affected by breast cancer or its treatments, but changes were noted for levels of plasma lipids, tocopherols, retinol, and beta-carotene. Those investigating the etiological relationship between breast cancer and circulating nutrients need to consider these effects in designing and interpreting epidemiological studies.

Adult↗