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Biomedical subjects

L Miles

Publications and source records attributed to L Miles.

At least 19 recordsLinked to original sources
PubMed2005

Hepatocyte glycogen accumulation in patients undergoing dietary management of urea cycle defects mimics storage disease.

OBJECTIVES: Anecdotal reports have described excess hepatocyte glycogen in patients with urea cycle enzyme defects. Retrospectively, the authors evaluated the prevalence and possible cause of liver glycogen accumulation in such patients. METHODS: The authors searched the files of the Division of Pathology at Cincinnati Children's Hospital from 1975 and 2004 for cases of urea cycle enzyme defects and identified 11 patients who had had liver biopsy performed and/or liver transplantation. All patients were on diets containing essential amino acids as the protein source before liver biopsy and/or transplantation. RESULTS: All but one patient had focal or diffuse glycogen accumulation in hepatocytes in at least one specimen by light microscopic examination. Two young infants also had cholestasis. Electron microscopy performed on six patients showed diffuse or focal glycogen excess in the cytoplasm of individual hepatocytes. Biochemical studies of three patients revealed two with hepatic glycogen content in the upper normal range and one that was abnormally high. Glycolytic enzyme activities were normal in two patients, and one patient had low phosphorylase activity. CONCLUSIONS: Hepatocyte glycogen accumulation in urea cycle enzyme defects resembles that seen in glycogen storage disease but can be distinguished in most cases by non-uniformity of distribution and/or the absence of sinusoidal compression by expanded hepatocytes. We speculate that therapeutic modification of dietary protein content by restriction to essential amino acids, including leucine, may promote glycogen accumulation by increasing insulin secretion.

Child↗
PubMed2004

Plasminogen regulates pro-opiomelanocortin processing.

BACKGROUND: Plasminogen-deficient mice exhibit behavioral differences in response to stress, including a markedly reduced acoustic startle reflex response compared with wild-type (WT) littermates. The acoustic startle reflex activates the hypothalamic-pituitary axis and is modulated by these hormones. OBJECTIVES: The purpose of this study was to investigate whether plasminogen plays a role in the processing of hormones in the hypothalamic-pituitary axis. METHODS: In this study the concentration of plasma, pituitary, and brain hypothalamic-pituitary axis hormones and precursor processing was examined in WT and plasminogen deficient (Plg-/-) mice before and after acoustic startle reflex testing. RESULTS: Plasma adrenocorticotropic hormone (ACTH), beta-endorphin and alpha-melanocyte stimulating hormone were elevated after acoustic startle reflex testing in both WT and (Plg-/-) mice. However, in the Plg-/- mice, beta-endorphin values were 43, 35, and 45% lower in the plasma, pituitary, and whole brain, respectively, compared with the WT mice. Plasmin readily degraded precursor peptides, the 23-kDa precursor, beta-lipotropin, and ACTH, when presented as purified proteins or as the secretory products of mouse pituitary cells (AtT-20). The precursor peptide, 23 kDa, for beta-endorphin and alpha-melanocyte stimulating hormone was reduced in the pituitaries from the Plg-/- mice, and the mRNA for Plg was found in pituitaries from WT mice. Infusion of beta-endorphin and alpha-melanocyte stimulating hormone into the brain of Plg-/- mice increased acoustic startle reflex. CONCLUSIONS: The results of this study show that plasmin is involved in the processing of hormones derived from the pro-opiomelanocortin precursor in the intermediate pituitary. A deficiency of plasminogen reduces processing of beta-endorphin and alpha-melanocyte stimulating hormone, and interferes with normal brain function.

Adrenocorticotropic Hormone↗
PubMed2001

Endometrial bleeding in hormone replacement therapy users: preliminary findings regarding the role of matrix metalloproteinase 9 (MMP-9) and tissue inhibitors of MMPs.

OBJECTIVE: To establish the effect of hormone replacement therapy (HRT) on the expression of matrix metalloproteinase 9 (MMP-9) and the tissue inhibitor of MMPs, TIMP-1, in the endometrium of postmenopausal and perimenopausal women. DESIGN: Prospective observational study. SETTING: United Kingdom teaching hospital. PATIENT(S): Thirty-one perimenopausal and postmenopausal HRT recipients, with a control group of eight postmenopausal women not undergoing HRT. INTERVENTION(S): Prospective record of bleeding patterns and endometrial biopsy. MAIN OUTCOME MEASURE(S): Endometrial histology, bleeding patterns, MMP-9, and TIMP-1 expression. RESULT(S): MMP-9 and TIMP-1 are expressed in benign postmenopausal endometrium. Expression of both molecules is reduced in HRT recipients compared with non-HRT recipients. CONCLUSION(S): Exposure to HRT appears to alter endometrial expression of MMP-9 and TIMP-1 and also the local balance between these molecules. This alteration may promote breakdown of the endometrial extracellular matrix and blood vessels and hence bleeding.

Base Sequence↗
PubMed1999

Commissioning--a postal questionnaire survey of the opinions of GPs and public health physicians in Wales.

A survey of general practitioners (GPs) and public health physicians (PHPs) in Wales was carried out to establish opinions on a range of matters concerning health care commissioning. Eighty-eight GPs and 46 PHPs were posted questionnaires, with responses received from 56 GPs and 40 PHPs. The results showed good support for the separation of the purchasing and providing roles of health management but little for the internal market or fundholding.

Attitude of Health Personnel↗
PubMed1998

Analysis of 1263 deaths in four general practices.

BACKGROUND: The death of a patient is a significant event that occurs often enough in general practice for it to have the potential to tell us much about the care we provide. There are few large series in the literature and we still know little about the collaborative use of this outcome measure. AIM: To determine the pattern of deaths and potentially preventable factors in our practices. METHOD: We completed a standard data collection form after each death in four general practices over a 40-month period. The results were discussed at quarterly meetings. RESULTS: A total of 1263 deaths occurred among our registered patients during the period of the audit. Preventable factors contributing to deaths were considered to be attributable to: patients (40%): mainly cigarette smoking, poor compliance, and alcohol problems; general practice teams (5%): mainly delayed referral, diagnosis and treatment, and failure to prescribe aspirin to patients with vascular disease; hospitals (6%): mainly delayed diagnosis and perceived treatment problems; the environment (3%): mainly falls, principally resulting in fractured neck of femur. CONCLUSION: A simple audit of deaths along the lines that we describe gives important information about the care provided by general practice teams and those in hospital practice. It has both educational value and is a source of ideas for service improvement and further study, particularly when carried out over several years.

Accidental Falls↗
PubMed1997

[Sleep and respiration at an altitude of 6,400 m (Aconcagua, Argentina].

UNLABELLED: Persons at extreme altitudes are known to experience disturbances in the regulation of ventilation and sleep structure. However, except for simulated studies using the decompression chamber, only single events of sleep or ventilation were measured so far in field studies up to an altitude of 5800 m. Modifying a portable sleep lab (Vitalog HMS 5000), we were able to conduct 7 channel polygraphy on our ascent to the Aconcagua up to an altitude of 6400 m. METHODS: In 6 climbers (age 38-62 y, 1 f, 6 m), ECG, EOG, SaO2, chest and abdominal movements, breathing and snoring sounds, body position, nasal and oral airflow were measured 4 weeks prior to the expedition at an altitude of 500 m, at base camp (4200 m) and in 3 climbers at 6400 m (2nd base camp) at the Aconcagua mountain. All participants had a repeat study at 500 m altitude 4 weeks after the expedition. RESULTS: The total number of obstructive apnoeas and hypopnoeas (OA/H) at night increased at an altitude of 4200 m in the mean of all 6 climbers from 36 to 67.7 compared to 500 m altitude, Central Apneas and Cheyne stokes (CA/CS) increased from 6.7 to 45.2. At 6400 m altitude the OA/H fell to 3 and 4 respectively in 2 climbers and CA to 1 and 2 respectively. In one climber, suffering from recurrent snoring with oxygen desaturation at 500 m altitude level, the number of OA/H and CA/CS increased further to 201 and 322, respectively, at 6400 m. Total sleep time including the REM position increased in all 6 climbers by 10% at base camp in comparison to an altitude of 500 m. Whereas the total sleep time remained constant in the 3 climbers at 6400 m altitude, the REM position declined by 10% in comparison to base camp (4200 m). However, significant fluctuations between individuals were noticed. CONCLUSION: Although significant alterations in sleep and breathing are noticeable at altitudes above 300 m, the respiratory drive in healthy subjects provides for a regular ventilation at high frequency at the extreme altitude above 6000 m. Sleep-related breathing disturbances at low altitude appear to be amplified at high altitudes.

Adult↗
PubMed1996

Structural and functional analysis of N-terminal point mutants of the human estrogen receptor.

Twenty N-terminal point mutations of the human estrogen receptor (hER) were constructed as ubiquitin fusion products and expressed under the control of the copper regulated promoter CUP1 in Saccharomyces cerevisiae. The objective of these studies was to overexpress hER in yeast and also to evaluate the functional properties of the N-terminal variants of hER. Fusion of the C-terminus of ubiquitin to the N-terminus of other proteins has been shown to increase the level of protein expression in yeast. Ubiquitin C-terminal hydrolases (UCHs) in yeast efficiently and precisely cleave at the junction with ubiquitin and render free hER with desired amino termini. The variant hER proteins, that were generated by mutating the N-terminus of hER, showed enormous differences in receptor protein levels and transactivation potential. All variant hER proteins were synthesized as 66 kDa species as identified by Western blotting with the exception of the proline-containing variant (Pro-ER). The UB-Pro-ER variant was cleaved inefficiently by UCHs in yeast. The UB-Pro-hER [correction of UB-Pro-hEr] variant also exhibited a different DNA band-shift profile compared to those of the other receptor variants and the wild-type. Val-, Thr-, and Lys-ER did not express, as measured by enzyme-immunoassay and Western blotting; nor did they transactivate a beta-galactosidase reporter gene in yeast. However, the Glu-ER was 50% more active in transactivation as compared to the wild-type. The results of the receptor content, DNA binding properties and transactivation analysis in yeast demonstrate that the N-terminal residue plays an important role in the structure and function of hER.

Amino Acid Sequence↗
PubMed1996

Development of circadian rhythmicity of temperature in full-term normal infants.

Twelve full-term infants (7 girls and 5 boys) with normal neurological, behavioral and somatic development were followed at regular intervals during the first 5 months of life to appreciate the development of circadian rectal temperature rhythmicity. Activity and temperature (oral at birth, rectal thereafter) were monitored for a minimum of 60 hours on seven separate occasions: at birth, 3 weeks, 6 weeks, 8 weeks, 10 weeks, 16 weeks and 20 weeks of age. Activity was measured using an actigraph worn on the infant's wrist, and rectal temperature was measured using a rectal probe attached to a portable microprocessor (Vitalog TM). Data points were collected every 2 minutes. No fewer than ten infants were monitored at each session, and no infant missed more than one session. Missing recordings were due to equipment malfunctions, probe expulsions and minor health problems. Six infants out of 12 were successfully monitored at each of the first four sessions, from birth to 8 weeks of age inclusively, and two subjects were successfully monitored at all seven sessions. Periodic regression analysis was performed by least squares curve fit with secondary analysis of variance. Analysis of covariance was performed on repeated measures. There was no evidence of rectal temperature circadian rhythmicity at 3 weeks. Two infants demonstrated a circadian rhythmicity at 6 weeks, and all infants had a circadian rhythmicity at 10 weeks post-natal age. At the time of the first observance of circadian rhythmicity of rectal temperature, the mean delta in temperature from peak to trough was 0.6 +/- 0.3 degrees C. This delta was greater at the 16th week, with a mean value of 1.2 +/- 0.3 degrees C. The trough was seen during the first part of the long nocturnal inactivity period. Circadian rhythmicity of rectal temperature was always observed in the studied subjects before the establishment of a consolidated, long daytime wake period.

Body Temperature Regulation↗
PubMed1996

An audit of 319 deaths across four general practices.

Death is a major outcome measure, and the value of an audit of the preventable factors leading to individual deaths is accepted in secondary care. Although approximately 20 of a typical general practitioner's patients will die every year, audits of deaths in general practice are seldom published. This is probably partly due to the difficulties posed by comparability, partly due to the wide range of causes of such deaths and possible contributory factors, and partly due to confidentiality considerations. We describe an audit of all death occurring in our practices over a 12-month period. Although cigarette smoking was considered to exceed all other contributory causes of death, preventable factors occurred in both primary and secondary care sufficiently often for important conclusions to be drawn. Comparison of causes of death between general practices is possible, and such enquiry can demonstrate important quality issues for both primary and secondary care.

Adolescent↗
PubMed1994

The Sleep Disorders Questionnaire. I: Creation and multivariate structure of SDQ.

The development of the Sleep Disorders Questionnaire (SDQ) from the Sleep Questionnaire and Assessment of Wakefulness (SQAW) of Stanford University is described in detail. The extraction of the best question items from the SQAW and their subsequent rewording in the SDQ to insure greater completion rates are described. Two item test-retest reliability studies are reported on 71 controls and on 130 sleep-disorder patients, which confirmed adequate reliability. To create multivariate scoring scales, SDQ was then given in a multicenter study to 519 persons, 435 of whom were sleep-disorder patients with full polysomnography. Canonical Discriminant Function Analysis was employed, which resulted in four clinical-diagnostic scales: SA for sleep apnea, NAR for narcolepsy, PSY for psychiatric sleep disorder and PLM for periodic limb movement disorder. Each was adjusted for male and female responses and transformed to a percentile using the observed distribution of raw scores. Using Receiver Operating Characteristics analysis, cutoff points were determined for each scale to maximize its sensitivity and specificity. Positive and negative predictive values were also calculated. The SA and NAR scales proved to be the most discriminating.

Adult↗
PubMed1993

Crisis stabilization services for children and adolescents: a brokerage model to reduce admissions to state psychiatric facilities.

There continues to be an increased interest in developing community-based services for children and adolescents as an alternative to inpatient care. However, there has been much more talk than action in creating such alternatives. This paper describes the success of a crisis stabilization program for children and adolescents in a community mental health center which historically over-utilized the State psychiatric facility for youth. The Crisis Stabilization Program consists of three components: (1) a two-person crisis team, (2) a four-person on-call team for after hours crises, and (3) funds which the crisis team utilized to broker for a wider array of community-based services.

Adolescent↗
PubMed1993

Protein domains governing interactions between E2F, the retinoblastoma gene product, and human papillomavirus type 16 E7 protein.

Human papillomaviruses (HPVs) are the etiological agents for genital warts and contribute to the development of cervical cancer in humans. The HPV E7 gene product is expressed in these diseases, and the E7 genes from HPV types 16 and 18 contribute to transformation in mammalian cells. Mutation and deletion analysis of this gene suggests that the transforming activity of the protein product resides in the same domain as that which is directly involved in complex formation with the retinoblastoma gene product (pRB). This domain is one of two conserved regions (designated CRI and CRII) shared by E7 and other viral oncoproteins which bind pRB, including adenovirus E1A protein. Binding of HPV type 16 E7 protein to pRB has previously been shown to affect pRB's ability to bind DNA and to form complexes with other cellular proteins. In the current study, we map the functional interaction between E7 protein and pRB by monitoring the association between a 60-kDa version of the pRB, pRB60, and the cellular transcription factor E2F. We observe that CRII of E7 (amino acids 20 to 29), which completely blocks binding of full-length E7 protein, is necessary but not sufficient to inhibit E2F/pRB60 complex formation. While CRI of E1A (amino acids 37 to 55) appears to be sufficient to compete with E2F for binding to pRB60, the equivalent region of E7 is neither necessary nor sufficient. Only E7 fragments that contained both CRII and at least a portion of the zinc-binding domain (amino acids 60 to 98) inhibited E2F/pRB60 complex formation. These results suggest that pRB60 associates with E7 and E2F through overlapping but distinct domains.

Amino Acid Sequence↗
PubMed1988

Periodic leg movement, sleep fragmentation and central sleep apnoea in two cases: reduction with Clonazepam.

Two subjects presented with periodic leg movement (PLM) syndrome during sleep that was characterized by marked sleep fragmentation and repetitive short central apnoeas. Treatment of PLM using Clonazepam, a benzodiazepine with hypnotic properties, markedly reduced the sleep fragmentation due to PLM and, despite its depressant properties on the central nervous system, controlled the repetitive central apnoeas. These two observations, although rare, give insight into the role of non-ventilatory variables in the development of sleep apnoea. Significant sleep fragmentation should be considered when assessing factors leading to respiratory instability during sleep and/or the pathophysiology of sleep apnoea syndromes.

Adult↗