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Biomedical subjects

K A Miller

Publications and source records attributed to K A Miller.

At least 37 records · Page 2Linked to original sources
PubMed1999

Molecular pharmacology of Agouti protein in vitro and in vivo.

Agouti protein and Agouti-related protein (Agrp) are paracrine signaling molecules that act by antagonizing the effects of melanocortins, and several alternatives have been proposed to explain their mechanisms of action. Genetic crosses in a sensitized background uncover a phenotypic difference between overexpression of Agouti and loss of Mc1r function, demonstrate that a functional Mc1r is required for the pigmentary effects of Agouti, and suggest that Agouti protein can act as an agonist of the Mc1r in a way that differs from alpha-MSH stimulation. In vitro, Agouti protein inhibits melanocortin action by two mechanisms: competitive antagonism that depends on the carboxyterminus of the protein, and downregulation of melanocortin receptor signaling that depends on the aminoterminus. Our findings provide evidence of a novel signaling mechanism whereby alpha-MSH and Agouti protein function as independent ligands that inhibit each other's binding and transduce opposite signals through a single receptor.

Agouti Signaling Protein↗
PubMed1999

The mouse mahogany locus encodes a transmembrane form of human attractin.

Agouti protein and agouti-related protein are homologous paracrine signalling molecules that normally regulate hair colour and body weight, respectively, by antagonizing signalling through melanocortin receptors. Expression of Agouti is normally limited to the skin, but rare alleles from which Agouti is expressed ubiquitously, such as lethal yellow, have pleiotropic effects that include a yellow coat, obesity, increased linear growth, and immune defects. The mahogany (mg) mutation suppresses the effects of lethal yellow on pigmentation and body weight, and results of our previous genetic studies place mg downstream of transcription of Agouti but upstream of melanocortin receptors. Here we use positional cloning to identify a candidate gene for mahogany, Mgca. The predicted protein encoded by Mgca is a 1,428-amino-acid, single-transmembrane-domain protein that is expressed in many tissues, including pigment cells and the hypothalamus. The extracellular domain of the Mgca protein is the orthologue of human attractin, a circulating molecule produced by activated T cells that has been implicated in immune-cell interactions. These observations provide new insight into the regulation of energy metabolism and indicate a molecular basis for crosstalk between melanocortin-receptor signalling and immune function.

Agouti Signaling Protein↗
PubMed1998

The performance of subcutaneously injected Fertinex when used as the sole gonadotropin for in vitro fertilization stimulation.

OBJECTIVE: To assess the performance of Fertinex (urofollitropin; Serono Laboratories, Norwell, MA) in stimulating the development of multiple follicles and initiating subsequent pregnancy in patients undergoing controlled ovarian hyperstimulation (COH) for IVF. DESIGN: Prospective observational study. SETTING: Private assisted reproductive technology (ART) center. PATIENT(S): Ninety-three women who underwent an IVF cycle of COH in which Fertinex was used as the sole gonadotropin. INTERVENTION(S): The COH protocol included Fertinex with leuprolide acetate down-regulation in the late luteal phase or the early follicular phase. Embryo transfer was performed after 3 days of culture. MAIN OUTCOME MEASURE(S): Stimulation parameters, embryologic data, and pregnancy rates (PRs). RESULT(S): Ninety-three patients underwent 97 cycles of COH, with a cancellation rate of 13.4%. The clinical PR was 42% per initiation, 49% per retrieval, and 51% per transfer. Shorter stimulation periods, lower estradiol levels either per follicle punctured or per oocyte retrieved, and slower embryo development were observed. Patients responded to Fertinex in three distinct stimulation patterns: escalating response with a peak estradiol level of < or =3,000 pg/mL, escalating response with a peak estradiol level of >3,000 pg/mL, or escalating response characterized by a drop in the estradiol level or a plateau before hCG administration. All three responses had similar PRs. CONCLUSION(S): Fertinex can be used successfully as the sole gonadotropin for COH in ART without compromising high PRs. Traditional estradiol response curves or cancellation criteria may not apply when Fertinex is used as the sole gonadotropin for COH in ART.

Adult↗
PubMed1998

Compatibility and stability of fentanyl admixtures in polypropylene syringes.

OBJECTIVE: To determine the physicochemical stability of fentanyl in combination with midazolam and either hyoscine butylbromide or metoclopramide, and stored in 30 ml polypropylene syringes. METHODS: Solutions containing approximately 40 microg/ ml of fentanyl in combination with midazolam (approximately 600 microg/ml) and either metoclopramide (approximately 700 microg/l) or hyoscine (approximately 850 microg/ml) were prepared from commercial ampoules of the drugs. The solutions were stored, in triplicate, in the dark at 32 degrees C (to simulate usage conditions) for 10 days, and the concentration of each constituent drug was periodically determined using a stability-indicating high-performance liquid chromatography assay. RESULTS: The combinations were relatively stable, with all drugs maintaining over 90% of their initial chemical potency for at least 1 week. There were no evident changes in either the physical appearance or pH values of the solutions over the course of the study. CONCLUSIONS: On the basis of physicochemical stability, polypropylene syringes containing fentanyl with midazolam and either hyoscine butylbromide or metoclopramide can be safely prepared and stored at or below 32 degrees C for periods of up to 1 week prior to use by palliative care patients receiving the drugs via a portable subcutaneous infusion device.

Adjuvants, Anesthesia↗
PubMed1997

Hemangioma of the umbilical cord mimicking an omphalocele.

A hemangioma of the umbilical cord was misdiagnosed as an omphalocele both antenatally and immediately after birth. The girl was full term and had no other anomalies. Complete resection, including an intraabdominal component, was performed on the first day of life. This rare anomaly and its possible pitfalls are discussed, and the literature is reviewed.

Adult↗
PubMed1997

Serotonin inhibition of 1-methylxanthine metabolism parallels its vasoconstrictor activity and inhibition of oxygen uptake in perfused rat hindlimb.

The effect of serotonin (5-HT) on the metabolism of infused 1-methylxanthine (1-MX), a putative substrate of capillary endothelial xanthine oxidase (XO), and on the distribution of infused fluorescent microspheres (15 microns) by the artificially constant-flow perfused rat hindlimb preparation was investigated. 1-MX (5-100 microM) caused a slight inhibition of oxygen uptake (Vo2) but was not vasoactive, either alone or with 5-HT. 1-MX was converted to 1-methylurate (1-MU) and this conversion was inhibited by allopurinol and xanthine. 5-HT (0.35 microM), which caused vasoconstriction and decreased Vo2, also inhibited the conversion of 1-MX, indicated by a lowered venous perfusate steady-state 1-MU:1-MX ratio from 1.14 +/- 0.02 to 0.71 +/- 0.02 (P < 0.001), which is equivalent to the rate of conversion decreasing from 0.83 +/- 0.03 to 0.63 +/- 0.05 nmol min-1 g-1. This change closely followed the time course for changes in Vo2 and perfusion pressure and all three changes reversed in parallel when 5-HT was removed. Recoveries of 1-MU plus 1-MX at all times were high (100 +/- 5%). 5-HT did not act to inhibit XO. When compared with vehicle alone, 5-HT had either no effect (plantairs, gastrocnemius white, tibialis, extensor digitorum longus, vastus and thigh), or increased microsphere content (soleus and gastrocnemius red, P < 0.05) of muscles with only bone showing a significant decrease (P < 0.05). Since 5-HT did not inhibit XO or alter the net flow to individual muscles in this constant-flow model, the inhibition of conversion of 1-MX to 1-MU is concluded to be the result of a 5-HT-mediated decrease in the access of 1-MX to capillary XO within individual muscles. Possibilities include the redirection of flow to capillaries either in muscle or in connective tissue closely associated with muscle, where resistance is low and effective surface area is less. 1-MX has potential as a marker for muscle nutritive flow.

Animals↗
PubMed1997

Genetic studies of the mouse mutations mahogany and mahoganoid.

The mouse mutations mahogany (mg) and mahoganoid (md) are negative modifiers of the Agouti coat color gene, which encodes a paracrine signaling molecule that induces a swithc in melanin synthesis from eumelanin to pheomelanin. Animals mutant for md or mg synthesize very little or no pheomelanin depending on Agouti gene background. The Agouti protein is normally expressed in the skin and acts as an antagonist of the melanocyte receptor for alpha-MSH (Mc1r); however, ectopic expression of Agouti causes obesity, possibly by antagonizing melanocortin receptors expressed in the brain. To investigate where md and mg lie in a genetic pathway with regard to Agouti and Mc1r signaling, we determined the effects of these mutations in animals that carried either a loss-of-function Mc1r mutation (recessive yellow, Mc1re) or a gain-of-function Agouti mutation (lethal yellow, Ay). We found that the Mc1re mutation suppressed the effects of md and mg, but that md and mg suppressed the effects of Ay on both coat color and obesity. Plasma levels of alpha-MSH and of ACTH were unaffected by md or mg. These results suggest that md and mg interfere directly with Agouti signaling, possibly at the level of protein production or receptor regulation.

Adrenocorticotropic Hormone↗
PubMed1997

Joining forces to improve point-of-care testing.

Point-of-care (POC) testing takes a "laboratory" test directly to the patient's bedside. Although bedside testing is not new, the compliance standards are relatively new. Regulations ensure that all personnel are trained to properly perform the test. The central laboratory and nursing of this hospital merge the best skills of both units to create a successful POC testing program.

Cooperative Behavior↗
PubMed1996

Pituitary response to early follicular-phase minidose gonadotropin releasing hormone agonist (GnRHa) therapy: evidence for a second flare.

PURPOSE: Our purpose was to determine the pituitary response to minidose follicular-phase GnRHa and see if a second flare can be achieved. METHOD: A prospective, consecutive series of 12 couples with tubal-factor infertility underwent 14 cycles of minidose GnRHa. Women were given a 25- or 50-migrograms dose of leuprolide acetate (LA) on cycle days 2 and 5. On cycle days 3 and 4 no LA was given but 2 ampoules of pure follicle stimulating hormone (FSH) was administered. Beginning day 6, a combination of LA and FSH was administered. RESULTS: Following a dose of only 25 micrograms of LA on cycle day 2, mean FSH, LH, and E2 levels were significantly elevated over the baseline levels. Following no LA on cycle day 3 or 4, a repeat dose of 25 micrograms LA caused a second flare of LH and E2 on cycle day 6. Of the 14 cycles, 6 were canceled because of poor stimulation. Two of the eight patients who underwent retrieval delivered a live birth. CONCLUSIONS: This is the first study to examine both the pituitary response and the recovery time from minidose follicular-phase GnRHa. An extremely small dose of LA is needed to cause a pituitary flare of gonadotropins. Following a flare from 25 micrograms of LA on cycle day 2, the pituitary is able to recover and respond with a repeat flare on cycle day 5.

Adult↗
PubMed1996

Purine and pyrimidine nucleotide metabolism of vascular smooth muscle cells in culture.

1. Cultures of vascular smooth muscle cells accumulate extracellular breakdown products of purine and pyrimidine nucleotides that, over 9 hr, represent 60 +/- 7 and 78 +/- 17%, respectively, of the intracellular nucleotide content. 2. The accumulation is stimulated during contracture with 20 mM KCl or 70 microM carbachol, consistent with the notion that both pyrimidine and purine nucleotides are involved in the energetics of smooth muscle contracture. 3. Because the intracellular levels of pyrimidine and purine nucleotides remain constant, it appears likely that rates of synthesis match the rates of release. 4. Ectonucleotidases are present that can degrade ATP, UTP, and CTP. High-energy nucleotides may be the primary products released.

Animals↗
PubMed1996

Evaluation of serum CA 125 concentrations as predictors of pregnancy with human in vitro fertilization.

OBJECTIVE: To determine if CA 125, a product of human endometrium, may be an indicator of early endometrial function. To test this hypothesis we examined CA 125 concentrations before oocyte retrieval in IVF cycles. DESIGN: Retrospective data analysis of 111 consecutive IVF cycles. SETTING: Tertiary care academic medical center. PATIENTS: All women who received luteal leuprolide acetate (LA) suppression followed by hMG for IVF and had sera available for analyses were entered into the study. MAIN OUTCOME MEASURE: Serum CA 125 was measured in the previous luteal cycle, day 7 of hMG, day before, and day of hCG administration. Twelve other variables were analyzed. RESULTS: Fifty-six cycles (47 women) qualified for evaluation and included 25 pregnant cycles (45%) and 31 nonpregnant cycles. Higher serum CA 125 concentrations were associated with pregnancy in both endometriosis and nonendometriosis subgroups. CA 125 values on the day of hCG administration were the best predictors of pregnancy, with levels > or = 16 U/mL having a sensitivity of 72%, specificity of 97%, and a positive predictive value of 95% for pregnancy. The other variables were not predictive of pregnancy. CONCLUSIONS: With a LA and hMG stimulation protocol, increased CA 125 concentrations before retrieval are associated with very high pregnancy rates. The source(s) of the serum CA 125, although as yet undertermined, may be of endometrial origin. The study supports further evaluation of CA 125 concentrations in IVF as a preretrieval predictor of pregnancy.

CA-125 Antigen↗
PubMed1996

Serum from women with polycystic ovary syndrome inhibits fertilization and embryonic development in the murine in vitro fertilization model.

OBJECTIVE: To study the effects of serum collected from women with polycystic ovary syndrome (PCOS) on the fertilization and early embryonic development of the murine oocyte. DESIGN: Sera from women with anovulation were used as a supplement in a murine IVF model. SETTING: Tertiary care academic medical center. PATIENTS: Four fertile, four hypothalamic amenorrheic, seven PCOS (three with elevated LH and four with elevated T), and three anovulatory women with normal hormone levels. RESULTS: When compared with serum from fertile women, serum from women with PCOS reduced fertilization rates (60% versus 42%) and subsequent early embryonic development rates (87% versus 31%). Serum from women with PCOS and elevated T levels had the lowest fertilization rates (22%). Polycystic ovary syndrome serum with elevated T or LH levels significantly decreased early embryonic development rates in comparison to fertile women (22%, 41% versus 87%). CONCLUSIONS: Serum from women with PCOS inhibited fertilization and blastocyst development. Because both T and LH caused inhibited blastocyst development, these data have implications regarding low pregnancy rates and live birth rates during ovulation induction in women with anovulation. These data also raise questions regarding the use of serum during IVF.

Amenorrhea↗
PubMed1995

Interpretation of abnormal lumbosacral spine radiographs. A test comparing students, clinicians, radiology residents, and radiologists in medicine and chiropractic.

STUDY DESIGN: Controlled comparison of radiographic interpretive performance based on training and experience. OBJECTIVES: This study compared each of these groups in medicine and chiropractic by testing abilities to interpret abnormal plain film radiographs of the lumbosacral spine and pelvis. SUMMARY OF BACKGROUND DATA: Low back pain is a common and costly problem that is evaluated and treated primarily by medical physicians, orthopedists, and chiropractors. Although radiology is used extensively in patients with low back pain, the radiographic interpretations of students, clinicians, radiology residents, and radiologists have never been compared. METHODS: Four hundred ninety-six eligible volunteers from nine target groups completed a test of radiographic interpretation consisting of nineteen cases with clinically important radiographic findings. The nine groups included 22 medical students, 183 chiropractic students, 27 medical radiology residents, 13 chiropractic radiology residents, 66 medical clinicians (including 12 general practice physicians, 25 orthopedic surgeons, 21 orthopedic residents, and 8 rheumatologists), 46 chiropractic clinicians, 48 general medical radiologists, 55 chiropractic radiologists, and 36 skeletal radiologists and fellows. RESULTS: The test established a high level of internal consistency reliability (0.880) and revealed that, in the interpretation of abnormal plain film radiographs of the lumbosacral spine and pelvis, significant differences were found among professional groups (P < 0.0001). Post hoc tests (P < 0.05) revealed that skeletal radiologists achieved significantly higher test results than did all other medical groups; that the test results of general medical radiologists and medical radiology residents was significantly higher than those of medical clinicians; that test results of medical students was significantly poorer than that of all other medical groups; that the performance of chiropractic radiologists and chiropractic radiology residents was significantly higher than that of chiropractic clinicians and chiropractic students; that no significant differences was revealed in the mean values of performance of chiropractic clinicians and chiropractic students; that the test results of chiropractic radiologists, chiropractic radiology residents, and chiropractic students was significantly higher than that of the corresponding medical categories (general medical radiologists, medical radiology residents, and medical students, respectively); that no significant difference in test results was identified between chiropractic radiologists and skeletal radiologists or between chiropractic and medical clinicians; and that the length of time in practice for clinicians and radiologists was not a significant factor in the test results. CONCLUSIONS: These data demonstrate a substantial increase in test results of all radiologists and radiology residents when compared to students and clinicians in both medicine and chiropractic related to the interpretation of abnormal radiographs of the lumbosacral spine and pelvis. Furthermore, the study reinforces the need for radiologic specialists to reduce missed diagnoses, misdiagnoses, and medicolegal complications.

Chiropractic↗
PubMed1995

The effect of serum from infertile women with endometriosis on fertilization and early embryonic development in a murine in vitro fertilization model.

OBJECTIVE: To evaluate the effect of serum from infertile women with endometriosis on fertilization and embryonic development in a murine IVF model. DESIGN: Pretreatment and post-treatment comparison of murine oocyte fertilization and early embryonic development with the addition of serum supplements from infertile women with endometriosis. SETTING: Tertiary care academic medical center. PATIENTS: Sera from 10 fertile women without endometriosis and 28 infertile women with endometriosis both before and after laser laparoscopy. RESULTS: When compared with serum from fertile women, serum from infertile women with endometriosis inhibited fertilization rates (51% versus 81%) and subsequent embryonic development rates (46% versus 79%). The inhibitory effect was greater as the stage of endometriosis increased. Treatment of endometriosis by laser laparoscopy improved both fertilization (51% versus 56%) and early embryonic development rates (46% versus 58%). CONCLUSIONS: Serum from infertile women with endometriosis inhibits both fertilization and early embryonic development in the murine IVF model. Inhibition of fertilization and early embryonic development rates increases as the stage of endometriosis increases. Improved fertilization and early embryonic development rates are observed after treatment of endometriosis by laser laparoscopy.

Adolescent↗
PubMed1995

Clinical evaluation of CA-125 concentrations as a prognostic factor for pregnancy in infertile women with surgically treated endometriosis.

OBJECTIVE: To extend and confirm earlier observations that serial CA-125 determinations appear to have prognostic value in some infertile women with surgically treated endometriosis using a new automated enzyme immunoassay. DESIGN: A prospective consecutive case series. SETTING: A university-based tertiary practice. PATIENTS: Of 342 women having a laparoscopy for infertility, 123 (36%) had endometriosis. Fifty-six of 123 (45%) infertile women with endometriosis had preoperative CA-125 values > or = 16 U/mL and were followed for 12 months with serial CA-125 determinations. MAIN OUTCOME MEASURE: Proportion of women achieving a pregnancy within 12 months from surgery. RESULTS: Mean preoperative CA-125 concentrations were not statistically different for women conceiving, but mean postoperative CA-125 values were significantly lower for women achieving a pregnancy. Univariate analyses indicated that preoperative CA-125 values between 16-25 U/mL and postoperative CA-125 values < 16 U/mL were associated with significantly higher pregnancy rates. Multivariate analyses of 10 covariables indicated only postoperative CA-125 concentrations to be associated with pregnancy even after controlling for all covariables. CONCLUSION: Using a newly developed assay for CA-125, the study confirms and extends earlier observation that CA-125 concentrations have prognostic value for pregnancy in infertile women with surgically treated endometriosis. The findings provide additional support for the clinical use of CA-125 concentrations in selected women with endometriosis.

Adult↗
PubMed1994

Differences in dorsal and ventral pigmentation result from regional expression of the mouse agouti gene.

The agouti coat color gene encodes a paracrine signaling molecule that controls the production of yellow and black pigment by melanocytes within hair follicles. Some agouti alleles affect the dorsum and ventrum independently, which has provided the basis for speculation that agouti gene action in different regions of the body is controlled by distinct genetic loci that are closely linked. Using a combination of cDNA cloning and RNA expression studies, we find that alternative isoforms of agouti mRNA contain different noncoding first exons located 100 kb apart, whose patterns of expression indicate independent control by regulatory elements that are either ventral specific or hair cycle specific. These results demonstrate that the apparent genetic complexity of the agouti locus is explained by the existence of multiple regulatory elements exerting control over a single coding sequence and provide a conceptual basis for understanding differences in dorsal and ventral hair coloration in many mammalian species. The ventral-specific agouti isoform represents an example of a transcript whose expression is restricted to ventral skin and provide an approach to investigate the mechanisms by which dorsal-ventral differences in gene expression are established and maintained.

Age Factors↗