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Biomedical subjects

M M Martin

Publications and source records attributed to M M Martin.

At least 19 recordsLinked to original sources
PubMed2007

KBG syndrome: report of twins, neurological characteristics, and delineation of diagnostic criteria.

KBG syndrome is a multiple congenital anomaly (MCA) syndrome comprising developmental delay, postnatal short stature, and delayed bone age. Many physical anomalies involving the face, hands, and costovertebral axis have been described in this syndrome. We present twin males with KBG syndrome and a review of 50 published case reports, with particular emphasis on the neurological aspects of KBG syndrome, including seizures, MRI findings, and behavior difficulties. It is argued that diagnostic criteria for KBG syndrome should include neurological involvement, that is, global developmental delay, seizures, and/or mental retardation (MR). The characteristic facial changes and representative hand and costovertebral anomalies are also defined. These diagnostic criteria were obtained from 50 publications and appeared to support the diagnosis in 43 cases. They will be helpful to pediatricians, geneticists, and neurologists in evaluating patients for this condition.

Abnormalities, Multiple↗
PubMed2002

beta-Adrenoceptor density and adenylyl cyclase activity in obese rabbit hearts.

OBJECTIVE: To determine whether decreased cardiac responsiveness to isoproterenol in obesity is associated with alterations in beta-receptors and/or adenylyl cyclase activity. ANIMALS AND DESIGN: After 12 weeks of control or ad libitum high-fat diets, left ventricular tissue from lean and obese female New Zealand white rabbits was assayed for beta-receptor binding density (11 lean, 11 obese) and isoproterenol-stimulated adenylyl cyclase activity (eight lean, 10 obese). MEASUREMENTS: Nonlinear least squares regression analysis was used to determine maximum density of beta-receptors and receptor affinity for (125)I-iodocyanopindolol. Four-parameter logistic regression was used to determine minimum, maximum, slope and EC(50) for isoproterenol-stimulated adenylyl cyclase activity. RESULTS: Obese rabbits had elevated resting blood pressure and heart rate, and higher ventricular weights. However, beta-adrenoceptor density and affinity were not significantly different in lean and obese rabbits. Basal and maximum isoproterenol-stimulated adenylyl cyclase activity did not differ between lean and obese rabbits. In addition, maximal stimulation in response to sodium flouride did not differ between lean and obese. EC(50) for isoproterenol-stimulated adenylyl cyclase activity did not differ between lean and obese rabbits. CONCLUSION: Obesity-related decreases in responsiveness of the isolated heart to isoproterenol are not associated with alterations in beta-receptor density and affinity. In addition, adenylyl cyclase activity appeared unchanged in ventricular preparations from obese rabbits. Decreased responsiveness to isoproterenol in obesity may be due to defects downstream of adenylyl cyclase activation of cyclic AMP.

Adenylyl Cyclases↗
PubMed2001

The transcription factors Sp1 and Sp3 are required for human angiotensin II type 1 receptor gene expression in H295-R cells.

The peptide hormone angiotensin II regulates a variety of physiological responses which are mediated by its interaction with high affinity G protein-coupled receptors localized on the surface of target cells. Our previous studies have demonstrated that a 145 bp sequence within the promoter region was required for basal level expression of the human angiotensin II type 1 receptor (hAT(1)R) gene. In the present study, deletional analysis of the hAT(1)R promoter localized the major regulatory sequence to two overlapping GC boxes harbored within the -105 to -85 bp region relative to the transcription start site in H295-R cells. Electrophoretic mobility shift assays (EMSAs) using a double-stranded (ds) oligonucleotide corresponding to this region and H295-R cell nuclear extract resulted in five specific DNA-protein complexes. EMSAs performed with competitive ds-oligonucleotides which harbored the consensus binding site for Sp1 prevented the formation of the DNA-protein complexes. Supershift EMSAs also demonstrated that Sp1 and Sp3 could bind to the GC boxes present within the -105 to -85 bp region of the hAT(1)R promoter. Transactivation experiments utilizing Drosophila SL2 cells, which lack endogenous Sp family transcription factors, demonstrated that Sp1 and Sp3 activated the hAT(1)R promoter and that maximal activation was only achieved when both GC boxes were present. Taken together, these findings suggest that Sp1 and Sp3 are necessary for the expression of the hAT(1)R gene in H295-R cells.

Acetaldehyde↗
PubMed2001

Identification and characterization of functional angiotensin II type 1 receptors on immortalized human fetal aortic vascular smooth muscle cells.

Studies investigating the mechanisms that govern the expression of the human angiotensin II type 1 receptor (hAT(1)R) gene have progressed slowly due to the lack of human cell lines that express the AT(1)R. Recently, however, an immortalized human fetal aortic vascular smooth muscle cell line (FLTR) was generated using an amphotropic recombinant retroviral construct containing the E6/E7 open reading frames of the human papillomavirus type 16. Radioligand binding studies were undertaken to determine whether angiotensin II (Ang II) receptors were expressed on these cells. FLTR cell membranes were shown to express high-affinity Ang II receptors having a B(max) value of 324+/-43 fmol/mg protein and a K(d) of 0.36+/-0.1 nM. In both membranes and intact cells, Ang II, Ang III and the selective AT(1)R antagonist, Losartan, all had a high affinity for the receptor, suggesting that FLTR cells express the AT(1)R subtype. The expression of the hAT(1)R was validated by Northern and Western blot and RT-PCR experiments. In intact FLTR cells, Ang II (100 nM) evoked an increase in intracellular calcium ([Ca(2+)](i)) and induced hyperplasia. Additionally, our results demonstrated that FLTR cells were readily transfected, and hAT(1)R promoter luciferase constructs exhibited robust promoter activity (i.e. approximately 22-fold increase over pGL3-Basic only). Finally, our results demonstrated that the hAT(1)R gene is differentially regulated in FLTR cells vs. H295-R cells, a human adrenocarcinoma cell line that also abundantly expresses the AT(1)R. Taken together, our results suggest that FLTR cells express functional AT(1)Rs and will provide an excellent model system in which to investigate hAT(1)R gene regulation.

Angiotensins↗
PubMed2001

Antibody, cytokine and cytotoxic T lymphocyte responses in chimpanzees immunized with human papillomavirus virus-like particles.

We evaluated antibody, cytokine (IFN-gamma, IL-5, TNF-alpha), and cytotoxic T lymphocyte (CTL) responses in chimpanzees immunized with monovalent or quadrivalent (HPV-6, -11, -16, -18) L1 virus-like particle (VLP) vaccines administered i.m. on aluminum hydroxyphosphate (alum) at weeks 0, 8 and 24. Maximum serum antibody titers to type-specific, neutralizing, conformational epitopes on HPV-11 or -16 L1 VLPs were detected by radioimmunoassay (RIA) four weeks after the second and third immunizations. HPV-11 and -16 neutralizing antibodies were also detected at similar time points with an Human papillomaviruses (HPV) neutralization assay using pseudovirions. Depending on the VLP type used for immunization, HPV type-specific cytokine responses were most frequently seen four weeks after the second or third immunizations and between weeks 44-52. Transient HPV-16 L1-specific CTL activity was observed only between weeks 16-24 in 3 of 22 (13.6%) chimpanzees immunized with HPV-16 L1 VLPs. These findings provide evidence that immunization with multivalent L1 VLPs on alum can evoke both neutralizing antibodies and Th1 and Th2 cytokine responses to several HPV types; however, induction of CTLs is infrequent.

Animals↗
PubMed2001

Antioxidant defenses in caterpillars: role of the ascorbate-recycling system in the midgut lumen.

This study demonstrates that an ascorbate-recycling system in the midgut lumen can act as an effective antioxidant defense in caterpillars that feed on prooxidant-rich foods. In tannin-sensitive larvae of the forest tent caterpillar, Malacosoma disstria (Lasiocampidae), ingested tannic acid is oxidized in the midgut lumen, generating significant quantities of peroxides, including hydrogen peroxide, which readily diffuses across cell membranes and is a powerful cytotoxin. By contrast, in the tannin-tolerant larvae of the white-marked tussock moth, Orgyia leucostigma (Lymantriidae), tannic acid oxidation and the generation of peroxides are suppressed. The superior defense of O. leucostigma against oxidative stress imposed by the oxidation of ingested polyphenols can be explained by the presence of higher concentrations of ascorbate and glutathione in the midgut lumen. In O. leucostigma at least 50% of the ingested ascorbate present in the anterior midgut is still present in the posterior midgut, whereas in M. disstria, only 10% of the ascorbate is present in the posterior half of the midgut. We propose that the maintenance of higher levels of ascorbate in the midgut lumen of O. leucostigma than in M. disstria is explained by the secretion of glutathione into the midgut lumen by O. leucostigma, thereby forming a complete ascorbate-recycling system. The concentration of glutathione in the midgut lumen of O. leucostigma is 3.5-fold higher than in M. disstria and more than double the concentration in the diet. Our results emphasize the importance of a defensive strategy in herbivorous insects based on the maintenance of conditions in the gut lumen that reduce or eliminate the potential prooxidant behavior of ingested phenols.

Journal Article↗
PubMed2001

Human angiotensin II type 1 receptor isoforms encoded by messenger RNA splice variants are functionally distinct.

Human tissues that express the angiotensin II (Ang II) type 1 receptor (hAT(1)R) can synthesize four distinct alternatively spliced hAT(1)R mRNA transcripts. In this study, we show that the relative abundance of these mRNA transcripts varies widely in human tissues, suggesting that each splice variant is functionally distinct. Here we demonstrate, for the first time, that the hAT(1)R-B mRNA splice variant encodes a novel long hAT(1)R isoform in vivo that has significantly diminished affinity for Ang II (i.e. >3-fold) when compared with the short hAT(1)R isoform (encoded by hAT(1)R-A mRNA splice variant). This reduced agonist affinity caused a significant shift to the right in the dose-response curve for Ang II-induced inositol trisphosphate production and Ca(2+) mobilization of the long hAT(1)R when compared with that of the short hAT(1)R. The functional differences between these isoforms allows Ang II responsiveness to be fine-tuned by regulating the relative abundance of the long and short hAT(1)R isoform expressed in a given human tissue.

Adrenal Cortex Neoplasms↗
PubMed2000

Neutralization of human papillomavirus (HPV) pseudovirions: a novel and efficient approach to detect and characterize HPV neutralizing antibodies.

The development of vaccines against human papillomaviruses (HPVs) has long been hampered by the inability to grow HPVs in tissue culture and the lack of an efficient neutralization assay. To date, less than 10% of more than 100 different HPV types can be grown in athymic and "SCID" mouse xenograft systems or raft culture systems. Recently, the in vitro generation of HPV pseudovirions and their use in neutralization assays were demonstrated. The major shortcomings of the current approaches to HPV neutralization are the lack of HPV virions for most types for the xenograft methods and the time-consuming and inefficient generation of infective pseudovirions for the latter methods, which precludes their use in large-scale HPV clinical trials or epidemiological studies. We describe here a novel and efficient approach to generating pseudovirions in which HPV virus-like particles (VLPs) are coupled to the beta-lactamase gene as a reporter. We show that it is not necessary to encapsidate the reporter gene constructs into the pseudovirions. Using sera from human volunteers immunized with HPV-11 VLPs expressed in yeast, we demonstrate that our novel neutralization assay compares favorably with the athymic mouse neutralization assay. Furthermore, our assay was used to define neutralizing monoclonal antibodies to HPV-6, which were previously unknown.

Animals↗
PubMed2000

Basal level transcriptional regulation of the human angiotensin II type 1 receptor gene.

The peptide hormone angiotensin II regulates a variety of physiological responses which are mediated by its interaction with high affinity G protein-coupled receptors localized on the surface of target cells. To gain insights into the transcriptional regulation of the human angiotensin II type 1 receptor (hAT(1)R) gene, we have isolated 1 kb of the 5'-flanking sequence of this gene. Expression constructs containing various 5'-deletions of the hAT(1)R promoter region, fused upstream to the luciferase reporter gene, were transiently transfected into H295-R, HEC-1B and A549 cells. It was demonstrated that a 145 bp sequence within the promoter region was required for basal level expression of the hAT(1)R gene in all of the three cell lines investigated. Computer analysis indicated the existence of numerous putative transcription factor binding sites in this region. Further detailed deletion data suggested essential transcription factor binding sites between -98 and -79 bp. Electrophoretic mobility shift assays revealed that four protein-DNA complexes were formed within the -98 to -79 bp region of the hAT(1)R gene when incubated with H295-R cell nuclear extract. Site-directed mutagenesis experiments showed that a putative Sp1 binding site was critical for the basal level expression of the hAT(1)R gene.

Base Sequence↗
PubMed2000

Molecular cloning and characterization of the human phosducin-like protein (hPhLP) promoter.

Phosducin-like protein (PhLP) is an inducible Gbetagamma binding protein which is hypothesized to be a ubiquitous G protein regulator. To elucidate the mechanisms regulating the expression of the human PhLP (hPhLP) gene, we have cloned and characterized its 5'-flanking region. Primer extension analysis identified a major transcription initiation site 172 bp upstream of the ATG start codon. Analysis of the 5'-flanking region revealed that, although it lacked a TATA box element, the hPhLP promoter did contain several consensus binding motifs including AP4, CCAAT, CREB, NF-kappaB, SP1 and E2F. Transient transfection analyses using a series of 5'-flanking deletion/luciferase reporter gene constructs identified a 25 bp sequence (-80 to -55 bp) that is necessary for basal level transcription of the hPhLP gene in all the cell lines investigated. Interestingly, dependent upon the cell line, distinct transcription factors bind to this region suggesting that basal level hPhLP gene transcription may be regulated in a tissue-specific manner.

Base Sequence↗
PubMed2000

Lack of effects of nose-only inhalation exposure on testicular toxicity in male rats.

Reductions in testicular mass, sperm motility, and mating frequency have been attributed to the stresses caused by confinement of Sprague-Dawley male rats in nose-only inhalation exposure tubes. Testicular changes, including an increase in testicular atrophy, have been detected at an increased incidence in male rats used in inhalation studies as compared with rats of the same age and strain used in oral toxicity studies. This study was designed to determine whether nose-only exposure of male rats caused testicular toxicity under conditions of cooling of the exposure room and appropriate acclimation to the exposure tubes. In order to acclimate the rats to the nose-only inhalation exposure apparatus, all male rats were placed in the exposure tubes for at least four successively increasing time intervals (15, 30, 45, and 60 min) on 4 separate days, with a rest period of approximately 48 h between the first and second acclimation. Twenty male rats were exposed nose-only to filtered air for approximately 2 h per day for 28 days before cohabitation and continuing throughout a 14-day cohabitation period. To reduce thermal stress, the exposure room temperature was maintained at 64 to 70 degrees F. Twenty control rats were housed in the same room as the exposed rats but were not placed in exposure tubes. End points monitored were body weight, testicular weight, sperm count, sperm motility, and histopathology of the testes, epididymides, prostate, and seminal vesicles. The control rats gained weight more rapidly than the exposed rats. All the rats in both groups mated successfully, and testicular weights, normalized to body weight, were similar for both groups. More importantly, there were no microscopic changes that could be considered an adverse effect on the reproductive tissues in the male rats placed in exposure tubes. Thus, nose-only exposure for up to 2 h per day for a total of 42 days did not cause adverse effects on the reproductive organs, fertility, or reproductive performance of male rats under the conditions of this study.

Animals↗
PubMed1999

Human phosducin-like protein (hPhLP) messenger RNA stability is regulated by cis-acting instability elements present in the 3'-untranslated region.

Phosducin (Pd) and phosducin-like protein (PhLP) have been shown to regulate G-protein signaling by binding G beta gamma subunits. To better define the function and regulation of PhLP, and to begin to investigate its potential role in human pathophysiological states, we have cloned the human PhLP (hPhLP) cDNA. The hPhLP shows 92% identity with the rat PhLP (rPhLP). However, unlike the rPhLP, no evidence of hPhLP isoforms were detected in the human tissues investigated. Additionally, unlike the rPhLP, alternative polyadenylation sites were detected in hPhLP cDNA clones which corresponded with two distinct mRNA transcripts, 1.2 kb and 3.1 kb, respectively. Interestingly, the predominantly expressed long transcript contains multiple AU-rich elements (AREs) in its 3'-untranslated region (3'-UTR) which have been shown to correlate with rapid mRNA turnover and translational control. This study shows that the hPhLP AREs are functional both in vitro and in vivo, with the long transcript exhibiting a much shorter mRNA half-life. We also demonstrate that subcloning of either the full-length 3'-UTR or the ARE-rich region of the long transcript immediately following the stop codon of luciferase reporter gene confers instability to the luciferase mRNA and results in a ninefold reduction of luciferase activity in the cell types investigated. Taken together, these findings suggest that the AREs present in the long hPhLP mRNA may play a critical role in the regulation of hPhLP gene expression.

Amino Acid Sequence↗
PubMed1999

Perceived understanding and self-disclosure in the stepparent-stepchild relationship.

The relationship between self-disclosure and perceived understanding in the stepparent-stepchild relationship was investigated. Stepchildren (N = 165) completed a questionnaire about their communication with their stepparents. Participants reported on their self-disclosure (intentionality, amount, positiveness, depth, and honesty) and their feelings of being understood by their stepparents. The results showed that self-disclosure was positively related to perceived understanding. This was especially true for the relationship between honesty of self-disclosure and perceived understanding. Analyses involving gender of the individuals in the stepchild-stepparent dyad showed several differences. The relationship between self-disclosure and perceived understanding was more significant for stepdaughters than for stepsons.

Adoption↗
PubMed1998

A tacrolimus-related immunosuppressant with biochemical properties distinct from those of tacrolimus.

BACKGROUND: Tacrolimus (FK506) is an immunosuppressive drug 50-100 times more potent than cyclosporine (CsA), the current mainstay of organ transplant rejection therapy. Despite being chemically unrelated, CsA and tacrolimus exert their immunosuppressive effects through the inhibition of calcineurin (CaN), a critical signaling molecule during T-lymphocyte activation. Although numerous clinical studies have proven the therapeutic efficacy of drugs within this class, tacrolimus and CsA also have a strikingly similar profile of unwanted side effects. METHOD: Our objective has been to identify a less toxic immunosuppressant through the modification of ascomycin (FK520). Quantitative in vitro immunosuppression and toxicity assays have demonstrated (see the accompanying article, p. 18) that we achieved our goal with L-732,531 (indolyl-ascomycin; indolyl-ASC), a 32-O-(1-hydroxyethylindol-5-yl) ascomycin derivative with an improved therapeutic index relative to tacrolimus. RESULTS: We report that the attributes of indolyl-ASC may result from its distinctive biochemical properties. In contrast to tacrolimus, indolyl-ASC binds poorly to FK506 binding protein 12 (FKBP12), the major cytosolic receptor for tacrolimus and related compounds. However, the stability of the interaction between the FKBP12-indolyl-ASC complex and CaN is much greater than that of the FKBP12-tacrolimus complex. These distinguishing properties of indolyl-ASC result in the potent inhibition of CaN within T lymphocytes but may lower the accumulation of the drug at sites of toxicity. CONCLUSIONS: Indolyl-ASC may define those properties needed to increase the therapeutic efficacy of a macrolactam immunoregulant for treating both human autoimmune disease and organ transplant rejection.

Base Sequence↗
PubMed1998

Testicular seminoma in a patient with a constitutively activating mutation of the luteinizing hormone/chorionic gonadotropin receptor.

A white man who had been diagnosed, 35 years previously at the age of 27 months, to have precocious puberty, was later determined to have familial male-limited precocious puberty (FMPP), on the basis of his family history, increased serum testosterone, prepubertal concentrations of follicle stimulating hormone and luteinizing hormone, and Leydig cell hyperplasia. Recently, this diagnosis was confirmed by molecular genetic analysis that demonstrated the presence of a heterozygous constitutive activating mutation of the luteinizing hormone/chorionic gonadotropin receptor. This dominant gain-of-function Asp578Gly mutation has been shown constitutively to activate the receptor in the absence of the agonist, leading to enhanced synthesis of cAMP and, in turn, to increased, sustained production of testosterone. In 1994, this patient was found to have a testicular seminoma. He represents the first case of a testicular germ cell tumor described in an FMPP patient, raising the possibility of a potentially harmful effect of prolonged increased concentrations of sex hormones, with onset early in life, upon the cellular components of the testes.

Adult↗
PubMed1998

Method to protect rabbit eyes and reduce potential stress from eye irritation or injury associated with exposure to vapors and particulates in inhalation studies.

Many pharmaceuticals are administered to children and adults as sprays provided in nebulizers or metered-dose inhalers. Stress associated with possible eye irritation and injury attributable to exposure to vapors and particulates during the required safety testing procedures of such medicines is a potential confounding factor in these studies. Reducing stress and the potential changes associated with stress is particularly important in safety studies involving pregnant animals because maternal stress has been known to be associated with adverse outcomes for the offspring. Training and acclimating rabbits to wearing modified pediatric swim goggles during exposure to vapors and aerosol particles provides a simple, inexpensive method to reduce or eliminate potential stress from eye irritation.

Administration, Inhalation↗