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Biomedical subjects

M R Wallace

Publications and source records attributed to M R Wallace.

At least 19 recordsLinked to original sources
PubMed2006

Nf1 haploinsufficiency augments angiogenesis.

Mutations in the NF1 tumor-suppressor gene underlie neurofibromatosis type 1 (NF1), in which patients are predisposed to certain tumors such as neurofibromas and may associate with vascular disorder. Plexiform neurofibromas are slow growing benign tumors that are highly vascular and can progress to malignancy. The development of neurofibromas requires loss of both Nf1 alleles in Schwann cells destined to become neoplastic and may be exacerbated by Nf1 heterozygosity in other non-neoplastic cells. This study tested the hypothesis that Nf1 heterozygosity exaggerates angiogenesis. We found that Nf1 heterozygous mice showed increased neovascularization in both the retina and cornea in response to hypoxia and bFGF, respectively, compared to their wild-type littermates. The increase in corneal neovascularization was associated with heightened endothelial cell proliferation and migration, and increased infiltration of inflammatory cells. In addition, Nf1 heterozygous endothelial cell cultures showed an exaggerated proliferative response to angiogenic factors, particularly to bFGF. These findings support the conclusion that Nf1 heterozygosity in endothelial cells and perhaps inflammatory cells augments angiogenesis, which may promote neurofibroma formation in NF1.

Animals↗
PubMed2005

Association between beta-adrenergic receptor polymorphisms and their G-protein-coupled receptors with body mass index and obesity in women: a report from the NHLBI-sponsored WISE study.

OBJECTIVES: The beta-adrenergic receptor (betaAR) genes are candidate genes for obesity because of their roles in energy homeostasis and promotion of lipolysis in human adipose tissue. Objective is to determine the association between obesity and polymorphisms in genes of the beta(1)AR (ADRB1), beta(2)AR (ADRB2), beta(3)AR (ADRB3), Gs protein alpha (GNAS1), to which all three beta-receptors couple and the G protein beta3 subunit (GNB3), to which beta(3)ARs couple. DESIGN: A case-control genetic association study. SUBJECTS: A total of 643 black or white women enrolled in Women's Ischemia Syndrome Evaluation (WISE) study. MEASUREMENTS: Genotypes were determined by PCR with single primer extension. Associations between genotype and body mass index (BMI), waist-to-hip ratio (WHR), waist circumference, and obesity were made. RESULTS: Polymorphisms in the three betaAR genes, GNAS1, and GNB3 were not associated with BMI, WHR, waist circumference, or obesity. Linear and logistic regression analyses found no contribution of either genotype or haplotype with anthropometric measurements or obesity. CONCLUSIONS: Our study suggests that among American women with suspected coronary heart disease, polymorphisms in the betaARs and their G-protein-coupled receptors do not contribute to increased BMI, WHR, waist circumference, or obesity. Given that 50% of all women die from coronary heart disease, and a higher percentage have heart disease during their lifetime, our results are likely generalizable to many American women.

Adipose Tissue↗
PubMed2005

Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans.

BACKGROUND: A recent genetic study in mice and humans revealed the modulatory effect of MC1R (melanocortin-1 receptor) gene variants on kappa-opioid receptor mediated analgesia. It is unclear whether this gene affects basal pain sensitivity or the efficacy of analgesics acting at the more clinically relevant mu-opioid receptor. OBJECTIVE: To characterise sensitivity to pain and mu-opioid analgesia in mice and humans with non-functional melanocortin-1 receptors. METHODS: Comparisons of spontaneous mutant C57BL/6-Mc1r(e/e) mice to C57BL/6 wildtype mice, followed by a gene dosage study of pain and morphine-6-glucuronide (M6G) analgesia in humans with MC1R variants. RESULTS: C57BL/6-Mc1r(e/e) mutant mice and human redheads--both with non-functional MC1Rs--display reduced sensitivity to noxious stimuli and increased analgesic responsiveness to the mu-opioid selective morphine metabolite, M6G. In both species the differential analgesia is likely due to pharmacodynamic factors, as plasma levels of M6G are similar across genotype. CONCLUSIONS: Genotype at MC1R similarly affects pain sensitivity and M6G analgesia in mice and humans. These findings confirm the utility of cross species translational strategies in pharmacogenetics.

Adolescent↗
PubMed2005

Genetic linkage of a novel autosomal dominant restrictive cardiomyopathy locus.

BACKGROUND: In recent years, non-syndromic idiopathic cardiomyopathies have increasingly been characterised as autosomal dominant conditions caused by single gene mutations. Loci have been identified for hypertrophic and dilated cardiomyopathy, and in some cases the same loci are associated with restrictive cardiomyopathy (RCM). In a kindred with RCM that we previously reported, we ruled out the known cardiomyopathy loci and other candidate genes by linkage analysis and mutation screening. METHODS AND RESULTS: Here we report a genome-wide analysis in this family that has resulted in linkage to a region on chromosome 10. CONCLUSIONS: There are no genes in the interval that are known to cause idiopathic cardiomyopathy, and thus this linkage represents localisation of a new RCM locus.

Cardiomyopathy, Restrictive↗
PubMed2004

Blood lymphocyte chimerism associated with IVF and monochorionic dizygous twinning: case report.

We report on dizygotic (DZ) twins, conceived by IVF and ICSI with assisted hatching, who each had a mixture of 46,XX and 46,XY cells in blood lymphocytes. The female twin had mild genitalia abnormalities but further study revealed anatomically normal reproductive anatomy. Chromosome and fluorescence in situ hybridization studies of buccal, skin and ovarian tissue were normal, as were buccal tissue DNA studies. Fetal ultrasound and fetal membrane pathology were consistent with a monochorionic, diamniotic placenta (MCDAP). These twins thus have blood chimerism but are not chimeric in the other tissues studied. The mechanism for the chimerism could be due to either placental vascular anastamoses (after the development of the haematoblast stem cells) or due to an admixture of trophoblast cells during early blastocyst development. Such trophoblast cell admixtures would be restricted to the extraembryonic tissues so that general physical development in the fetus is normal and without somatic cell chimerism. This case in combination with others previously reported suggests that in IVF conceptions, the prevalence of blood chimerism associated with twinning, and the occurrence of DZ twinning associated with MCDAP, may be higher than previously thought.

Adult↗
PubMed2002

Predictors of HIV-specific lymphocyte proliferative immune responses induced by therapeutic vaccination.

We treated a cohort of 38 HIV-infected individuals with a therapeutic vaccine (REMUNE, HIV-1 Immunogen) in an open label study. We then determined whether baseline parameters, such as CD4 cell count, viral load and IgG levels, were predictive of the magnitude of the HIV-specific lymphocyte proliferative responses (LPRs). We demonstrate herein that there is a significant enhancement from baseline for both HIV and p24 antigen-stimulated LPRs after immunization. Using a responder definition of a stimulation index of >5 on at least two post-immunization time-points, 29/38 (76%) responded to HIV-1 antigen while 27/38 (71%) responded to native p24 antigen. Viral load and total IgG were negatively correlated, while CD4 cell counts were positively associated with the magnitude of the HIV antigen LPR. In a multivariable analysis, baseline CD4 was the best predictor of HIV antigen LPR post-immunization.

AIDS Vaccines↗
PubMed2001

Supravalvular aortic stenosis: genetic and molecular dissection of a complex mutation in the elastin gene.

We have identified two elastin gene (ELN) mutations located in cis in two related families with supravalvular aortic stenosis (SVAS). These mutations included an in-frame duplication in exon 18 (1034-1057dup) and a single base substitution in exon 26 (1829G-->A) predicted to result in the amino acid substitution R610Q. Haplotype analysis in one of the families identified an individual with a recombination between exon 18 and 26 of the elastin gene. This individual was unaffected and carried the exon 18 insertion mutation but not 1829G-->A. Skin fibroblasts were established from this recombinant normal individual and from an affected individual carrying both of the mutations. Reverse transcription/polymerase chain reaction (RT-PCR) analysis indicated that the expression of the mutant allele was reduced to 12%-27% of the normal allele in the affected but not in the unaffected individual. RNA-blot hybridization and immunoprecipitation experiments revealed reduced steady-state elastin mRNA levels and tropoelastin synthesis in the affected individual. RT-PCR analysis of the mRNA rescued by cycloheximide treatment indicated that mutation 1829G-->A created a cryptic donor splice site within exon 26, resulting in the deletion of four nucleotides at the 3'-end of exon 26 and a frameshift in the mRNA. This frameshift mutation generated a premature termination codon in the domain encoded by exon 28, clearly resulting in nonsense-mediated decay (NMD) of this frameshift RNA product. Despite considerable variability in the molecular nature of mutations responsible for SVAS, the unifying mechanism appears to be the generation of null alleles by NMD leading to elastin haploinsufficiency.

Alleles↗
PubMed2001

The utility of serologic testing for varicella in an adolescent population.

The purpose of this study was to determine what proportion of adolescents without a history of varicella are seropositive, and if serologic testing of this adolescent subpopulation is cost-effective. We identified 122 patients with 'no' or 'unknown' histories of chicken pox from our adolescent clinic. Of these, 58 (48%) were found to be Varicella Zoster Virus (VZV) seropositive. Cost to the government for batched serologic testing of all unknowns was $682.65, while each adolescent vaccinated cost $59.60. Serologic testing prior to routine immunization of adolescents with unclear varicella histories saved $2774.15 (38% of routine immunization costs). In this population, serologic testing is more cost effective than routinely immunizing all unknowns.

Adolescent↗
PubMed2001

Randomized, placebo-controlled clinical trial of oral azithromycin prophylaxis against respiratory infections in a high-risk, young adult population.

Military Special Forces trainees undergo intense psychological and physical stressors that often lead to respiratory infection. During 1998-2000, 477 Navy Special Forces trainees were enrolled in a double-blind trial of oral azithromycin (1 g given weekly) plus a placebo injection, compared with benzathine penicillin G (1.2 million U) plus azithromycin placebo tablets. Among the 464 subjects with complete data, 44 developed acute respiratory infection (20 with pneumonia) during the 2 weeks of most intense training; of these subjects, 12 (27.3%) had evidence of Chlamydia pneumoniae infection and 7 (15.9%) had evidence of Mycoplasma pneumoniae infection. Trainees who received azithromycin were less likely than were trainees who received benzathine penicillin G to develop acute respiratory infection (risk ratio, 0.50; 95% confidence interval [CI], 0.28-0.92) and less likely at the end of training to report episodes of breathing difficulty (odds ratio [OR], 0.59; 95% CI, 0.34-1.01) or sore throat (OR, 0.66; 95% CI, 0.41-1.05). Compared with benzathine penicillin G prophylaxis, weekly oral azithromycin was superior in preventing respiratory infection in this population at transient high risk.

Adult↗
PubMed2001

Tumorigenic properties of neurofibromin-deficient neurofibroma Schwann cells.

Dermal and plexiform neurofibromas are peripheral nerve sheath tumors that arise frequently in neurofibromatosis type 1. The goal of the present study was to examine the tumorigenic properties of neurofibromin-deficient human Schwann cells (SCs) that were found to represent a subset of SCs present in approximately half of the total neurofibromas examined. Highly enriched SC cultures were established from 10 dermal and eight plexiform neurofibromas by selective subculture using glial growth factor-2 and laminin. These cultures had low tumorigenic potential in classical in vitro assays yet several unique preneoplastic properties were frequently observed, including delayed senescence, a lack of density-limited growth, and a strong propensity to spontaneously form proliferative cell aggregates rich in extracellular matrix. Western blot analysis failed to detect full-length neurofibromin in any of the neurofibroma SC cultures, indicating that neurofibromin-deficient SCs had a substantial growth advantage. Immunohistochemical staining of the originating tumors showed the majority were comprised principally of neurofibromin-negative SCs, whereas the remainder contained both neurofibromin-negative and neurofibromin-positive SCs. Lastly, engraftment of neurofibromin-deficient SC cultures into the peripheral nerves of scid mice consistently produced persistent neurofibroma-like tumors with diffuse and often extensive intraneural growth. These findings indicate that neurofibromin-deficient SCs are involved in neurofibroma formation and, by selective subculture, provide a resource for the development of an in vivo model to further examine the role of these mutant SCs in neurofibroma histogenesis.

Adolescent↗
PubMed2001

The role of antibiotics in the treatment of infectious diarrhea.

Infectious diarrhea is a significant cause of morbidity and mortality and a common complaint in clinical practice. Routine empirical use of antibiotics for infectious diarrhea should be avoided because of the self-limited nature of most cases, the cost of antibiotics, and the potential to worsen the already significant problem of antibiotic resistance of enteric pathogens. For patients with severe invasive or prolonged diarrhea or who are at high risk of complications, such as the elderly, diabetics, cirrhotics, and immunocompromised patients, empirical treatment with a quinolone antibiotic for 3 to 5 days can be considered. Antibiotic treatment can be highly effective for Shigella, ETEC, and V. cholerae infections, and metronidazole is indicated for C. difficile colitis. The impact of antibiotics for other specific pathogens is modest, and antibiotic therapy should be reserved for the same group of patients who would be considered for empirical treatment. The most significant problem in the antibiotic treatment of infectious diarrhea is the progressive increase in resistance among enteric pathogens; only the prudent use of antimicrobials in all areas of daily practice can limit or delay the impact of this serious problem.

Aged↗
PubMed2001

Clinical and molecular studies of a large family with desmin-associated restrictive cardiomyopathy.

Patients with restrictive cardiomyopathy (RC) have impaired diastolic function, but intact systolic function until later stages of the disease, ultimately leading to heart failure. Primary RC is often sporadic, but also may be inherited in an autosomal dominant fashion, particularly the idiopathic forms. Recently there has been great interest in inherited cardiomyopathy associated with myocyte desmin deposition ('desminopathies'). In some such families, desmin or alpha-B crystallin gene mutation is the underlying cause, and the desmin accumulation affects skeletal muscle as well, usually causing skeletal myopathy. We describe a large family with apparent autosomal dominant inheritance of desmin-associated RC spanning four generations, with the age of onset and severity/rate of progression being highly variable. This family is relatively unique in that there is no symptom-based evidence of skeletal muscle involvement, and the known desminopathy and cardiomyopathy genes/loci have been ruled out. These data support literature suggesting that desmin deposition may be associated with different underlying gene defects, and that a novel desminopathy gene is responsible for the condition in this family.

Adolescent↗
PubMed2001

Expression of perforin on HIV-1-specific CD8+ lymphocytes after immunization with a gp120-depleted, whole-killed HIV-1 immunogen.

We examined HIV-1 antigen specific intracellular expression of perforin on CD4+ and CD8+ lymphocytes in subjects with chronic HIV-1 infection on antiviral drug therapy after immunization with a gp120-depleted, whole killed HIV-1 immunogen (inactivated, gp120-depleted HIV-1 in IFA, REMUNE). Based upon previous results, we hypothesized that the restoration of adequate T helper immune responses by vaccination against HIV-1 could result in the augmentation of CD8+ lymphocyte immune responses measured as perforin expression. In the current study we observed an increase in the frequency of perforin in CD8+ lymphocytes in HIV infected individuals immunized with a gp120-depleted HIV-1 immunogen while on antiviral drug therapy. Furthermore, the frequency of HIV-specific CD8+ perforin expressing cells correlated with the T helper immune response as measured by the lymphocyte proliferative response (LPR). The induction of such responses with immunization may have direct antiviral consequences and is being studied in ongoing clinical trials.

AIDS Vaccines↗
PubMed2001

Bartonella henselae serostatus is not correlated with neurocognitive decline in HIV infection.

Bartonella henselae has been implicated as a significant cause of HIV-associated dementia. We attempted to confirm this association by utilizing the database of the San Diego HIV Neurobehavioral Research Center, which collects longitudinal neurocognitive and laboratory data on over 500 HIV-infected participants. Utilizing an immunofluorescent assay we found that 11% of 177 subjects, half of whom had documented neurocognitive decline, were seropositive for B. henselae. There was no correlation between B. henselae seropositivity and neurocognitive decline. The role of B. henselae in HIV-associated dementia remains ambiguous.

AIDS Dementia Complex↗
PubMed2001

The changing economics of HIV care.

New advances in human immunodeficiency virus (HIV) monitoring and therapeutics have led to dramatic changes in the course of HIV disease. We evaluated our closed clinic of 425 HIV patients over the period 1995-1998 to determine the cost effectiveness of these changes in care. We found that the costs of antiretroviral therapy tripled over the period of observation, but that these increases were largely offset by major declines in inpatient and home health expenditures. In addition, we found that annual mortality among our HIV patients had declined by 90%. We calculated that the cost per life-year gained is about $17,500, which compares favorably with medical expenditures for renal dialysis or advanced cardiac disease.

Antiviral Agents↗
PubMed2001

Symptomatic HIV seroconverting illness is associated with more rapid neurological impairment.

OBJECTIVES: To establish whether symptomatic seroconverting illness in HIV infected people is associated with more rapid development of neurological impairment. METHODS: 166 HIV infected subjects with a known date of HIV infection enrolled in a longitudinal study of neurocognitive function were stratified by whether or not they had experienced a symptomatic serconverting illness. RESULTS: 29 of 166 (17.5%) dated HIV seroconverters had a history of symptomatic seroconverting illness. Though baseline neurocognitive function was similar, subjects with a symptomatic seroconverting illness developed clinical neurocognitive impairment significantly more rapidly than their asymptomatic counterparts in a survival analysis model (636 v 1075 days till impaired). CONCLUSION: Symptomatic seroconverting illness predisposes to more rapid neurocognitive impairment.

AIDS Dementia Complex↗