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Biomedical subjects

M Mahowald

Publications and source records attributed to M Mahowald.

At least 19 recordsLinked to original sources
PubMed2004

Lack of association of matrix metalloproteinase 3 (MMP3) genotypes with ankylosing spondylitis susceptibility and severity.

OBJECTIVE: To study the linkage and association of ankylosing spondylitis (AS) with genotypes for matrix metalloproteinase 3 (MMP3), a gene located at chromosome 11q22.3 and lying within the 101-124 cM region observed in a recent genome-wide scan as a region associated with AS susceptibility. METHODS: MMP3 genotypes were examined in 229 pedigrees with AS, 131 sporadic AS cases and 87 Caucasian controls. Eight single-nucleotide polymorphisms (SNPs) were selected and genotyped using Taqman. Non-parametric linkage (NPL) analysis was conducted between the eight MMP3 SNPs and AS using the NPL-all statistic and two-point parametric linkage analysis using GeneHunter Plus. Unrelated AS cases and controls were compared using chi2 statistics, and family-based controls using the transmission disequilibrium test and pedigree disequilibrium test. RESULTS: None of the eight MMP3 SNPs were significantly associated with AS, either using the 131 sporadic cases alone or in analyses which combined these cases with the 226 unrelated affected AS patients derived from the pedigrees. Analysis of linkage disequilibrium (LD) demonstrated that seven of the eight SNPs studied were in strong LD except for rs626750, which is about 6 kb upstream of the 5' end of the gene. No significant linkage was observed using NPL and LODs in the families. No association was seen of any of the MMP3 SNPs with disease severity (defined by patient functioning), as measured either by the Bath Ankylosing Spondylitis Functional Index or the modified Health Assessment Questionnaire. CONCLUSION: These data suggest that MMP3 genotypes are not involved in AS susceptibility or severity.

Adult↗
PubMed2004

Clinical responses following nonmyeloablative allogeneic stem cell transplantation for renal cell carcinoma are associated with expansion of CD8+ IFN-gamma-producing T cells.

Nonmyeloablative allogeneic stem cell transplantation (NST) is thought to be an immunologic therapy in which donor T cells mediate a graft-versus-tumor effect. We recently reported the clinical outcome of a phase II trial of NST in metastatic renal cell carcinoma (RCC). However, the immune response correlates of clinical activity remain unknown. We now describe the analysis of T-cell subsets and T-cell cytokine-producing potential for those patients evaluable for immune monitoring. The incidence of graft-versus-host disease (GVHD) correlated with clinical outcome, with all responders exhibiting chronic GVHD. Following initial tapering of immunosuppression, an increase in the total numbers of CD8+ T cells but not CD4+ T cells was observed among responders compared to nonresponders. In addition, a greater ratio of CD8+ to CD4+ T cells producing IFN-gamma and IL-2 was seen in clinical responders at the time when clinical responses were first detected (day 180 after transplantation). Our results support the hypothesis that the antitumor effects of NST may be mediated by IFN-gamma-producing CD8+ T cells, and indicate that isolation of putative tumor antigen-specific T cells, ideally, should be pursued around day +180.

Adult↗
PubMed2004

Depletion of normal B cells with rituximab as an adjunct to IL-2 therapy for renal cell carcinoma and melanoma.

BACKGROUND: We postulated that in patients with metastatic renal cell carcinoma (RCC) or melanoma, depletion of normal B cells using the anti-CD20 mAb rituximab before treatment with low-dose interleukin (IL)-2 would improve clinical outcome. PATIENTS AND METHODS: Rituximab (375 mg/m(2)) weekly for 4 weeks. IL-2 [11 (million units) daily] s.c., 4 days a week for weeks 5-8, followed by a 2-week rest (weeks 9 and 10). Patients without disease progression continued on IL-2. Disease re-evaluation was performed after rituximab and after every course of IL-2. RESULTS: Fifteen patients with RCC and six with melanoma were enrolled. One patient had a partial response and seven patients had stable disease. Toxicities were similar to those expected with IL-2 alone, and there were no grade 4 events. Circulating B cells were depleted in all patients. The subsequent low-dose IL-2 increased absolute numbers of natural killer cells, activated CD4(+) and activated CD8(+) T cells. Expanded T cells produced interferon-gamma, but not IL-4. Proliferation of peripheral blood lymphocytes to phytohemagglutinin was diminished following rituximab treatment, suggesting that B cells participate in this response in vitro. CONCLUSIONS: Our results suggest that depletion of circulating B cells with rituximab does not increase the response rate, alter the toxicity profile or change the biological activity in response to low-dose IL-2 in patients with RCC or melanoma.

Adult↗
PubMed2001

Circadian rhythms and circadian rhythm disorders in children and adolescents.

A clinically applicable review of circadian rhythm physiology is presented, including a detailed examination of the interaction of circadian and homeostatic systems and the maturation of the circadian system from preconception through adolescence. Emphasis is placed on the clinical evaluation gathering information through the history, sleep log, and if necessary, actigraphy and polysomnography. Circadian disorders, including advanced sleep phase syndrome, circadian disorders seen in blind children, delayed sleep phase syndrome, and non-24-hour sleep phase are described. Case descriptions of each are provided. Treatment and interventions for these disorders are described, including the importance of education, light therapy, sleep-wake schedule adjustments, and the occasional use of medications, such as sedative hypnotics and melatonin.

Adolescent↗
PubMed2000

Tolerability and efficacy of nabumetone and naproxen in the treatment of rheumatoid arthritis.

OBJECTIVE: The purpose of this study was to compare the tolerability and efficacy of nabumetone and naproxen in the treatment of patients with rheumatoid arthritis (RA). The occurrence of gastrointestinal (GI) adverse events was compared. BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have similar efficacy at equipotent doses, but the therapeutic response to various NSAIDs often differs in individual patients. METHODS: This was a 3-month, randomized, double-blind, multicenter, parallel-group study conducted in adult patients with RA. The study had 2 phases: a 3- to 14-day washout period and a 12-week treatment period. During the treatment phase, the tolerability and efficacy of nabumetone 2000 mg/d were compared with those of naproxen 1000 mg/d. The change from baseline in efficacy variables, including global assessments, number of tender or swollen joints, and pain, was evaluated. The study was sized to provide an 80% power to detect a 15% difference in the percentage improvement on the physician's global assessment (alpha = 0.05). GI safety was assessed by monitoring the occurrence of clinically important adverse GI events. RESULTS: A total of 346 RA patients at 31 US rheumatology centers were randomly assigned to treatment (173 patients per group). The study population was predominantly white (87.0%) and female (70.5%), with a mean age of 54 years. Both treatments improved the signs and symptoms of RA, with no statistically significant differences between groups for any efficacy variables. No serious GI adverse events occurred with either NSAID. The most frequent treatment-related adverse events in both groups were predominantly GI in origin, as were those that resulted in withdrawal from the study. Diarrhea with lower abdominal pain was the most common adverse event in the nabumetone group; upper abdominal pain was the most common adverse event in the naproxen group. The only significant difference between the 2 groups was a higher incidence of diarrhea (P < 0.01) in patients receiving nabumetone. CONCLUSIONS: Nabumetone 2000 mg/d was as effective as naproxen 1000 mg/d in relieving the signs and symptoms of RA. In this study, no serious GI adverse events were observed with either NSAID, but nabumetone was associated with a higher incidence of diarrhea.

Adult↗
PubMed1999

Feedback interactions between neuronal pointers and maps for attentional processing.

Neural networks combining local excitatory feedback with recurrent inhibition are valuable models of neocortical processing. However, incorporating the attentional modulation observed in cortical neurons is problematic. We propose a simple architecture for attentional processing. Our network consists of two reciprocally connected populations of excitatory neurons; a large population (the map) processes a feedforward sensory input, and a small population (the pointer) modulates location and intensity of this processing in an attentional manner dependent on a control input to the pointer. This pointer-map network has rich dynamics despite its simple architecture and explains general computational features related to attention/intention observed in neocortex, making it interesting both theoretically and experimentally.

Attention↗
PubMed1999

Effect of sleep state on the laryngeal chemoreflex in neonatal piglets.

The laryngeal chemoreflex (LCR) is a brain stem-mediated response that is a potential mechanism for sudden infant death syndrome. The vast majority of sudden infant death occurs during sleep, yet it remains to be established whether there is a particular sleep state that makes an infant animal more susceptible to apneic events via the LCR. The purpose of this study was to investigate the LCR during different sleep states in the neonatal piglet. In this study, continuous physiologic monitoring and electroencephalographic, electro-oculographic, and electromyographic techniques were utilized to study neonatal piglets during a hypnotic induced sleep model. Propofol drip anesthetic was utilized to provide an anesthetic state and was titrated for dose-dependent sedation. The LCR was initiated in 11 animals during quiet sleep, rapid eye movement sleep, and the anesthetic state. Baseline respiratory and cardiovascular responses were measured. Durations of apnea were recorded and compared. This study found that despite known physiologic differences in respiratory control during different sleep states as compared to the anesthetic state, there appears to be no increased risk of profound apnea in one state versus another in piglets 19 to 28 days old.

Anesthesia↗
PubMed1998

The Taskforce 2000 survey on medical education in sleep and sleep disorders.

Previous research has shown evidence of a widening gap between scientific research and clinical teaching in sleep and sleep disorders. To address the deficiencies in current medical education in sleep, the Taskforce 2000 was established by the American Sleep Disorders Association. The present study was undertaken to assess the teaching activities, needs and interests of the membership of the two largest professional sleep societies (American Sleep Disorders Association and Sleep Research Society). Survey instruments included a brief, 5-item postcard survey, which was mailed to all members, followed by an in-depth, 34-item questionnaire, which was completed by 158 respondents from the intitial postcard survey (N = 808). Results indicated that the majority of respondents (65.2%) are currently involved in teaching sleep to medical students or postgraduate trainees, although the average amount of teaching time was only 2.1 hours for undergraduate and 4.8 hours for graduate education in sleep. Teaching of sleep laboratory procedures and clinical evaluation of sleep-disordered patients is limited at either an undergraduate or postgraduate level. The major deficiencies noted were the lack of time in the medical curriculum and the need for better resources and teaching facilities. A large majority of respondents indicated their willingness to be involved in sleep education for physicians, and rated this a high priority for the professional organization.

Curriculum↗
PubMed1998

Identification of high-copy disruptors of telomeric silencing in Saccharomyces cerevisiae.

The ends of chromosomes in Saccharomyces cerevisiae initiate a repressive chromatin structure that spreads internally and inhibits the transcription of nearby genes, a phenomenon termed telomeric silencing. To investigate the molecular basis of this process, we carried out a genetic screen to identify genes whose overexpression disrupts telomeric silencing. We thus isolated 10 DOT genes (disruptor of telomeric silencing). Among these were genes encoding chromatin component Sir4p, DNA helicase Dna2p, ribosomal protein L32, and two proteins of unknown function, Asf1p and Ifh1p. The collection also included genes that had not previously been identified: DOT1, DOT4, DOT5, DOT6, and TLC1, which encodes the RNA template component of telomerase. With the exception of TLC1, all these genes, particularly DOT1 and DOT4, also reduced silencing at other repressed loci (HM loci and rDNA) when overexpressed. Moreover, deletion of the latter two genes weakened silencing as well, suggesting that DOT1 and DOT4 normally play important roles in gene repression. DOT1 deletion also affected telomere tract length. The function of Dot1p is not known. The sequence of Dot4p suggests that it is a ubiquitin-processing protease. Taken together, the DOT genes include both components and regulators of silent chromatin.

Amino Acid Sequence↗
PubMed1996

The role of synapses in cortical computation.

The synapse, first introduced as physiological hypothesis by C.S. Sherrington at the close of the nineteenth century, has, 100 years on, become the nexus for anatomical and functional investigations of interneuronal communication. A number of hypotheses have been proposed that give local synaptic interactions specific roles in generating an algebra or logic for computations in the neocortex. Experimental work, however, has provided little support for such schemes. Instead, both structural and functional studies indicate that characteristically cortical functions, e.g., the identification of the motion or orientation of objects, involve computations that must be achieved with high accuracy through the collective action of hundreds or thousands of neurons connected in recurrent microcircuits. Some important principles that emerge from this collective action can effectively be captured by simple electronic models. More detailed models explain the nature of the complex computations performed by the cortical circuits and how the computations remain so remarkably robust in the face of a number of sources of noise, including variability in the anatomical connections, large variance in the synaptic responses and in the trial-to-trial output of single neurons, and weak or degraded input signals.

Animals↗
PubMed1995

Recurrent excitation in neocortical circuits.

The majority of synapses in the mammalian cortex originate from cortical neurons. Indeed, the largest input to cortical cells comes from neighboring excitatory cells. However, most models of cortical development and processing do not reflect the anatomy and physiology of feedback excitation and are restricted to serial feedforward excitation. This report describes how populations of neurons in cat visual cortex can use excitatory feedback, characterized as an effective "network conductance", to amplify their feedforward input signals and demonstrates how neuronal discharge can be kept proportional to stimulus strength despite strong, recurrent connections that threaten to cause runaway excitation. These principles are incorporated into models of cortical direction and orientation selectivity that emphasize the basic design principles of cortical architectures.

Animals↗
PubMed1994

Sleepiness and sleep disorders. Causes and consequences.

Sleepiness and sleep disorders are prevalent in our society. Symptoms of sleepiness and complaints referable to sleep disorders have generally--and incorrectly--been discounted as being of minor importance and are often thought to be manifestations of psychological problems or character defects. It is now apparent that the cost to the American public--both to individuals and the larger society--is substantial. Sleep medicine has become established as an independent field, and knowledge of sleep, sleepiness, and sleep disorders has grown dramatically. This knowledge, when applied to individuals, will enhance the lives of patients with sleep disorders, and when applied to society as a whole, will have important socioeconomic implications.

Arousal↗
PubMed1992

Uvulopalatopharyngoplasty for obstructive sleep apnea: a community's experience.

Uvulopalatopharyngoplasty (UPPP) has become an accepted method for treating obstructive sleep apnea (OSA), with a reported success rate as high as 77%, depending upon inclusionary and outcome criteria. The authors reviewed the records of 90 patients with moderately severe OSA (apnea plus hypopnea index [AHI] greater than 20) who underwent UPPP at either a private community or an academic hospital. Forty percent of patients experienced more than a 50% reduction in their AHI with UPPP. Only 22 (24%) of the patients had a postoperative AHI less than 50% of the preoperative AHI and less than 20, i.e., met the authors' criteria for surgical success. The success rate for community otolaryngologists was no different than that achieved in the academic institution. When data from previously published reports were analyzed using these criteria for success, similar results were observed. This study suggests that the effectiveness of UPPP performed by the general otolaryngologic community is equivalent to that reported in the literature. However, more rigorous criteria must be applied to UPPP when evaluating its results and in counseling potential candidates for this procedure.

Adult↗
PubMed1991

Central sleep apnoea in congenital muscular dystrophy.

Sleep-disordered breathing may occur in a wide variety of neuromuscular syndromes, and may present with diverse, often isolated, symptoms or findings such as excessive daytime sleepiness, pulmonary hypertension, congestive heart failure, morning headaches, or hypoxia-induced nocturnal seizures. The authors report two sisters with congenital muscular dystrophy in whom central sleep apnoea resulted in the isolated symptom of nocturnal seizures in one, and morning headaches in the other. Review of the literature reveals that sleep-disordered breathing may be common in neuromuscular disorders, and may often be present when clinical weakness is mild, and insufficient to result in diurnal respiratory dysfunction.

Adult↗
PubMed1991

Single night studies in obstructive sleep apnea.

The role of single night studies and the determinants of effective nasal continuous positive airway (CPAP) pressures were determined in 412 consecutive patients between 1984 and 1989. Patients chosen for analysis had an apnea index (AI) of greater than or equal to 20 hr-1 prior to CPAP. The AI was 67 +/- 30 hr-1, the body mass index (BMI) was 36 +/- 9 kg/m2, the age was 51 +/- 13 yr and the lowest oxygen saturation was 72 +/- 14%. Effective CPAP (9 +/- 3 cm H2O) was documented in 320 patients on single night studies and resulted in a 99% reduction in the frequency of obstructive events and improvement in the lowest O2 saturation to 94 +/- 5%. Only 18% of the variability in effective CPAP could be explained by AI and BMI. Single night studies are sufficient to establish effective CPAP in 78% of patients and offer considerable conservation of resources compared to routine multiple night studies. Effective CPAP pressures are variable and must be determined by incremental CPAP trials.

Arousal↗