Biomedical subjects

A C Smith

Publications and source records attributed to A C Smith.

At least 73 records · Page 4Linked to original sources

PubMed1998

Differential effects of calcium channel blockers on size selectivity of proteinuria in diabetic glomerulopathy.

BACKGROUND: Calcium channel blockers (CCBs) are known to have differential effects on both changes in proteinuria as well as progression of diabetic nephropathy. No clinical study, however, has evaluated whether the differential antiproteinuric effects of CCBs may be explained by their effect on glomerular membrane permeability. We, therefore, tested the hypothesis that certain subclasses of CCBs reduce proteinuria by changing size selectivity of the glomerular membrane, hence changing its permeability. METHODS: Twenty-one patients with type 2 diabetes and the presence of nephropathy with hypertension were randomized to receive either diltiazem CD or nifedipine GITS after baseline data for mean systolic and diastolic pressure, urinary protein excretion, glomerular filtration rate, renal plasma flow, neutral dextran and IgG clearances were obtained. Glomerular filtration rate, renal plasma flow, neutral dextran and IgG clearance were measured every three months, arterial pressure and heart rate every month. Patients were followed for 21 months. RESULTS: At 21 months, both patient groups had similar levels of blood pressure control, however, only the diltiazem group had a change in proteinuria (4+/-10%delta, nifedipine vs. -57+/-18%delta, diltiazem; P < 0.001) with improvement in glomerular size selectivity and change in IgG clearance. CONCLUSIONS: These data support the hypothesis that CCBs that provide sustained reductions in proteinuria do so, in part, by improving glomerular size permselectivity.

Adult↗

PubMed1998

Are medical students ready to provide HIV-prevention counseling?

PURPOSE: To determine whether medical students were prepared to assess risk and counsel patients about prevention of HIV infection, and whether HIV-related experience produced better knowledge and counseling skills. METHOD: In 1995, students at four North Carolina medical schools interviewed a standardized patient portraying a young woman concerned about HIV infection. The standardized patient recorded whether students asked risk-behavior questions and provided risk-reduction advice. A 21-item questionnaire assessed the students' knowledge of HIV testing and prevention. Students indicated whether they had had experience in educational settings related to HIV or STDs. RESULTS: 415 students completed both the patient interview and the questionnaire. Many failed to ask the patient about several HIV-risk behaviors. Although nearly all (98%) inquired about condom use, fewer than two thirds asked about the patient's history of STDs, number of sexual partners, or specific sexual practices. Most students advised the patient to use condoms. The average score on the knowledge test was 79%; 70% of students confused anonymous with confidential testing, more than half overestimated the risk of HIV transmission from a needle stick, and nearly one in ten did not know how to use a condom. Educational exposures did not produce significantly better risk assessment, counseling information, or knowledge scores. CONCLUSION: A majority of experienced medical students did not assess several important risk factors of a patient concerned about HIV infection, and many would have provided incorrect information related to HIV testing and prevention of infection. Patient contact in traditional clinical settings did not influence prevention knowledge or behavior. More innovative methods are needed to train students in HIV-infection prevention and counseling.

Counseling↗

PubMed1998

Does training location influence the clinical skills of medical students?

PURPOSE: To examine the benefits of the shift of medical education into ambulatory primary care settings by investigating whether medical students exposed to a common primary care problem (low back pain) in ambulatory care settings develop better clinical skills. METHOD: In 1995, the authors categorized 420 students from all four North-Carolina medical schools into groups that had previously encountered patients with low back pain in ambulatory primary care settings, tertiary care settings, both, or neither. The clinical skills of the groups were determined using data collected during standardized-patient examination in which students took the history of, physically examined, and chose a diagnostic strategy for patients with acute, uncomplicated low back pain. RESULTS: In general, there was no difference between the performances of the student groups associated with the settings of their previous encounters with low back pain. On average, the students failed to ask 35% of the history items and failed to perform 35% of the physical examination items. Many students chose inappropriate diagnostic strategies. CONCLUSION: The lack of difference between the groups' clinical performances indicates a need to more rigorously define and evaluate outcomes of education in ambulatory care settings. The generally poor clinical performance of all groups suggests that the current curriculum inadequately teaches clinical skills needed to assess and manage common problems. Clearer expectations of competencies and assurances that preceptors in ambulatory care settings will help students meet those learning objectives might lead to better outcomes.

Ambulatory Care↗

PubMed1998

Brief report: association of sex chromosome anomalies with childhood-onset psychotic disorders.

OBJECTIVE: An apparent excess of sex chromosome aneuploidies (XXY, XXX, and possibly XYY) has been reported in patients with adult-onset schizophrenia and with unspecified psychoses. This study describes the results of cytogenetic screening carried out for pediatric patients meeting DMS-III-R criteria for childhood-onset schizophrenia (COS) and a subgroup of patients with childhood-onset psychotic disorder not otherwise specified, provisionally labeled by the authors as multidimensionally impaired (MDI). METHOD: From August 1990 to July 1997, karyotypes were determined for 66 neuroleptic-nonresponsive pediatric patients (28 MDI, 38 COS), referred to the National Institute of Mental Health for an inpatient treatment trial of clozapine. RESULTS: Four (6.1%) of 66 patients (3 MDI, 1 COS) were found to have sex chromosome anomalies (mosaic 47,XXY; 47,XXY; 47,XYY; mosaic 45,XO, respectively), which is higher than the expected rate of 1 per 426 children or 2.34 per 1,000 in the general population (4/66 versus 1/426, chi 2 = 19.2, df = 1, p = .00001). All cases had been previously undiagnosed. CONCLUSIONS: These findings lend support to a hypothesis that a loss of balance of gene products on the sex chromosomes may predispose affected individuals to susceptibility to additional genetic and environmental insults that result in childhood-onset psychotic disorders. Karyotyping of children with psychotic disorders should be routine.

Adolescent↗

PubMed1997

Toxicity of cordycepin in combination with the adenosine deaminase inhibitor 2'-deoxycoformycin in beagle dogs.

For 3 consecutive days, the nucleoside cordycepin (3'-deoxyadenosine) was administered as 1-hr iv infusions (0, 1, 4, 8, 10, or 20 mg/kg/day) to dogs. These doses were given 1 hr after a bolus iv injection (0.25 mg/kg/day) of 2'-deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase. The hypothesis was that dCF would affect the toxicity of cordycepin. Plasma adenosine deaminase activity was strongly inhibited during the dose period and for 5 days following the final dose of dCF. Dogs given cordycepin alone showed no drug-related toxicities. In dogs given only dCF, drug-related toxicity to lymphoid tissue (lymphopenia and thymus lymphoid depletion), thrombocytopenia, and decreases in food consumption were observed. Cordycepin in combination with dCF produced symptoms associated with severe gastrointestinal toxicity (decreased body weights, emesis, diarrhea, decreased food consumption, and necrosis of the gastrointestinal tract) and bone marrow toxicity (lymphopenia, thrombocytopenia, and depletion of hematopoietic cells). The gastrointestinal tract and bone marrow were sites associated with dose-limiting toxicities. In surviving dogs, most of the effects were reversible by Day 30. The maximum tolerated dose of cordycepin administered in combination with dCF was 8 mg/kg/day (160 mg/m2/day) given daily for 3 days.

Adenosine Deaminase↗

PubMed1997

Musculoskeletal pain in cardiac ultrasonographers: results of a random survey.

Myalgias and arthralgias are common among workers whose jobs require repetitive isometric maneuvers or malalignment of body position. However, few systematic studies have been performed to evaluate the frequency of these complaints among cardiac ultrasonographers. Therefore the purpose of this study was to determine the prevalence of musculoskeletal pain (MSP) among ultrasonographers and to identify risk factors related to their occurrence. Two hundred twenty ultrasonographers randomly chosen from a list of more than 1600 active members of the American Society of Echocardiography were mailed surveys consisting of 22 questions. Included were questions regarding height, age, years of experience, frequency and type of physical exercise, and job-related parameters such as a number of scans per day, scanning from right or left side of bed, number of hours, bed type, type of equipment, and manual or self-propelled machines. Respondents were asked whether they had had back, neck, or shoulder pain related to their profession and to describe treatment rendered and its effectiveness. One hundred thirteen (51%) of 220 ultrasonographers responded to the survey. Ninety (80%) of 113 respondents reported new pain that was not present before they began scanning, with 42 of this group (46%) requiring either physiotherapy (n = 17) or medication (n = 23). Treatment was believed to be helpful in 63% of cases. Factors found to have a positive relationship to MSP included ultrasonographer height less than 63 inches, performing 100 or more scans per month, average scan time of 25 minutes or more per patient, and use of manually propelled machines (each p < 0.05). Factors found to have no relationship to MSP included age, type of equipment, right or left scan position, physical conditioning, bed type, and time between patients. Musculoskeletal pain is prevalent among cardiac ultrasonographers, and may have specific work-related factors for its occurrence.

Adult↗

PubMed1997

Calcium antagonism abolishes the antipressor action of vasopressin (V1) receptor antagonism.

Previous studies demonstrate that vasopressin (V1) receptor antagonism lowers arterial pressure in blacks. This action of V1 receptor blockade may be mediated through various mechanisms including changes in intracellular calcium fluxes. This study was undertaken to test the hypothesis that inhibition of calcium entry may attenuate the reduction in arterial pressure observed with V1 receptor blockade. Sixteen hypertensive patients, 8 whites and 8 blacks, were examined. Each had their antihypertensive therapy stopped for 1 week. Following three baseline blood pressure measurements, all patients were given an intravenous bolus injection of a V1 receptor antagonist. Blood pressure was monitored every 10 min for a period of 3 h. Subjects were then randomized to either 0.2 mg clonidine twice daily or 300 mg diltiazem CD daily for a period of 3 days and the previous experiments repeated. Patients were then crossed over to the other drug for an additional 3 days and the experiments repeated. There was a significant reduction from baseline in the mean arterial pressure among blacks but not whites (-11 +/- 3 delta mm Hg blacks versus -1 +/- 2 delta mm Hg whites, P < .01). In the presence of clonidine, there were similar reductions in arterial pressure in both groups (P = .026) with a further reduction following V1 receptor blockade only in the blacks (-7 +/- 3 delta mm Hg blacks versus 6 +/- 2 delta mm Hg whites; P < .001). Conversely, in the presence of diltiazem CD, there were no further reductions in arterial pressure in either group following the V1 receptor antagonist. We conclude that calcium channel blockade abolishes the blood pressure lowering response of V1 receptor blockade in blacks.

Aged↗

PubMed1997

A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3.

Miller-Dieker syndrome (MDS) is a multiple malformation syndrome characterized by classical lissencephaly and a characteristic facies. It is associated with visible or submicroscopic deletions within chromosome band 17p13.3. Lissencephaly without facial dysmorphism has also been observed and is referred to as isolated lissencephaly sequence (ILS). Apparently partial and non-overlapping deletions of the 5' or 3' end of a candidate gene LIS1 in one ILS and one MDS patient had suggested that MDS was a single gene disorder, and that LIS1 spans in excess of 400 kb. However, the originally presumed 5' end of LIS1 was found to belong to the 14-33 epsilon gene residing more distally on 17p13.3. We have now isolated the correct 5' end of LIS1, constructed a approximately 500 kb genomic contig encompassing LIS1, and estimated its gene to be approximately 80 kg. Fluorescence in situ hybridization analysis of an ILS patient with a de novo balanced translocation, as well as analysis of several other key MDS and ILS deletion patients, localizes the lissencephaly critical region within the LIS1 gene. Therefore, LIS1 remains the strongest candidate gene for the lissencephaly phenotype in ILS and MDS. Our analyses also suggest that additional genes distal to LIS1 may be responsible for the facial dysmorphology and other abnormalities seen in MDS but not in ILS patients, supporting our original concept MDS as a contiguous gene deletion syndrome.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1997

Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome.

Classical lissencephaly (smooth brain) or generalized agyria-pachygyria is a severe brain malformation which results from an arrest of neuronal migration at 9-13 weeks gestation. It has been observed in several malformation syndromes including Miller-Dieker syndrome (MDS) and isolated lissencephaly sequence (ILS). A gene containing beta-transducin like repeats, now known as LIS1, was previously mapped to the ILS/MDS chromosome region on 17p13.3. We recently localized the classical lissencephaly critical region to the LIS1 gene locus by molecular analysis of key ILS and MDS patients. We have now characterized the structure of LIS1, which consists of 11 exons, and have searched for the presence of subtle mutations in 19 ILS patients who showed no gross rearrangements of LIS1. Single strand conformational polymorphism (SSCP) analysis revealed band-shifts for three patients, each involving a different coding exon, which were not observed in their respective parental DNAs. Sequence analysis identified these de novo mutations as dA --> dG transition in exon VI at nucleotide 446, a dC --> dT transition in exon VIII at nucleotide 817, and a 22 bp deletion at the exon IX-intron 9 junction from nucleotide 988 to 1,002+7, which causes skipping of exon IX in the mature LIS1 transcript. These changes are predicted to result in an H149R amino acid substitution, an R273X premature translation termination, and abolition of amino acids 301-334, in the respective LIS1 proteins. These data thus confirm LIS1 as the gene responsible for classical lissencephaly in ILS and MDS.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1997

Inferior alveolar nerve damage following removal of mandibular third molar teeth. A prospective study using panoramic radiography.

Permanent alteration of sensation in the lip after the removal of mandibular third molar teeth is an unusual but important complication. Studies have been performed to assess the risk of nerve damage but most of these have been retrospective and poorly controlled. This prospective trial predicted the outcome of altered sensation prior to surgery based on assessment of a panoramic radiograph and correlated this with the result postoperatively in the consecutive removal of 479 third molar teeth. Results indicated that 5.2 per cent had transient alteration in sensation but only one patient (0.2 per cent) had prolonged anaesthesia. As 94.8 per cent of teeth extracted had no neurological sequelae the figures for prediction were skewed and a kappa statistical analysis of 0.27 illustrated a fair level of agreement between prediction and outcome. This study supports previously reported levels of neurological damage and confirms that panoramic radiography is the optimum method for radiological assessment for mandibular third molar teeth prior to their removal.

Adolescent↗

PubMed1997

Medical school culture and generalist education: perceptions of a medical school faculty.

BACKGROUND AND OBJECTIVES: As part of an initiative to promote the education of generalist physicians at the University of North Carolina, a series of meetings were held over a 12-month period between generalist senior faculty and faculty from a range of departments in the School of Medicine and other health professions schools. Through open discussion about generalist initiatives, we hoped to understand their issues, attitudes, and opinions regarding generalists and generalist education. The major themes arising from these dialogues were 1) uncertainty about the definition of the generalist physician, 2) beliefs about the poor clinical reputations of generalists, 3) lack of a scientific basis for generalist practice, and 4) beliefs that few new resources are needed to undertake and expand generalist education. We comment on the validity and possible reasons for these perceptions and suggest strategies that can enhance generalist culture in the medical school.

Attitude of Health Personnel↗

PubMed1996

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 1. Indole-3-acetamides.

Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A2 (hnps-PLA2) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA2. One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure--activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X-ray crystal structures of complexes between the inhibitors and hnps-PLA2 which were of great value in directing the SAR.

Animals↗

PubMed1996

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 2. Indole-3-acetamides with additional functionality.

As reported in our previous paper, a series of indole-3-acetamides which possessed potency and selectivity as inhibitors of human nonpancreatic secretory phospholipase A2(hnps-PLA2) was developed. The design of these compounds was based on information derived from x-ray crystal structures determined for complexes between the enzyme and its inhibitors. We describe here the further implementation of this structure-based design strategy and continued SAR development to produce indole-3-acetamides with additional functionalities which provide increased interaction with important residues within the enzyme active site. These efforts led to inhibitors with substantially enhanced potency and selectivity.

Crystallography, X-Ray↗

PubMed1996

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 3. Indole-3-glyoxamides.

The preceding papers of this series detail the development of functionalized indole-3-acetamides as inhibitors of hnps-PLA2. We describe here the extension of the structure-activity relationship to include a series of indole-3-glyoxamide derivatives. Functionalized indole-3-glyoxamides with an acidic substituent appended to the 4- or 5-position of the indole ring were prepared and tested as inhibitors of hnps-PLA2. It was found that the indole-3-glyoxamides with a 4-oxyacetic acid substituent had optimal inhibitory activity. These inhibitors exhibited an improvement in potency over the best of the indole-3-acetamides, and LY315920 (6m) was selected for evaluation clinically as an hnps-PLA2 inhibitor.

Crystallography, X-Ray↗

PubMed1996

Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously.

BACKGROUND: Prompt recognition of the reversal of respiratory failure may permit earlier discontinuation of mechanical ventilation, without harm to the patient. METHODS: We conducted a randomized, controlled trial in 300 adult patients receiving mechanical ventilation in medical and coronary intensive care units. In the intervention group, patients underwent daily screening of respiratory function by physicians, respiratory therapists, and nurses to identify those possibly capable of breathing spontaneously; successful tests were followed by two-hour trials of spontaneous breathing in those who met the criteria. Physicians were notified when their patients successfully completed the trials of spontaneous breathing. The control subjects had daily screening but no other interventions. In both groups, all clinical decisions, including the decision to discontinue mechanical ventilation, were made by the attending physicians. RESULTS: Although the 149 patients randomly assigned to the intervention group had more severe disease, they received mechanical ventilation for a median of 4.5 days, as compared with 6 days in the 151 patients in the control group (P=0.003). The median interval between the time a patient met the screening criteria and the discontinuation of mechanical ventilation was one day in the intervention group and three days in the control group (P<0.001). Complications -- removal of the breathing tube by the patient, reintubation, tracheostomy, and mechanical ventilation for more than 21 days -- occurred in 20 percent of the intervention group and 41 percent of the control group (P=0.001). The number of days of intensive care and hospital care was similar in the two groups. Total costs for the intensive care unit were lower in the intervention group (median, $15,740, vs. $20,890 in the controls, P=0.03); hospital costs were lower, though not significantly so (median, $26,229 and $29,048, respectively; P=0.3). CONCLUSIONS: Daily screening of the respiratory function of adults receiving mechanical ventilation, followed by trials of spontaneous breathing in appropriate patients and notification of their physicians when the trials were successful, can reduce the duration of mechanical ventilation and the cost of intensive care and is associated with fewer complications than usual care.

Adult↗

PubMed1996

Prenatal diagnosis of uniparental disomy 15 following trisomy 15 mosaicism.

Maternal uniparental disomy 15 (UPD15), responsible for approximately 25 per cent of Prader-Willi syndrome cases, is usually caused by maternal meiosis I non-disjunction associated with advanced maternal age. These cases may initially be detected as mosaic trisomy 15 during routine prenatal diagnostic studies. In such cases, PCR (polymerase chain reaction) microsatellite analysis of uncultured cells makes prospective prenatal diagnosis for UPD15 possible with results available in 2-4 days. We have performed molecular analyses on a series of seven cases of mosaic trisomy 15 identified in amniotic fluid (AF, n = 3) or chorionic villus samples (CVS, n = 4) from patients initially referred for advanced maternal age or abnormal triple screen. In all cases, the maternal ages were > or = 35 years and maternal meiosis I non-disjunction was documented as the cause of the trisomy in all informative cases (n = 5). Of the three case with mosaic trisomy 15 at amniocentesis, two showed the presence of the trisomy in the fetus. Molecular analysis showed one case with maternal UPD15 in the euploid cell line and one case with biparental inheritance. Both of these families elected to terminate the pregnancies based on the presence of true fetal mosaicism. In the third case, low-level trisomy 15 mosaicism in the amniotic fluid was not confirmed in a follow-up amniotic fluid sample and molecular analysis indicated biparental inheritance in the fetus. For the four trisomy 15 mosaics detected at CVS, molecular analysis was performed on direct amniotic fluid cell lysates for prospective diagnosis of UPD at 14-16 weeks' gestation. Follow-up cytogenetic analysis of the amniotic fluid in all four cases was normal, indicating confined placental mosaicism. Molecular analysis showed one of these four cases to have maternal heterodisomy 15. Based on the likelihood of Prader-Willi syndrome due to maternal UPD15, the couple chose to terminate the pregnancy. The total of two of seven cases of trisomy 15 mosaicism resulting in UPD15 is consistent with the theoretical expectation of one-third and indicates a high risk of UPD in such pregnancies. Therefore, UPD testing should be offered in all cases of mosaic trisomy 15 encountered in CVS or amniocentesis.

Adult↗

PubMed1996

Guided osteogenesis using synthetic membranes: an experimental pilot study.

The aim of this pilot study was to develop an experimental model for the assessment of bone augmentation, and in doing so compare the use of various synthetic membranes by relating osteogenesis to their microstructural and physical properties. Calvarial sites in nine Sprague Dawley rats were prepared for bone augmentation and three different membranes were used to cover the healing sites. Specimens were retrieved at sequenced intervals and subjected to macroscopic, histologic and histomorphometric analysis. The results obtained suggest that while current membranes are adequate for the regeneration of bone they may not be ideal for bone augmentation.

Animals↗

PubMed1996

Overexpressions of cDNAs for beta-amyloid precursor proteins 695, 751, and 770 enhance the secretion of beta-amyloid precursor protein derivatives and the survival of P19-derived neurons.

P19 is a C3H mouse-derived line of multipotent embryonic carcinoma cells that differentiate into neural cells. P19 cell clones overexpressing the three major forms of beta-amyloid precursor protein from their cDNA constructs were established. Unlike a previous study in which P19-derived neurons had a limited alpha-secretase activity, all of these clones produced significant amounts of secreted beta-amyloid precursor protein. When treated with retinoic acid, these transformed lines differentiated into neurons and survived better than did nontransformed parental P19 cells. Furthermore, P19-derived neurons survived better in medium conditioned by the transformed P19 line, and survival was reduced by immunoabsorption with an antibody to beta-amyloid precursor protein. These results suggest neurotrophic effects of secreted beta-amyloid precursor protein and contrast with a previous report in which overexpression of a full-length cDNA for beta-amyloid precursor protein led to degeneration of P19-derived neurons. Western blot analysis suggested that this difference might result from different levels of expression of putative neurotoxic C-terminal fragments of beta-amyloid precursor protein; moreover, P19-derived neurons differ from P19 stem cells in the processing of these C-terminal fragments.

Amyloid beta-Protein Precursor↗