Showing papers by "University of Tennessee Health Science Center published in 1993"

CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome

Abstract: The ligand for CD40 (CD40L) is a membrane glycoprotein on activated T cells that induces B cell proliferation and immunoglobulin secretion. Abnormalities in the CD40L gene were associated with an X-linked immunodeficiency in humans [hyper-IgM (immunoglobulin M) syndrome]. This disease is characterized by elevated concentrations of serum IgM and decreased amounts of all other isotypes. CD40L complementary DNAs from three of four patients with this syndrome contained distinct point mutations. Recombinant expression of two of the mutant CD40L complementary DNAs resulted in proteins incapable of binding to CD40 and unable to induce proliferation or IgE secretion from normal B cells. Activated T cells from the four affected patients failed to express wild-type CD40L, although their B cells responded normally to wild-type CD40L. Thus, these CD40L defects lead to a T cell abnormality that results in the failure of patient B cells to undergo immunoglobulin class switching.

Gun Ownership as a Risk Factor for Homicide in the Home

Abstract: Background It is unknown whether keeping a firearm in the home confers protection against crime or, instead, increases the risk of violent crime in the home. To study risk factors for homicide in the home, we identified homicides occurring in the homes of victims in three metropolitan counties. Methods After each homicide, we obtained data from the police or medical examiner and interviewed a proxy for the victim. The proxies' answers were compared with those of control subjects who were matched to the victims according to neighborhood, sex, race, and age range. Crude and adjusted odds ratios were calculated with matched-pairs methods. Results During the study period, 1860 homicides occurred in the three counties, 444 of them (23.9 percent) in the home of the victim. After excluding 24 cases for various reasons, we interviewed proxy respondents for 93 percent of the victims. Controls were identified for 99 percent of these, yielding 388 matched pairs. As compared with the controls, the victims more often ...

Arachidonic acid status correlates with first year growth in preterm infants.

Abstract: Diets deficient in the omega-6 fatty acid linoleic acid reduce arachidonic acid (Ach) concentrations and retard growth of developing animals and humans Nevertheless, plasma phosphatidylcholine Ach concentrations declined from 84 +/- 23 mg/liter at birth to a nadir of 38 +/- 11 mg/liter at 4 mo of age in preterm infants fed commercial formulas with linoleic acid, and weight normalized to that of term infants fell progressively beginning at 2 mo of age The nadir of plasma phosphatidylcholine Ach (31 +/- 7 mg/liter) and growth were further reduced by formula containing marine oil compared with the commercial formulas Ach status (defined as the mean plasma phosphatidylcholine Ach concentration at 2, 4, and 65 mo) correlated with one or more measures of normalized growth through 12 mo Ach status and maternal height accounted for as much as 59% of the weight variance and 68% of the length variance in infants fed standard formulas Better Ach status was not from higher energy intakes A conditional Ach deficiency in preterm infants may contribute to growth over the first year of life On the strength of the relationship between Ach status and growth, we hypothesize that dietary Ach could improve first year growth of preterm infants

Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction.

Abstract: Interleukin 3 (IL-3) regulates the proliferation and differentiation of hematopoietic cells. Although the IL-3 receptor chains lack kinase catalytic domains, IL-3 induces tyrosine phosphorylation of cellular proteins. To investigate the potential role of the JAK family of protein-tyrosine kinases in IL-3 signal transduction, we have obtained full-length cDNA clones for murine Jak1 and Jak2 protein-tyrosine kinases and prepared antiserum against the predicted proteins. Using antisera against Jak2, we demonstrate that IL-3 stimulation results in the rapid and specific tyrosine phosphorylation of Jak2 and activates its in vitro kinase activity.

The A.B.F.O. study of third molar development and its use as an estimator of chronological age.

Abstract: Radiographs depicting third molars (M3s) have been used to estimate chronological age in juvenile and adult suspects, but accuracy of the method has been in question. This study provides age benchmarks for American whites (age range: 14 to 24 years) based on cases (n = 823) drawn from diplomates of the American Board of Forensic Odontologists in the United States and Canada. Maxillary M3 formation was slightly advanced over mandibular M3s, and root formation occurred earlier in males than females. Mean and median ages for M3 formation are tabled using Demirjian's eight-grade classification. Regression formulas and empirical probabilities are provided relative to the medicolegal question of whether an individual is at least 18 years of age. The M3 is the most variable tooth in the dentition, but situations arise where M3 formation is the only usable datum for age estimation.

Plasma Triglyceride Level and Mortality from Coronary Heart Disease

Abstract: Background Whether the plasma triglyceride level is a risk factor for coronary heart disease has been controversial, and evaluation of the triglyceride level as a risk factor is fraught with methodologic difficulties. Methods We studied the association between plasma triglyceride levels and the 12-year incidence of death from coronary heart disease in 10 North American populations participating in the Lipid Research Clinics Follow-up Study, while adjusting for the potential confounding effects of other risk factors for cardiovascular disease, including the level of high-density lipoprotein (HDL) cholesterol. All analyses were sex-specific, and separate analyses were performed in high and low strata of HDL cholesterol, low-density lipoprotein (LDL) cholesterol, fasting plasma glucose, and age. Results The rates of coronary death in both men and women increased with the triglyceride level. In Cox proportional-hazards models adjusted for age, in which the natural log of the triglyceride levels was used to gi...

The generation of natural firing patterns in neostriatal neurons.

Abstract: Publisher Summary In one of the first single unit recording studies of the mammalian neostriatum, Albe-Fessard and co-workers observed that spontaneously active neostriatal neurons in unanesthetized (decerebrate) animals fired at low rates in an irregular, somewhat bursty pattern. They further observed that upon onset of chloralose anesthesia, the bursts of activity were more pronounced and began to occur rhythmically at 3–10 Hz. A later study by Sedgwick and Williams showed that this rhythmic bursting was also characteristic of light barbituate anesthesia, and deeper anesthesia could lead to slowing and complete cessation of firing. Using intracellular recordings, Sedgwick and Williams were able to demonstrate prolonged depolarizing potentials that underlay the bursts of firing in the lightly anesthetized animals, and they postulated that these arose from a rhythmic excitatory synaptic input to the neostriatum, acting in conjunction with inhibitory processes that terminated the bursts. Numerous studies published over the past 25 years have repeated these observations, usually emphasizing the low firing rates of the neurons, the large number of neurons with practically no spontaneous firing (in both anesthetized and unanesthetized preparations), and the rhythmic bursting of neurons under light anesthesia.

A neuronal group theory of sleep function

Abstract: SUMMARY A new theory of sleep function is presented within the context of the neuronal group selection hypothesis, which emphasizes that neuronal groups compete for neurons via use-dependent synaptic formation and atrophy. It is hypothesized that sleep serves to stabilize these competitive processes by providing a pattern of stimulation that serves to maintain a synaptic infrastructure upon which wakefulness-driven synaptic changes are superimposed. Sleep is ‘quantal’ in nature in that sleep is a statistical property of a population of neuronal groups in different states. The theory unifies past theories of sleep function yet simultaneously provides a fundamental new paradigm for sleep research.

Comparison of Atovaquone (566C80) with Trimethoprim-Sulfamethoxazole to Treat Pneumocystis carinii Pneumonia in Patients with AIDS

Abstract: Background Both trimethoprim-sulfamethoxazole and pentamidine are effective as treatments for Pneumocystis carinii pneumonia, but adverse effects frequently limit their use. Atovaquone (566C80) is a new hydroxynaphthoquinone with activity against P. carinii. Methods We conducted a double-blind, multicenter study in patients with the acquired immunodeficiency syndrome and mild or moderately severe P. carinii pneumonia. They were randomly assigned to 21 days of orally administered treatment three times daily with either atovaquone (750 mg) or trimethoprim (320 mg) plus sulfamethoxazole (1600 mg). Results Of the 322 patients with histologically confirmed P. carinii pneumonia, 160 received atovaquone and 162 received trimethoprim-sulfamethoxazole. Of those who could be evaluated for therapeutic efficacy, 28 of 138 patients given atovaquone (20 percent) and 10 of 146 patients given trimethoprim-sulfamethoxazole (7 percent) did not respond (P = 0.002). Treatment-limiting adverse effects required a change of the...

Comparison of Ondansetron Versus Placebo to Prevent Postoperative Nausea and Vomiting in Women Undergoing Ambulatory Gynecologic Surgery

Abstract: BACKGROUND:Postoperative nausea and emesis, especially in ambulatory surgical patients, remains a troublesome problem. This study was performed to compare the incidence of nausea and emesis during the 24-h postoperative period in ondansetron-treated patients versus placebo-treated patients. METHODS:Using a randomized prospective double-blind study design, women between the ages of 18 and 70 yr undergoing gynecologic surgical procedures with general opioid anesthesia on an outpatient basis were enrolled. Ondansetron or placebo was administered prior to induction of anesthesia. Patients were stratified according to history of nausea and emesis during previous exposure to general anesthesia and randomized to dose received. RESULTS:Data from the 544 women showed that all doses of intravenous ondansetron tested (1, 4, and 8 mg) were significantly more effective (62%, 76%, and 77%, respectively) than placebo (46%) in reducing the incidence of emesis following surgery until 24 h after recovery room entry. All these doses were more effective than placebo in patients with no prior history of emesis following surgery and the 4- and 8-mg doses were more effective than placebo in patients with a prior history of emesis following surgery. All doses of ondansetron tested were generally well tolerated with adverse events, clinical laboratory tests, and recovery room vital signs similar to those of placebo. Serum aspartate transaminase (AST) was increased in five patients (1 mg, 2 patients; 4 mg, 1 patient; 8 mg, 2 patients). In the three patients in whom subsequent analysis were performed, the serum AST had decreased to preoperative levels. CONCLUSIONS:Ondansetron given intravenously to prevent postoperative nausea and emesis was highly effective in the 4- and 8-mg doses in women having ambulatory gynecologic surgery.

Predictors of long-term smoking cessation in head and neck cancer patients.

Abstract: Cigarette smoking is a major risk factor for head and neck cancer, and individuals who continue to smoke past diagnosis and treatment are at elevated risk for further disease. In a randomized controlled trial, a state of the art provider-delivered smoking cessation intervention was compared to a usual care advice control condition. The intervention consisted of surgeon- or dentist-delivered advice to stop smoking, a contracted quit date, tailored written materials, and booster advice sessions. Subjects were 186 patients with newly diagnosed first primary squamous cell carcinomas of the upper aerodigestive tract who had smoked cigarettes within the past year. At randomization, 88.2% of subjects were current smokers. At 12-month follow-up, 70.2% of subjects completing the trial (n = 114) were continuous abstainers; among baseline smokers alone the continuous abstinence (CA) rate was 64.6%. The cotinine validation rate at 12 months was 89.6%. Modeling techniques were utilized in order to derive expected CA rates, which included noncompleter subjects (n = 72). The CA rate expected at 1 year for the entire patient population was 64.2%, and for smokers alone the expected CA rate was 59.4%. Logistic regression analysis carried out on baseline smokers identified predictors of 12-month CA status. These included medical treatment, stage of change, age, nicotine dependence, and race. The intervention effect was not significant, although the sign of the effect was positive. Based on these findings, we recommend systematic brief advice to stop smoking for head and neck cancer patients, with a stepped care approach for patients less able to quit.

The Effects of the Timing of Ethanol Exposure during the Brain Growth Spurt on the Number of Cerebellar Purkinje and Granule Cell Nuclear Profiles

Abstract: Ethanol exposure during development is particularly deleterious to cerebellar Purkinje cells and granule cells, but the mechanism(s) underlying this sensitivity and the variables which affect it remain unknown. One important variable that has not been fully investigated, is the timing of the ethanol exposure. Ethanol exposure during the brain growth spurt causes a differential loss of Purkinje cells across the 10 lobules of the vermal cerebellum. However, whether or not changing the timing of the ethanol exposure during the brain growth spurt alters the extent and location of the loss of Purkinje cells within the cerebellar vermis has not been investigated. Moreover, the loss of cerebellar granule cells has been shown to parallel the loss of Purkinje cells, leading to the conclusion that the loss of granule cells occurred as a function of the loss of their targets, the Purkinje cells. The purpose of this study was to address both issues. Male rat pups were exposed to ethanol, via an artificial-rearing method, during one of the following 2-day time periods: postnatal days (PD) 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, or 12-13. Gastrostomy control (GC) and suckle control (SC) groups also were included. All pups were sacrificed on PD21. The number of Purkinje cell nuclear profiles from three vermal sections were counted in all groups, while the number of granule cell nuclear profiles in the ten lobules was estimated from pups in selected groups. No loss of Purkinje cells was observed in pups exposed to ethanol on PD7-8 or at any of the later exposure times. Additionally, among the three exposure groups in which significant Purkinje cell loss was observed (PD4-5, PD5-6 and PD6-7), seven lobules exhibited significant differences particularly between the PD4-5 and PD6-7 groups. The group with the greatest loss of Purkinje cells (PD4-5) also was the group with the greatest loss of granule cells. A significant loss of granule cells did not occur without a corresponding loss of Purkinje cells. The loss of both the Purkinje and granule cells was affected by the timing of the ethanol exposure, and that the extent and the location of Purkinje cell loss were extremely sensitive to the effects of the timing of the ethanol exposure.

Significance of Serial C-Reactive Protein Responses in Neonatal Infection and Other Disorders

Abstract: Objective. This study was performed to determine prospectively whether, in the presence of proved or presumed bacterial infection, the sensitivity of serum C-reactive protein (CRP) response could be enhanced by serial rather than single determinations. We also sought to assess CRP responses to clinically identified noninfectious disorders. Design. The CRP responses of 491 infants on 691 occasions of suspected infection were assessed. CRP levels were measured initially and twice again at 12-hour intervals (rate immunonephelometry). Assessments also included a blood culture, complete blood cell count, and chest radiograph and culture of spinal fluid when appropriate. CRP responses were correlated with four designated clinical groups: (1) positive blood or cerebrospinal fluid cultures (n = 190); (2) negative blood culture-definite infection (necrotizing enterocolitis stages 2 and 3, pneumonia, subcutaneous abscess) (n = 52); (3) negative blood culture-possible infection (antenatal risk factors, meconium aspiration, positive urine group B streptococcus antigen, necrotizing enterocolitis stage 1, febrile infants) (n = 287); and (4) negative blood culture-no infection (respiratory distress syndrome, transient tachypnea of the newborn, patent ductus arteriosus, tissue trauma) (n = 160). Diagnoses were made before CRP results were known. Results. In all, 187 (27%) of the blood cultures were positive. A single organism was recovered from 174 of these; two organisms from 13. Among the single-organism cultures, 50 (29%) were Gram-negative, 120 (69%) were Gram-positive, and 4 (2%) were budding yeasts. CRP levels were elevated in various groups as follows: in the positive blood culture group (by organism), Gram-negative rods, 92% (46/50); group B streptococcus, 92% (12/13); Staphylococcus aureus, 89% (8/9); group D streptococcus, 71% (10/14); Streptococcus viridans, 60% (6/10); Staphylococcus epidermidis, 55% (40/73). In the negative blood culture-definite infection group, CRP levels were abnormal in 88%; in the negative culture-possible infection group, CRP was elevated in 33%; and in the negative blood culture-no infection group, CRP was elevated in 9%. Serial determinations of CRP resulted in enhanced sensitivity in the positive blood culture group, the negative blood culture-definite infection group, and the negative blood culture-possible infection group. Initial determinations by themselves were inadequatey sensitive. Serial determinations did not enhance sensitivity of the negative blood culture-no infection group. High specificity (91%) is suggested by the low incidence of abnormal CRP levels among infants who were not infected. Conclusions. These data suggest that it would be appropriate to conduct a cautious, controlled trial to assess the safety of discontinuing antibiotic therapy if three serial CRP measurements are normal and if there are no other clinical factors suggestive of infection. The data also indicate the necessity for serial determinations of CRP for optimal sensitivity.

GABAergic circuits of the striatum.

Abstract: Publisher Summary The neostriatum contains a large number of neurons and terminals that contain y-aminobutyric acid (GABA), an inhibitory transmitter. GABAergic inhibition has been thought to play a major role in regulating the neuronal activities of the striatum. This chapter discusses the studies on the GABAergic circuits and their functions in the striatum. First, it describes the anatomical organizations and then discusses the functional implications of GABAergic elements. The neostriatum contains many GABAergic neurons and GABAergic synaptic terminals, which are considered to be major elements in regulating the neuronal activities of the striatum. Anatomical and physiological studies indicate that GABAergic interneurons play a major role in the regulation of the firing activity of the spiny projection neurons through their feedforward connection. It is also suggested by anatomical studies that cholinergic and dopaminergic inputs affect the activity of GABAergic interneurons.

A prospective analysis of diagnostic laparoscopy in trauma.

Abstract: Objective This study was performed to assess current and potential future application for laparoscopy (DL) in the diagnosis of penetrating and blunt injuries. Efficacy, safety, and cost analyses were performed. Summary background data Diagnostic peritoneal lavage (DPL) and computed tomography (CT) have been the mainstays in recent years for diagnosis of equivocal nontherapeutic laparotomy, whereas CT is not helpful for the vast majority of penetrating wounds. DL may be a useful adjunct to fill in these gaps. Methods Hemodynamically stable patients with equivocal evidence of intraabdominal injury were prospectively entered into the protocol. DL was performed under general anesthesia; patients with wounds penetrating the peritoneum or blunt injury with significant organ injury underwent laparotomy. Results Over 19 months, 182 patients (55% stab, 36% GSW, 9% blunt) were studied. No peritoneal penetration was found at DL in 55% of penetrating wounds with 66% of the remainder having therapeutic laparotomy, 17% nontherapeutic laparotomy, and 17% negative laparotomy. Therapeutic laparotomy was performed in 53% of blunt injuries after DL. Tension pneumothorax occurred in one patient and one had an iatrogenic small bowel injury. Charges for DL were $3,325 per patient compared with $3,320 for a similar group undergoing negative laparotomy before this protocol. Conclusions DL is a safe modality for trauma. With current technology, DL is most efficacious for evaluation of equivocal penetrating wounds. Significant cost savings would be gained by performance under local anesthesia. Development of miniaturized optics, bowel clamps, retractors, and stapling devices will reduce overall costs and permit some therapeutic applications for laparoscopy in trauma management.

Isolating Fetal Cells From Maternal Blood: Advances in Prenatal Diagnosis Through Molecular Technology

Abstract: Objectives. —To review the rationale for and progress toward the goal of isolating and analyzing fetal cells circulating in maternal blood, and to explore the feasibility of this method in providing noninvasive prenatal cytogenetic diagnosis. Data Sources. —Critical review of data published since the first report (1969) of fetal metaphases in maternal blood. Emphasis is placed on data since the demonstration by polymerase chain reaction (PCR) in 1989 and 1990 that fetal cells indeed exist in maternal blood. Data Synthesis. —Clinical evaluations have not yet been conducted, but it is already clear that molecular technologies have allowed the unequivocal demonstration of fetal cells in maternal blood. Using PCR, our own group and others have demonstrated Y sequences and single gene sequences (eg, hemoglobin LeporeBoston) in maternal blood. Thus, fetal DNA sequences indeed exist in maternal blood. Among the various candidate cells, the most promising appear to be fetal nucleated red blood cells. We isolated nucleated red blood cells on the basis of flow-sorting for the transferrin receptor and glycophorin-A. Enriched samples were then subjected to fluorescence in situ hybridization with chromosome-specific probes. This approach allowed us to detect trisomy 21 and trisomy 18, work later confirmed by others. Conclusions. —Isolating and analyzing fetal cells from maternal blood is clearly possible. Several key biologic questions remain—the optimal cells for isolation, frequency of cells in maternal blood, timing during gestation for maternal blood sampling, and the likelihood of persistence of fetal cells after delivery. Clinical evaluations planned by the National Institute of Child Health and Human Development will determine the sensitivity and specificity of this method and its precise role in prenatal cytogenetic diagnosis. (JAMA. 1993;270:2357-2361)

Glial Boundaries in the Developing Nervous System

Abstract: Advances in the biology of glial cells, particularly the development of new molecular markers and the refinement of in vitro techniques, have now revealed many intriguing glial-neuronal interactions that occur both dur­ ing nervous system development and following injury. In recent years, many excellent reviews have focused on the well-accepted guidance role of radial glia during neuronal migration (Hatten et al 1 990; Rakic 1 988, 1 990) and numerous other aspects of neuron-glia interactions that influ­ ence cellular phenotype and differentiation, circuitry formation, and syn­ aptic activity (e.g. see Abbott 1991 ; Miller et al 1 989; Vernadakis 1 988). This review conceptualizes transient glial boundaries that surround func­ tional groups of neurons, their dendrites, and axons, during neural development. These boundaries are comprised of unique glial cells and glycoconjugates (i.e. glycoproteins, glycolipids, and glycosaminoglycans), which have been referred to as "cordones" (Steindler et al 1 989b). Boun­ daries are widespread during central nervous system (CNS) pattern for­ mation and disappear following synaptic stabilization (Steindler et al 1 989a,b, 1 990). These specialized cells may express numerous neurite growth­ inhibitory molecules (Schwab 1 990; Schwab & Schnell 1 991 ; Snow et al 1 990b; Steindler et al 1 990), as well as attractant molecules, that ultimately guide neurites to boundary regions where their neuritic arbors accumulate and fasciculate (Laywell & Steindler 1 991). Astrocyte/recognition molecule boundaries may represent intermediaries between neurons and neurites

Predicting the Outcome of Unsuccessful Prehospital Advanced Cardiac Life Support

Abstract: Objective. —To determine if failure to achieve return of spontaneous circulation following prehospital advanced cardiac life support (ACLS) warrants termination of efforts at the scene. Design. —Retrospective case series. Setting. —Memphis, Tenn, a city of 610337 people that is served by a fire department—based emergency medical service system. All city ambulances provide ACLS. Patients. —Adult victims of out-of-hospital cardiac arrest due to heart disease. Intervention. —All patients received prehospital ACLS according to the 1986 American Heart Association guidelines. Following prehospital ACLS, all patients were transported to the nearest hospital emergency department whether or not a pulse was restored in the field. Main Outcome Measures. —Survival to hospital admission, survival to hospital discharge, and neurological status at discharge. Results. —Over the 39-month study interval, the Memphis Fire Department treated 1068 victims of out-of-hospital cardiac arrest. Three hundred ten of these (29%) had return of spontaneous circulation prior to transport for some period. The remaining 758 patients (71%) never regained a pulse and were transported with ongoing cardiopulmonary resuscitation. Patients who had return of spontaneous circulation prior to transport were more likely to be admitted (69% vs 7.0%) and far more likely to be discharged alive (26.5% vs 0.4%) than patients who failed to respond to prehospital ACLS. Three patients who survived to hospital discharge despite failure to achieve return of spontaneous circulation prior to emergency medical service transport sustained their cardiac arrest after paramedic arrival. All three were discharged with moderate to severe cerebral disability. Conclusion. —Rapid transport of adults who fail to respond to an adequate trial of prehospital ACLS does not result in meaningful rates of survival. In such cases, on-line emergency medical service physicians should authorize paramedics to cease efforts in the field. ( JAMA . 1993;270:1433-1436)

Low Leukocyte Counts with Blast Cells in Cerebrospinal Fluid of Children with Newly Diagnosed Acute Lymphoblastic Leukemia

Abstract: Background Treatment of the central nervous system is crucial to the successful treatment of acute lymphoblastic leukemia in children. The intensity and timing of the therapy are based on the presence or predicted risk of central nervous system leukemia as assessed according to criteria that remain controversial. Methods The clinical importance of leukemic blast cells detected in cerebrospinal fluid at the time of diagnosis was evaluated in 351 children with acute lymphoblastic leukemia in a randomized trial of intensive chemotherapy. All patients received intrathecal chemotherapy during the first year. Patients considered to be at high risk of relapse because of their clinical and cytogenetic features also received cranial irradiation and intrathecal chemotherapy one year after remission. Patients were considered to have central nervous system leukemia at diagnosis if they had at least 5 leukocytes per microliter of cerebrospinal fluid, with leukemic blast cells apparent in cytocentrifuged preparations, ...