Showing papers by "University of Texas Medical Branch published in 1997"

Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress

Abstract: A significant amount of reactive oxygen species (ROS) is generated during mitochondrial oxidative phosphorylation. Several studies have suggested that mtDNA may accumulate more oxidative DNA damage relative to nuclear DNA. This study used quantitative PCR to examine the formation and repair of hydrogen peroxide-induced DNA damage in a 16.2-kb mitochondrial fragment and a 17.7-kb fragment flanking the β-globin gene. Simian virus 40-transformed fibroblasts treated with 200 μM hydrogen peroxide for 15 or 60 min exhibited 3-fold more damage to the mitochondrial genome compared with the nuclear fragment. Following a 60-min treatment, damage to the nuclear fragment was completely repaired within 1.5 hr, whereas no DNA repair in the mitochondrion was observed. Mitochondrial function, as assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction, also showed a sharp decline. These cells displayed arrested-cell growth, large increases in p21 protein levels, and morphological changes consistent with apoptosis. In contrast, when hydrogen peroxide treatments were limited to 15 min, mtDNA damage was repaired with similar kinetics as the nuclear fragment, mitochondrial function was restored, and cells resumed division within 12 hr. These results indicate that mtDNA is a critical cellular target for ROS. A model is presented in which chronic ROS exposure, found in several degenerative diseases associated with aging, leads to decreased mitochondrial function, increased mitochondrial-generated ROS, and persistent mitochondrial DNA damage. Thus persistent mitochondrial DNA damage may serve as a useful biomarker for ROS-associated diseases.

The National Depressive and Manic-Depressive Association consensus statement on the undertreatment of depression

Abstract: Objective. —A consensus conference on the reasons for the undertreatment of depression was organized by the National Depressive and Manic Depressive Association (NDMDA) on January 17-18, 1996. The target audience included health policymakers, clinicians, patients and their families, and the public at large. Six key questions were addressed: (1) Is depression undertreated in the community and in the clinic? (2) What is the economic cost to society of depression? (3) What have been the efforts in the past to redress undertreatment and how successful have they been? (4) What are the reasons for the gap between our knowledge of the diagnosis and treatment of depression and actual treatment received in this country? (5) What can we do to narrow this gap? (6) What can we do immediately to narrow this gap? Participants. —Consensus panel members were drawn from psychiatry, psychology, family practice, internal medicine, managed care and public health, consumers, and the general public. The panelists listened to a set of presentations with background papers from experts on diagnosis, epidemiology, treatment, and cost of treatment. Evidence. —Experts summarized relevant data from the world scientific literature on the 6 questions posed for the conference. Consensus Process. —Panel members discussed openly all material presented to them in executive session. Selected panelists prepared first drafts of the consensus statements for each question. All of these drafts were read by all panelists and were edited and reedited until consensus was achieved. Conclusions. —There is overwhelming evidence that individuals with depression are being seriously undertreated. Safe, effective, and economical treatments are available. The cost to individuals and society of this undertreatment is substantial. Long suffering, suicide, occupational impairment, and impairment in interpersonal and family relationships exist. Efforts to redress this gap have included provider educational programs and public educational programs. Reasons for the continuing gap include patient, provider, and health care system factors. Patient-based reasons include failure to recognize the symptoms, underestimating the severity, limited access, reluctance to see a mental health care specialist due to stigma, noncompliance with treatment, and lack of health insurance. Provider factors include poor professional school education about depression, limited training in interpersonal skills, stigma, inadequate time to evaluate and treat depression, failure to consider psychotherapeutic approaches, and prescription of inadequate doses of antidepressant medication for inadequate durations. Mental health care systems create barriers to receiving optimal treatment. Strategies to narrow the gap include enhancing the role of patients and families as participants in care and advocates; developing performance standards for behavioral health care systems, including incentives for positive identification, assessment, and treatment of depression; enhancing educational programs for providers and the public; enhancing collaboration among provider subtypes (eg, primary care providers and mental health professionals); and conducting research on development and testing of new treatments for depression.

Neuroanatomy of the pain system and of the pathways that modulate pain

Abstract: We review many of the recent findings concerning mechanisms and pathways for pain and its modulation, emphasizing sensitization and the modulation of nociceptors and of dorsal horn nociceptive neurons. We describe the organization of several ascending nociceptive pathways, including the spinothalami

Fear conditioning induces a lasting potentiation of synaptic currents in vitro

Abstract: The amygdala plays a critical role in the mediation of emotional responses, particularly fear, in both humans and animals. Fear conditioning, a conditioned learning paradigm, has served as a model for emotional learning in animals, and the neuroanatomical circuitry underlying the auditory fear-conditioning paradigm is well characterized. Synaptic transmission in the medial geniculate nucleus (MGN) to lateral nucleus of the amygdala (LA) pathway, a key segment of the auditory fear conditioning circuit, is mediated largely through N-methyl-D-aspartate (NMDA) and non-NMDA (such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)) glutamate receptors; the potential for neural plasticity in this pathway is suggested by its capacity to support long-term potentiation (LTP). Here we report a long-lasting increase in the synaptic efficacy of the MGN-LA pathway attributable to fear-conditioning itself, rather than an electrically induced model of learning. Fear-conditioned animals show a presynaptic facilitation of AMPA-receptor-mediated transmission, directly measured in vitro with whole-cell recordings in lateral amygdala neurons. These findings represent one of the first in vitro measures of synaptic plasticity resulting from emotional learning by whole animals.

Prospective study of blunt aortic injury: Multicenter trial of the American Association for the Surgery of Trauma

Abstract: Background: Blunt aortic injury is a major cause of death from blunt trauma. Evolution of diagnostic techniques and methods of operative repair have altered the management and posed new questions in recent years. Methods: This study was a prospectively conducted multicenter trial involving 50 trauma centers in North America under the direction of the Multi-institutional Trial Committee of the American Association for the Surgery of Trauma. Results: There were 274 blunt aortic injury cases studied over 2.5 years, of which 81% were caused by automobile crashes. Chest computed tomography and transesophageal echocardiography were applied in 88 and 30 cases, respectively, and were 75 and 80% diagnostic, respectively. Two hundred seven stable patients underwent planned thoracotomy and repair. Clamp and sew technique was used in 73 (35%) and bypass techniques in 134 (65%). Overall mortality was 31%, with 63% of deaths being attributable to aortic rupture; mortality was not affected by method of repair. Paraplegia occurred postoperatively in 8.7%. Logistic regression analysis demonstrated clamp and sew (p = 0.002) and aortic cross clamp time of 30 minutes (p = 0.01) to be associated with development of postoperative paraplegia. Conclusions: Rupture after hospital admission remains a major problem. Although newer diagnostic techniques are being applied, at this time aortography remains the diagnostic standard. Aortic cross clamp time beyond 30 minutes was associated with paraplegia; bypass techniques, which provide distal aortic perfusion, produced significantly lower paraplegia rates than the clamp and sew approach.

Yeast Rad55 and Rad57 proteins form a heterodimer that functions with replication protein A to promote DNA strand exchange by Rad51 recombinase.

Abstract: Saccharomyces cerevisiae RAD51, RAD55, and RAD57 genes, required for genetic recombination and DNA double-strand-break repair, encode proteins homologous to one another and to the Escherichia coli RecA protein. Rad51 protein catalyzes the DNA strand-exchange reaction with a dependence on ATP and on the heterotrimeric single-strand DNA (ssDNA) binding factor replication protein A (RPA). By several independent criteria, RAD55- and RAD57-encoded products are shown here to exist as a stable heterodimer, with a dissociation constant of <2 x 10(-10) M. In strand exchange, the reaction proceeds efficiently if RPA is incorporated after nucleation of Rad51 onto ssDNA, but if RPA is present during the nucleation phase, as is likely the case in vivo, the amount of strand-exchange products becomes relatively insignificant. Inclusion of the Rad55-Rad57 heterodimer with Rad51 and RPA results in a marked stimulation of strand exchange, providing evidence for a role of the Rad55-Rad57 heterodimer in overcoming the inhibitory effect of RPA.

A naturally occurring protective system in urea-rich cells: mechanism of osmolyte protection of proteins against urea denaturation.

Abstract: Trimethylamine N-oxide (TMAO) is a solute concentrated in the urea-rich cells of elasmobranchs and coelacanth to offset the damaging effects of urea on intracellular protein structure and function. On the basis of transfer free energy measurements, favorable interaction of TMAO with amino acid side chains promote protein denaturation. This effect is more than offset by highly unfavorable TMAO-peptide backbone interactions that not only oppose denaturation but also provide stabilization against denaturation by urea. By combining transfer free energies of side chains and backbone with surface area exposure in the native and unfolded states of ribonuclease T1, the transfer free energies of native and unfolded protein from water to 1 M TMAO are estimated as 1.7 and 5.9 kcal/mol, respectively. These estimates agree favorably with the respective values of 1.2 and 5.4 kcal/mol determined experimentally by Lin and Timasheff [(1994) Biochemistry 33, 12695-12701]. The unfavorable transfer free energies of native and unfolded protein from water to TMAO provides a molecular level rationale for preferential hydration of proteins by osmolytes. Promotion of denaturation by urea is found to be offset by TMAO in a manner that is roughly additive of the combined effects of both solutes. The favorable interaction of urea with the backbone provides the dominant driving force for protein unfolding by this denaturant, and the unfavorable interaction of TMAO with backbone is the dominant force opposing urea denaturation. In solutions that contain significant organic solute concentration, the ascendance of the role of the peptide backbone over that of side chains can explain many observed effects in protein denaturation and stability induced by a variety of stabilizing and destabilizing organic solutes.

Amylin, Calcitonin Gene-Related Peptide, Calcitonin, and Adrenomedullin: A Peptide Superfamily

Abstract: The calcitonin gene peptide superfamily consists of calcitonin (CT), calcitonin gene-related peptide (CGRP), and amylin. CT and CGRP derive from the CT/CGRP gene, which is encoded on chromosome 11. Alternative splicing of the primary RNA transcript leads to the translation of CGRP and CT peptides in a tissue-specific manner. CGRP (a 37-amino-acid neuropeptide) and its receptors are widely distributed in the body, and it is the most potent endogenous vasodilatory peptide discovered so far. CT (a 32-amino-acid peptide) is, however, a hormone primarily involved in protecting the skeleton during periods of "calcium stress" such as growth, pregnancy, and lactation. CT derives from the C cells of the thyroid gland and is the most potent peptide inhibitor of osteoclast-mediated bone resorption. Therefore, treatment with CT is highly effective for conditions associated with increased bone turnover such as Paget's disease, osteoporosis, Sudeck's atrophy, and hypercalcemia. Amylin (a 37-amino-acid peptide) is generated from a gene located on chromosome 12 (thought to be an evolutionary duplication of chromosome 11) and shares 46% amino acid sequence homology with CGRP and 20% with human CT. Amylin is predominantly located in the beta cells of the islets of the pancreas and may be involved in the pathogenesis of type II diabetes by deposition as amyloid within the pancreas, leading to beta cell destruction. Adrenomedullin, a recently discovered 52-amino-acid vasoactive peptide from adrenal tissue, shares 24% homology with CGRP and is also a member of this superfamily of peptides. A portion of the B-chain of insulin is strongly homologous to these four peptides. Not only does adrenomedullin (13-52) show 24% amino acid homology with CGRP, it also has a biological activity profile similar to that of CGRP.CGRP, CT, and amylin are related to the insulin gene superfamily of peptides, which may all have diverged from a common ancestral gene during evolution. When the crystallographic- and nuclear magnetic resonance-based molecular modeling of the three-dimensional structure of CGRP, CT, amylin, and adrenomedullin peptides and their receptors is available, it will lead to a greater understanding of the involvement of this family of peptides in pathophysiology. Together, CGRP, CT, amylin and adrenomedullin have overlapping biological effects owing to their structures and cross-reactivity between receptors. I propose that CT, CGRP, adrenomedullin, and amylin belong to a family of G-protein-coupled receptors (an "insulin superfamily" of peptides) and therefore share some of the characteristics of insulin, such as growth factor-like effects, and possible interaction at insulin receptor sites as an antagonist.

Comparison of three rodent neuropathic pain models

Abstract: To characterize various animal models of neuropathic pain, we compared three previously developed rat models using the same behavioral testing methods. These models involve: (1) chronic constriction injury by loose ligation of the sciatic nerve (CCI); (2) tight ligation of the partial sciatic nerve (PSL); and (3) tight ligation of spinal nerves (SNL). Comparisons were made for the time course of behavioral signs representing various components of neuropathic pain as well as for the effects of surgical sympathectomy. In general, all three methods of peripheral nerve injury produced behavioral signs of both ongoing and evoked pain with similar time courses. However, there was a considerable difference in the magnitude of each pain component between models. Signs of mechanical allodynia were largest in the SNL injury and smallest in the CCI model. On the other hand, behavioral signs representing ongoing pain were much more prominent in the CCI model than in the other two. Although the behavioral signs of neuropathic pain tended to decrease after sympathectomy in all three models, the change was most evident in the SNL model. The results of the present study suggest that the three rat models tested have contrasting features, yet all are useful neuropathic pain models, possibly representing different populations of human neuropathic pain patients.

Kaposi's sarcoma-associated human herpesvirus-8 encodes homologues of macrophage inflammatory protein-1 and interleukin-6

Abstract: Human herpesvirus-8 (HHV-8) has been detected in Kaposi's sarcoma (KS) lesions of all types (AIDS-related, classical and endemic), in body-cavity-based B-cell lymphomas (BCBLs) and in le-sions of multicentric Castleman's disease (MCD). We have identified a major gamma-herpesvirus-divergent locus (DL-B) in HHV-8 DNA encoding several HHV-8 unique open reading frames (ORFs), including a homologue of interleukin-6 (IL-6) and two homologues of macrophage inflammatory protein MIP-1. We show that the HHV-8-encoded IL-6 homologue (vlL-6) shares functional properties with endogenous IL-6 proteins and that both vlL-6 and vMIP-1 transcripts are present at high levels following butyrate induction of an HHV-8+ BCBL cell line. Low amounts of constitutive vlL-6, but not vMIP-1, mRNA were also detected. The presence of a functional IL-6 homologue encoded by HHV-8 may provide a mechanistic model for the hypothesized role of HHV-8 in KS, MCD and BCBL that involves the mitogenic effects of vlL-6 on surrounding cells. MIP-1 proteins may enhance these effects through the chemotactic recruitment of endogenous cy-tokine-producing cells into affected tissues and could potentially influence HIV disease progression in coinfected individuals through interactions with the HIV co-receptor CCR-5.

A Small-molecule Inhibitor Directed against the Chemokine Receptor CXCR4 Prevents its Use as an HIV-1 Coreceptor

Abstract: The chemokine receptor CXCR4 is the major coreceptor used for cellular entry by T cell– tropic human immunodeficiency virus (HIV)-1 strains, whereas CCR5 is used by macrophage (M)-tropic strains. Here we show that a small-molecule inhibitor, ALX40-4C, inhibits HIV-1 envelope (Env)-mediated membrane fusion and viral entry directly at the level of coreceptor use. ALX40-4C inhibited HIV-1 use of the coreceptor CXCR4 by T- and dual-tropic HIV-1 strains, whereas use of CCR5 by M- and dual-tropic strains was not inhibited. Dual-tropic viruses capable of using both CXCR4 and CCR5 were inhibited by ALX40-4C only when cells expressed CXCR4 alone. ALX40-4C blocked stromal-derived factor (SDF)-1α–mediated activation of CXCR4 and binding of the monoclonal antibody 12G5 to cells expressing CXCR4. Overlap of the ALX40-4C binding site with that of 12G5 and SDF implicates direct blocking of Env interactions, rather than downregulation of receptor, as the mechanism of inhibition. Thus, ALX40-4C represents a small-molecule inhibitor of HIV-1 infection that acts directly against a chemokine receptor at the level of Env-mediated membrane fusion.

The Hopelessness Depression Symptom Questionnaire

Abstract: Evaluated the Hopelessness Depression Symptom Questionnaire (HDSQ; Metalsky & Joiner, 1991). The HDSQ is a 32-item self-report measure of eight symptoms posited by L. Abramson, G. Metalsky, and L. Alloy (1989) to comprise a specific subtype of depression—hopelessness depression. Factor analytic results from 435 subjects suggested that: (a) Each of the eight subscales of the HDSQ reflects a distinct symptom of hopelessness depression; and (b) The eight subscales, taken together, reflect one higher-order construct—Hopelessness Depression Symptoms. Diathesis-stress results from a subset of 174 subjects indicated that the attributional diathesis × stress interaction predicted onset of hopelessness depression symptoms on the HDSQ but not nonhopelessness depression symptoms. The HDSQ should allow for enhanced precision in tests of the hopelessness theory of depression.

Mortality Determinants in Massive Pediatric Burns: An Analysis of 103 Children with ≥80% TBSA Burns (≥70% Full-Thickness)

Abstract: OBJECTIVE: Survivors and nonsurvivors among 103 consecutive pediatric patients with massive burns were compared in an effort to define the predictors of mortality in massively burned children. SUMMARY BACKGROUND DATA: Predictors of mortality in burns that are used commonly are age, burn size, and inhalation injury. In the past, burns over 80% of the body surface area that are mostly full-thickness often were considered fatal, especially in children and in the elderly. In the past 15 years, advances in burn treatment have increased rates of survival in those patients treated at specialized burn centers. The purpose of this study was to document the extent of improvement and to define the current predictors of mortality to further focus burn care. METHODS: Beginning in 1982, 103 children ages 6 months to 17 years with burns covering at least 80% of the body surface (70% full-thickness), were treated in the authors' institution by early excision and grafting and have been observed to determine outcome. The authors divided collected independent variables from the time of injury into temporally related groups and analyzed the data sequentially and cumulatively through univariate statistics and through pooled, cross-sectional multivariate logistic regression to determine which variables predict the probability of mortality. RESULTS: The mortality rate for this series of massively burned children was 33%. Lower age, larger burn size, presence of inhalation injury, delayed intravenous access, lower admission hematocrit, lower base deficit on admission, higher serum osmolarity at arrival to the authors' hospital, sepsis, inotropic support requirement, platelet count < 20,000, and ventilator dependency during the hospital course significantly predict increased mortality. CONCLUSIONS: The authors conclude that mortality has decreased in massively burned children to the extent that nearly all patients should be considered as candidates for survival, regardless of age, burn size, presence of inhalation injury, delay in resuscitation, or laboratory values on initial presentation. During the course of hospitalization, the development of sepsis and multiorgan failure is a harbinger of poor outcome, but the authors have encountered futile cases only rarely. The authors found that those patients who are most apt to die are the very young, those with limited donor sites, those who have inhalation injury, those with delays in resuscitation, and those with burn-associated sepsis or multiorgan failure.

Chronic central pain after spinal cord injury.

Abstract: Spinal cord injury (SCI) frequently results in dysesthesias that have remained refractory to clinical treatments despite a variety of interventions The failure of therapeutic strategies to treat dysesthesias after SCI is due to the lack of attention given to mechanisms that elicit chronic pain following SCI An overview of the literature with respect to the development of chronic pain in the SCI patient population will be given In addition, a mammalian model of chronic central pain following spinal cord trauma will be presented The model is characterized by the development of mechanical and thermal allodynia, as demonstrated by measuring the thresholds of accepted nociceptive tests, the paw withdrawal responses accompanied by changes in behavior consistent with the experience of noxious stimuli In addition, vocalization responses that are accompanied by postural and behavioral changes consistent with the receipt of a noxious stimulus and involving supraspinal pathways are measured Locomotor function was also tested and scored using the Basso, Beattie, and Bresnahan (BBB) open field test scale Our data indicate that somatosensory thresholds for both mechanical and thermal stimuli that elicit paw withdrawal (flexor reflex) or vocalizations, accompanied by complex changes in behavior, are significantly different following SCI These changes represent the development of mechanical and thermal allodynia To determine the underlying mechanism for the altered sensory responses, we used electrophysiological techniques to determine if nociceptive dorsal horn neurons demonstrated increased excitability to peripheral stimulation as evidenced by increased responses to natural somatosensory stimuli The data presented support the development of central sensitization of dorsal horn neurons after spinal cord hemisection This provides a mechanism for the development of mechanical and thermal allodynia after SCI Hypotheses that account for the development of the central pain state after SCI, as well as therapeutic interventions to ameliorate the pain state, are discussed

Assessment and Treatment of Suicidal Patients

Abstract: The assessment of suicidal thoughts or behavior and its management are topics relevant to all clinicians, not just mental health professionals. Up to two thirds of patients who commit suicide have seen a physician in the month before their death.1–5 Many patients who kill themselves do so by taking an overdose of prescribed medications, and physicians sometimes unwittingly provide the means for suicide in a single prescription.3 Few patients spontaneously report their suicidal thoughts and intentions to their physicians,4 so the clinician must be alert to signals that a patient may be at risk for suicide. Although the patient . . .

Estrogen and testosterone, but not a nonaromatizable androgen, direct network integration of the hypothalamo-somatotrope (growth hormone)-insulin-like growth factor I axis in the human: evidence from pubertal pathophysiology and sex-steroid hormone replacement.

Abstract: Activation of the gonadotropic and somatotropic axes in puberty is marked by striking amplification of pulsatile neurohormone secretion. In addition, each axis, as a whole, constitutes a regulated network whose feedback relationships are likely to manifest important changes at the time of puberty. Here, we use the regularity statistic, approximate entropy (ApEn), to assess feedback activity within the somatotropic (hypothalamo-pituitary/GH-insulin-like growth factor I) axis indirectly. To this end, we studied pubertal boys and prepubertal girls or boys with sex-steroid hormone deficiency treated short-term with estrogen, testosterone, or a nonaromatizable androgen in a total of 3 paradigms. First, our cross-sectional analysis of 53 boys at various stages of puberty or young adulthood revealed that mean ApEn, taken as a measure of feedback complexity, of 24-h serum GH concentration profiles is maximal in pre- and mid-late puberty, followed by a significant decline in postpubertal adolescence and young adulthood (P = 0.0008 by ANOVA). This indicates that marked disorderliness of the GH release process occurs in mid-late puberty at or near the time of peak growth velocity, with a return to maximal orderliness thereafter at reproductive maturity. Second, oral administration of ethinyl estradiol for 5 weeks to 7 prepubertal girls with Turner's syndrome also augmented ApEn significantly (P = 0.018), thus showing that estrogen per se can induce greater irregularity of GH secretion. Third, in 5 boys with constitutionally delayed puberty, im testosterone administration also significantly increased ApEn of 24-h GH time series (P = 0.0045). In counterpoint, 5 alpha-dihydrotestosterone, a nonaromatizable androgen, failed to produce a significant ApEn increase (P > 0.43). We conclude from these three distinct experimental contexts that aromatization of testosterone to estrogen in boys, or estrogen itself in girls, is likely the proximate sex-steroid stimulus amplifying secretory activity of the GH axis in puberty. In addition, based on inferences derived from mathematical models that mechanistically link increased disorderliness (higher ApEn) to network changes, we suggest that sex-steroid hormones in normal puberty modulate feedback within, and hence network function of, the hypothalamo-pituitary/GH-insulin-like growth factor I axis.

N-acetyl cysteine ameliorates ischemic renal failure.

Abstract: Recovery from ischemic renal injury is accompanied by enhanced DNA synthesis and a typical immediate early (IE) gene response. These two processes occur in distinct cell populations, suggesting that the IE gene response does not serve a proliferative function directly. As cellular stress induces an IE response through activation of the stress-activated protein kinases (SAPK) that is not proliferative and can be inhibited by N-acetyl-L-cysteine (NAC), we determined whether the Jun NH2-terminal kinases (JNK), members of the SAPKs, are activated during ischemia and whether NAC administration reduces the IE response and/or the induction of JNK activity. NAC (6 mM/kg body wt) infused 1 h prior to and 1 h following renal ischemia reduced c-fos and c-jun expression by 50 and 70%, respectively. Ischemia increased JNK activity, and this increase was inhibited by NAC. NAC infused animals had a higher glomerular filtration rate at 1 day (NAC, 0.9 +/- 0.2, vs. control, 0.05 +/- 0.01 ml/min, P < 0.001) and 7 days (NAC, 2.0 +/- 0.1, vs. control, 1.2 +/- 0.1, P < 0.001) after the induction of ischemia. NAC did not reduce the extent of proximal tubule necrosis at 24 h after reperfusion but improved histological appearance of the kidney at 7 days. The mechanism by which NAC ameliorates the loss of renal function is unknown but may involve its general properties as an antioxidant or a possible interaction with NAC and NO. We conclude that the IE gene response of the kidney to ischemia reperfusion is a consequence of the stress-activated kinase pathway and that part of the response is deleterious to kidney function and cellular integrity.

Multicenter evaluation of proposed standardized procedure for antifungal susceptibility testing of filamentous fungi.

Abstract: A multicenter study was conducted to expand the generation and analysis of data that supports the proposal of a reference method for the antifungal susceptibility testing of filamentous fungi. Broth microdilution MICs of amphotericin B and itraconazole were determined in 11 centers against 30 coded duplicate pairs of Aspergillus spp., Fusarium spp., Pseudallescheria boydii, and Rhizopus arrhizus. The effect of inoculum density (approximately 10(3) and 10(4) CFU/ml), incubation time (24, 48, and 72 h), and procedure of MIC determination (conventional and colorimetric [Alamar Blue] evaluation of growth inhibition) on intra- and interlaboratory agreement was analyzed. Based on intra- (97 to 100%) and interlaboratory (94 to 95%) agreement for both drugs, the overall optimal testing conditions identified were determination of colorimetric MICs after 48 to 72 h of incubation with an inoculum density of approximately 10(4) CFU/ml. These testing conditions are proposed as guidelines for a reference broth microdilution method.

Complement C5a, TGF-β1, and MCP-1, in Sequence, Induce Migration of Monocytes Into Ischemic Canine Myocardium Within the First One to Five Hours After Reperfusion

Abstract: Background Recent studies suggest that reperfusion promotes healing of formerly ischemic heart tissue even when myocardial salvage is no longer possible. Since monocyte-macrophage infiltration is the hallmark of the healing infarct, we have attempted to identify mechanisms that attract monocytes into the heart after reperfusion of ischemic canine myocardium. Methods and Results Isolated autologous 99m Tc-labeled mononuclear leukocytes injected into the left atrium localized preferentially in previously ischemic myocardium within the first hour after reperfusion. Histological studies revealed CD64+ monocytes in small venules and the perivascular connective tissue within the first hour after reperfusion. Flow cytometric analysis of cells in cardiac lymph showed systematically increasing numbers of neutrophils and monocytes between 1 and 4 hours after reperfusion; monocyte enrichment was eventually greater than neutrophil enrichment. Monocyte chemotactic activity in cardiac lymph collected in the first hour after reperfusion was wholly attributable to C5a. Transforming growth factor (TGF)-β1 contributed significantly to this chemotactic activity after 60 to 180 minutes, and after 180 minutes, monocyte chemotactic activity in lymph was largely dependent on monocyte chemoattractant protein (MCP)-1 acting in concert with TGF-β1. Conclusions Beginning in the first 60 minutes after reperfusion, C5a, TGF-β1, and MCP-1, acting sequentially, promote infiltration of monocytes into formerly ischemic myocardium. These events may promote the healing of myocardial injury facilitated by reperfusion.

Individual Patient Cohort Analysis of the Efficacy of Hypertonic Saline/Dextran in Patients with Traumatic Brain Injury and Hypotension

Abstract: Background: Resuscitation with hypertonic saline/dextran (HSD) has been suggested to be efficacious in patients who have traumatic brain injury and are hypotensive. We undertook a cohort analysis of individual patient data from previous prospective randomized double-blinded trials to evaluate improvements in survival at 24 hours and discharge after initial treatment with HSD in patients who had traumatic brain injury (head region Abbreviated Injury Score ≥ 4) and hypotension (systolic blood pressure ≤ 90 mm Hg). Methods: All variables and end points were defined before initiation of data handling. Investigators were blind as to the treatment. Case report forms were received from six studies. Of these, 223 patients met the inclusion for traumatic brain injury. Comparisons between HSD and standard of care were made using stratified analysis and logistic regression to assess efficacy, confounding, and interaction. Potential confounding variables of pre-fluid treatment, Glasgow Coma Scale score (3-8 vs. 9-15), injury type, and systolic blood pressure can be considered a priori factors that were known before randomization. Effects of the various trials was also considered. Results: Treatment with HSD resulted in a survival until discharge of 37.9% (39 of 103) compared with 26.9% (32 of 119) with standard of care (p = 0.080). Using logistic regression, adjusting for trial and potential confounding variables, the treatment effect can be summarized by the odds ratio of 2.12 (p = 0.048) for survival until discharge. Conclusion: Patients who have traumatic brain injuries in the presence of hypotension and receive HSD are about twice as likely to survive as those who receive standard of care.

The effects of phenytoin on impulsive and premeditated aggression: a controlled study

Abstract: Studies of the effects of phenytoin on aggression have produced equivocal results primarily because of a lack of (1) common objective criterion measures of aggressive acts across studies; (2) rigorous inclusion and exclusion criteria for selecting subjects; and (3) a nosologic basis for classifying different types of aggression. The current study was designed to remedy these deficiencies. Aggression was defined using a nosology that defines three types of aggression: (1) medically related; (2) premeditated; and (3) impulsive. The purpose of this study was to test the hypothesis that phenytoin will decrease impulsive aggressive acts but not have a significant influence on premeditated aggressive acts. Sixty inmates were divided into two groups on the basis of committing primarily impulsive aggressive acts or premeditated aggressive acts while in prison. Medical aggression was ruled-out by subject selection. The study used a double-blind, placebo-controlled, crossover design. As hypothesized, phenytoin (200 mg a.m. and 100 mg p.m.) significantly reduced impulsive aggressive acts but not premeditated aggressive acts. Event-related potentials (ERPs) measured information processing in the cortex during drug/placebo conditions. The amplitudes of P300 ERP waveforms among impulsive aggressive subjects were increased significantly during the phenytoin condition but not during the placebo condition. There were no significant changes in P300 ERP waveforms between drug/placebo conditions among nonimpulsive aggressive subjects.