Showing papers by "University of Texas Medical Branch published in 2000"

Lower Extremity Function and Subsequent Disability Consistency Across Studies, Predictive Models, and Value of Gait Speed Alone Compared With the Short Physical Performance Battery

Abstract: Background. Although it has been demonstrated that physical performance measures predict incident disability in previously nondisabled older persons, the available data have not been fully developed to create usable methods for determining risk profiles in community-dwelling populations. Using several populations and different follow-up periods, this study replicates previous findings by using the Established Populations for the Epidemiologic Study of the Elderly (EPESE) performance battery and provides equations for the prediction of disability risk according to age, sex, and level of performance. Methods. Tests of balance, time to walk 8 ft, and time to rise from a chair 5 times were administered to 4,588 initially nondisabled persons in the four sites of the EPESE and to 1,946 initially nondisabled persons in the Hispanic EPESE. Follow-up assessment for activity of daily living (ADL) and mobility-related disability occurred from 1 to 6 years later. Results. In the EPESE, compared with those with the best performance (EPESE summary performance score of 10‐ 12), the relative risks of mobility-related disability for those with scores of 4‐6 ranged from 2.9 to 4.9 and the relative risk of disability for those with scores of 7‐9 ranged from 1.5 to 2.1, with similar consistent results for ADL disability. The observed rates of incident disability according to performance level in the Hispanic EPESE agreed closely with rates predicted from models developed from the EPESE sites. Receiver operating characteristic curves showed that gait speed alone performed almost as well as the full battery in predicting incident disability. Conclusions. Performance tests of lower extremity function accurately predict disability across diverse populations. Equations derived from models using both the summary score and the gait speed alone allow for the estimation of risk of disability in community-dwelling populations and provide valuable information for estimating sample size for clinical trials of disability prevention.

Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire.

Abstract: OBJECTIVE: Bipolar spectrum disorders, which include bipolar I, bipolar II, and bipolar disorder not otherwise specified, frequently go unrecognized, undiagnosed, and untreated. This report describes the validation of a new brief self-report screening instrument for bipolar spectrum disorders called the Mood Disorder Questionnaire. METHOD: A total of 198 patients attending five outpatient clinics that primarily treat patients with mood disorders completed the Mood Disorder Questionnaire. A research professional, blind to the Mood Disorder Questionnaire results, conducted a telephone research diagnostic interview by means of the bipolar module of the Structured Clinical Interview for DSM-IV. RESULTS: A Mood Disorder Questionnaire screening score of 7 or more items yielded good sensitivity (0.73) and very good specificity (0.90). CONCLUSIONS: The Mood Disorder Questionnaire is a useful screening instrument for bipolar spectrum disorder in a psychiatric outpatient population.

A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression.

Abstract: Background Patients with chronic forms of major depression are difficult to treat, and the relative efficacy of medications and psychotherapy is uncertain. Methods We randomly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with nefazodone (maximal dose, 600 mg per day), the cognitive behavioral-analysis system of psychotherapy (16 to 20 sessions), or both. At base line, all patients had scores of at least 20 on the 24-item Hamilton Rating Scale for Depression (indicating clinically significant depression). Remission was defined as a score of 8 or less at weeks 10 and 12. For patients who did not have remission, a satisfactory response was defined as a reduction in the score by at least 50 percent from base line and a score of 15 or less. Raters were unaware of the patients' treatment assignments. Results Of the 681 patients, 662 attended at least one treatment session and were included in the analysis of response. The overall rate of response ...

Vancomycin-resistant enterococci.

Abstract: After they were first identified in the mid-1980s, vancomycin-resistant enterococci (VRE) spread rapidly and became a major problem in many institutions both in Europe and the United States. Since VRE have intrinsic resistance to most of the commonly used antibiotics and the ability to acquire resistance to most of the current available antibiotics, either by mutation or by receipt of foreign genetic material, they have a selective advantage over other microorganisms in the intestinal flora and pose a major therapeutic challenge. The possibility of transfer of vancomycin resistance genes to other gram-positive organisms raises significant concerns about the emergence of vancomycin-resistant Staphylococcus aureus. We review VRE, including their history, mechanisms of resistance, epidemiology, control measures, and treatment.

Importance of Zinc in the Central Nervous System: The Zinc-Containing Neuron

Abstract: Zinc is essential to the structure and function of myriad proteins, including regulatory, structural and enzymatic. It is estimated that up to 1% of the human genome codes for zinc finger proteins. In the central nervous system, zinc has an additional role as a neurosecretory product or cofactor. In this role, zinc is highly concentrated in the synaptic vesicles of a specific contingent of neurons, called "zinc-containing" neurons. Zinc-containing neurons are a subset of glutamatergic neurons. The zinc in the vesicles probably exceeds 1 mmol/L in concentration and is only weakly coordinated with any endogenous ligand. Zinc-containing neurons are found almost exclusively in the forebrain, where in mammals they have evolved into a complex and elaborate associational network that interconnects most of the cerebral cortices and limbic structures. Indeed, one of the intriguing aspects of these neurons is that they compose somewhat of a chemospecific "private line" of the mammalian cerebral cortex. The present review outlines (1) the methods used to discover, define and describe zinc-containing neurons; (2) the neuroarchitecture and synaptology of zinc-containing neural circuits; (3) the physiology of regulated vesicular zinc release; (4) the "life cycle" and molecular biology of vesicular zinc; (5) the importance of synaptically released zinc in the normal and pathological processes of the cerebral cortex; and (6) the role of specific and nonspecific stressors in the release of zinc.

Sensitivity of Human Immunodeficiency Virus Type 1 to the Fusion Inhibitor T-20 Is Modulated by Coreceptor Specificity Defined by the V3 Loop of gp120

Abstract: T-20 is a synthetic peptide that potently inhibits replication of human immunodeficiency virus type 1 by interfering with the transition of the transmembrane protein, gp41, to a fusion active state following interactions of the surface glycoprotein, gp120, with CD4 and coreceptor molecules displayed on the target cell surface. Although T-20 is postulated to interact with an N-terminal heptad repeat within gp41 in a trans-dominant manner, we show here that sensitivity to T-20 is strongly influenced by coreceptor specificity. When 14 T-20-naive primary isolates were analyzed for sensitivity to T-20, the mean 50% inhibitory concentration (IC50) for isolates that utilize CCR5 for entry (R5 viruses) was 0.8 log10 higher than the mean IC50 for CXCR4 (X4) isolates (P = 0.0055). Using NL4.3-based envelope chimeras that contain combinations of envelope sequences derived from R5 and X4 viruses, we found that determinants of coreceptor specificity contained within the gp120 V3 loop modulate this sensitivity to T-20. The IC50 for all chimeric envelope viruses containing R5 V3 sequences was 0.6 to 0.8 log10 higher than that for viruses containing X4 V3 sequences. In addition, we confirmed that the N-terminal heptad repeat of gp41 determines the baseline sensitivity to T-20 and that the IC50 for viruses containing GIV at amino acid residues 36 to 38 was 1.0 log10 lower than the IC50 for viruses containing a G-to-D substitution. The results of this study show that gp120-coreceptor interactions and the gp41 N-terminal heptad repeat independently contribute to sensitivity to T-20. These results have important implications for the therapeutic uses of T-20 as well as for unraveling the complex mechanisms of virus fusion and entry.

Protein kinase C isozymes and the regulation of diverse cell responses

Abstract: Individual protein kinase C (PKC) isozymes have been implicated in many cellular responses important in lung health and disease, including permeability, contraction, migration, hypertrophy, proliferation, apoptosis, and secretion. New ideas on mechanisms that regulate PKC activity, including the identification of a novel PKC kinase, 3-phosphoinositide-dependent kinase-1 (PDK-1), that regulates phosphorylation of PKC, have been advanced. The importance of targeted translocation of PKC and isozyme-specific binding proteins (like receptors for activated C-kinase and caveolins) is well established. Phosphorylation state and localization are now thought to be key determinants of isozyme activity and specificity. New concepts on the role of individual PKC isozymes in proliferation and apoptosis are emerging. Opposing roles for selected isozymes in the same cell system have been defined. Coupling to the Wnt signaling pathway has been described. Phenotypes for PKC knockout mice have recently been reported. More specific approaches for studying PKC isozymes and their role in cell responses have been developed. Strengths and weaknesses of different experimental strategies are reviewed. Future directions for investigation are identified.

DNA-bound structures and mutants reveal abasic DNA binding by APE1 DNA repair and coordination

Abstract: Non-coding apurinic/apyrimidinic (AP) sites in DNA are continually created in cells both spontaneously and by damage-specific DNA glycosylases. The biologically critical human base excision repair enzyme APE1 cleaves the DNA sugar-phosphate backbone at a position 5' of AP sites to prime DNA repair synthesis. Here we report three co-crystal structures of human APE1 bound to abasic DNA which show that APE1 uses a rigid, pre-formed, positively charged surface to kink the DNA helix and engulf the AP-DNA strand. APE1 inserts loops into both the DNA major and minor grooves and binds a flipped-out AP site in a pocket that excludes DNA bases and racemized beta-anomer AP sites. Both the APE1 active-site geometry and a complex with cleaved AP-DNA and Mn2+ support a testable structure-based catalytic mechanism. Alanine substitutions of the residues that penetrate the DNA helix unexpectedly show that human APE1 is structurally optimized to retain the cleaved DNA product. These structural and mutational results show how APE1 probably displaces bound glycosylases and retains the nicked DNA product, suggesting that APE1 acts in vivo to coordinate the orderly transfer of unstable DNA damage intermediates between the excision and synthesis steps of DNA repair.

A Randomized, Placebo-Controlled 12-Month Trial of Divalproex and Lithium in Treatment of Outpatients With Bipolar I Disorder

Abstract: Background Long-term outcomes are often poor in patients with bipolar disorder despite treatment; more effective treatments are needed to reduce recurrences and morbidity. This study compared the efficacy of divalproex, lithium, and placebo as prophylactic therapy. Methods A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted over a 52-week maintenance period. Patients who met the recovery criteria within 3 months of the onset of an index manic episode (n=372) were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2:1:1 ratio. Psychotropic medications were discontinued before randomization, except for open-label divalproex or lithium, which were gradually tapered over the first 2 weeks of maintenance treatment. The primary outcome measure was time to recurrence of any mood episode. Secondary measures were time to a manic episode, time to a depressive episode, average change from baseline in Schedule for Affective Disorders and Schizophrenia–Change Version subscale scores for depression and mania, and Global Assessment of Function scores. Results The divalproex group did not differ significantly from the placebo group in time to any mood episode. Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis in the study and less deterioration in depressive symptoms and Global Assessment Scale scores. Conclusions The treatments did not differ significantly on time to recurrence of any mood episode during maintenance therapy. Patients treated with divalproex had better outcomes than those treated with placebo or lithium on several secondary outcome measures.

Hematogenous pyogenic spinal infections and their surgical management.

Abstract: Study design Mainly a retrospective study of 101 cases of pyogenic spinal infection, excluding postoperative infections. Data were obtained through medical record review, imaging examination, and patient follow-up evaluation. Summary of background data Hematogenous pyogenic spinal infection has been described variously as spondylodiscitis, discitis, vertebral osteomyelitis, and epidural abscess. Recommended treatment options have included conservative methods (antibiotics and bracing) and surgical intervention. However, a comprehensive classification that would aid in diagnosis, treatment planning, and prognosis has not yet been devised. Objectives To analyze the bacteriology, pathologic entities, complications, and results of treatment options for pyogenic spinal infection. Method All patients received plain radiographs, gadolinium-enhanced magnetic resonance imaging scans, and bone/gallium radionuclide studies. All patients had tissue biopsies. Bacteriology, hematology, and predisposing factors were analyzed. All patients received intravenous and oral antibiotics. A total of 58 patients underwent surgery. Patient outcomes were correlated with clinical status, with treatment method and, where applicable, with location and nature of epidural compression. Statistical analyses were performed. Results Spondylodiscitis occurred most commonly with primary epidural abscess, spondylitis, discitis, and pyogenic facet arthropathy, all occurring rarely. Staphylococcus aureus was the main organism. Infection elsewhere was the most common predisposing factor. Leukocyte counts were elevated in 42.6% of spondylodiscitis cases. The erythrocyte sedimentation rate was elevated in all cases of epidural abscess. There were 35 cases of epidural abscess (frank abscess, 29; granulation tissue, 6). Epidural abscess complicating spondylodiscitis occurred most often in the cervical spine, followed by thoracic and lumbar areas. The rate of paraplegia or paraparesis also was highest in cervical and thoracic regions. There were no cases of quadriplegia. All patients with either epidural granulation tissue or paraparesis recovered completely after surgical decompression. Only 18% of patients with frank epidural abscess and 23% of patients with paralysis recovered completely after surgical decompression. Patients with spondylodiscitis who were treated nonsurgically reported residual back pain more often (64%) than patients treated surgically (26.3%). Conclusions Pyogenic spinal infection can be thought of as a spectrum of disease comprising spondylitis, discitis, spondylodiscitis, pyogenic facet arthropathy, and epidural abscess. Spondylodiscitis is more prone to develop epidural abscesses in the cervical spine (90%) than the thoracic (33.3%) or lumbar (23.6%) areas. Thecal sac neurocompression has a greater chance of causing neurologic deficit in the thoracic spine (81.8%). Treatment of neurologic deficit caused by epidural abscess is prompt surgical decompression, with or without fusion. Patients with frank abscess had less favorable outcomes than those with granulation tissue, and paraplegia responded to treatment more poorly than paraparesis. Surgery was preferable to nonsurgical treatment for improving back pain.

History and evolution of the monoamine hypothesis of depression

Abstract: The symptoms of depression can be improved by agents that act by various mechanisms to increase synaptic concentrations of monoamines. This finding led to the adoption of the monoamine hypothesis of depression, first put forward over 30 years ago, which proposes that the underlying biological or neuroanatomical basis for depression is a deficiency of central noradrenergic and/or serotonergic systems and that targeting this neuronal lesion with an antidepressant would tend to restore normal function in depressed patients. The hypothesis has enjoyed considerable support, since it attempts to provide a pathophysiologic explanation of the actions of antidepressants. However, in its original form it is clearly inadequate, as it does not provide a complete explanation for the actions of antidepressants, and the pathophysiology of depression itself remains unknown. The hypothesis has evolved over the years to include, for example, adaptive changes in receptors to explain why there should be only a gradual clinical response to antidepressant treatment when the increase in availability of monoamines is rapid. Still, the monoamine hypothesis does not address key issues such as why antidepressants are also effective in other disorders such as panic disorder, obsessive-compulsive disorder, and bulimia, or why all drugs that enhance serotonergic or noradrenergic transmission are not necessarily effective in depression. Despite these limitations, however, it is clear that the development of the monoamine hypothesis has been of great importance in understanding depression and in the development of safe and effective pharmacologic agents for its treatment.

Re-emergence of Chikungunya and O'nyong-nyong viruses: evidence for distinct geographical lineages and distant evolutionary relationships.

Abstract: Chikungunya (CHIK) virus is a member of the genus Alphavirus in the family Togaviridae. Serologically, it is most closely related to o’nyong-nyong (ONN) virus and is a member of the Semliki Forest antigenic complex. CHIK virus is believed to be enzootic throughout much of Africa and historical evidence indicates that it spread to other parts of the world from this origin. Strains from Africa and Asia are reported to differ biologically, indicating that distinct lineages may exist. To examine the relatedness of CHIK and ONN viruses using genetic data, we conducted phylogenetic studies on isolates obtained throughout Africa and Southeast Asia. Analyses revealed that ONN virus is indeed distinct from CHIK viruses, and these viruses probably diverged thousands of years ago. Two distinct CHIK virus lineages were delineated, one containing all isolates from western Africa and the second comprising all southern and East African strains, as well as isolates from Asia. Phylogenetic trees corroborated historical evidence that CHIK virus originated in Africa and subsequently was introduced into Asia. Within the eastern Africa and southern Africa/Asia lineage, Asian strains grouped together in a genotype distinct from the African groups. These different geographical genotypes exhibit differences in their transmission cycles: in Asia, the virus appears to be maintained in an urban cycle with Aedes aegypti mosquito vectors, while CHIK virus transmission in Africa involves a sylvatic cycle, primarily with Ae. furcifer and Ae. africanus mosquitoes.

The disease spectrum of Helicobacter pylori: the immunopathogenesis of gastroduodenal ulcer and gastric cancer.

Abstract: Helicobacter pylori is a gram-negative bacterium that resides under microaerobic conditions in a neutral microenvironment between the mucus and the superficial epithelium of the stomach. From this site, it stimulates cytokine production by epithelial cells that recruit and activate immune and inflammatory cells in the underlying lamina propria, causing chronic, active gastritis. Although epidemiological evidence shows that infection generally occurs in children, the inflammatory changes progress throughout life. H. pylori has also been recognized as a pathogen that causes gastroduodenal ulcers and gastric cancer. These more severe manifestations of the infection usually occur later in life and in a minority of infected subjects. To intervene and protect those who might be at greatest risk of the more severe disease outcomes, it is of great interest to determine whether bacterial, host, or environmental factors can be used to predict these events. To date, several epidemiological studies have attempted to define the factors affecting the transmission of H. pylori and the expression of gastroduodenal disease caused by this infection. Many other laboratories have focused on identifying bacterial factors that explain the variable expression of clinical disease associated with this infection. An alternative hypothesis is that microorganisms that cause lifelong infections can ill afford to express virulence factors that directly cause disease, because the risk of losing the host is too great. Rather, we propose that gastroduodenal disease associated with H. pylori infection is predominantly a result of inappropriately regulated gastric immune responses to the infection. In this model, the interactions between the immune/inflammatory response, gastric physiology, and host repair mechanisms would dictate the disease outcome in response to infection.

Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice

Abstract: Obesity is a disorder of energy balance. Hormone-sensitive lipase (HSL) mediates the hydrolysis of triacylglycerol, the major form of stored energy in the body. Perilipin (encoded by the gene Plin), an adipocyte protein, has been postulated to modulate HSL activity. We show here that targeted disruption of Plin results in healthy mice that have constitutively activated fat-cell HSL. Plin -/- mice consume more food than control mice, but have normal body weight. They are much leaner and more muscular than controls, have 62% smaller white adipocytes, show elevated basal lipolysis that is resistant to beta-adrenergic agonist stimulation, and are cold-sensitive except when fed. They are also resistant to diet-induced obesity. Breeding the Plin -/- alleles into Leprdb/db mice reverses the obesity by ncreasing the metabolic rate of the mice. Our results demonstrate a role for perilipin in reining in basal HSL activity and regulating lipolysis and energy balance; thus, agents that inactivate perilipin may prove useful as anti-obesity medications.

An oral essential amino acid-carbohydrate supplement enhances muscle protein anabolism after resistance exercise

Abstract: This study was designed to determine the response of muscle protein to the bolus ingestion of a drink containing essential amino acids and carbohydrate after resistance exercise. Six subjects (3 me...

Social functioning in depression: a review

Abstract: OBJECTIVE: This article reviews the available data on social functioning in depression and provides clinical guidelines and opinion on this important and expanding field. DATA SOURCES: A MEDLINE search was conducted to identify all English-language articles (1988-1999) using the search terms depression and social functioning, depression and social adjustment, depression and psychosocial functioning, and social functioning and antidepressant. Further articles were obtained from the bibliographies of relevant articles. DATA SYNTHESIS: Depressive disorders are frequently associated with significant and pervasive impairments in social functioning, often substantially worse than those experienced by patients with other chronic medical conditions. The enormous personal, social, and economic impact of depression, due in no small part to the associated impairments in social functioning, is often underappreciated. Both pharmacologic and psychotherapeutic approaches can improve social impairments, although there is a lack of extended, randomized controlled trials in this area using consistent assessment criteria. CONCLUSION: Despite this lack, it is becoming clear that not all treatments are equally effective in relieving the impaired social functioning associated with depressive disorders. Furthermore, efficacy in relieving the core symptoms of depression does not necessarily guarantee efficacy in relieving impaired social functioning.

The Response of Muscle Protein Anabolism to Combined Hyperaminoacidemia and Glucose-Induced Hyperinsulinemia Is Impaired in the Elderly

Abstract: Muscle mass declines with aging. Amino acids alone stimulate muscle protein synthesis in the elderly. However, mixed nutritional supplementation failed to improve muscle mass. We hypothesized that the failure of nutritional supplements is due to altered responsiveness of muscle protein anabolism to increased amino acid availability associated with endogenous hyperinsulinemia. We measured muscle protein synthesis and breakdown, and amino acid transport in healthy young (30 ± 3 yr) and elderly (72 ± 1 yr) volunteers in the basal postabsorptive state and during the administration of an amino acid-glucose mixture, using l-[ring-2H5]phenylalanine infusion, femoral artery and vein catheterization, and muscle biopsies. Basal muscle amino acid turnover was similar in young and elderly subjects. The mixture increased phenylalanine leg delivery and transport into the muscle in both groups. Phenylalanine net balance increased in both groups (young, −27 ± 8 to 64 ± 17; elderly, −16 ± 4 to 29 ± 7 nmol/(min·100 mL); P ...

Emotional well-being predicts subsequent functional independence and survival.

Abstract: OBJECTIVE: To determine whether positive affect has an independent effect on functional status, mobility, and survival in an older Mexican American sample DESIGN: A 2-year prospective cohort study SETTING: Five Southwestern states: Texas, California, Arizona, New Mexico, and Colorado PARTICPANTS: A population-based sample of 2282 Mexican Americans aged 65 to 99 who reported no functional limitations at baseline interview MEASUREMENTS: In-home interviews in 1993–1994 and again in 1995–1996 assessed demographic variables, health conditions, activities of daily living, performance-based mobility, survival, and a rating of positive and negative affect RESULTS: In multivariate analyses, there was a direct relationship between positive affect scores at baseline and mobility, functional status, and survival 2 years later, controlling for functional status, sociodemographic variables, major chronic conditions, body mass index (BMI), smoking status, drinking status, and negative affect at baseline Subjects with high positive affect were half as likely (odds ratio (OR) = 048; 95% confidence interval (CI) 029, 093) to become disabled in activities of daily living (ADLs), two-thirds as likely (OR = 064; 95% CI 051, 079) to have a slow walking speed, and half as likely (OR 053; 95% CI 030, 093) to have died during the 2-year follow-up compared to those with lower positive affect scores CONCLUSIONS: Our results support the concept that positive affect, or emotional well-being, is different from the absence of depression or negative affect Positive affect seems to protect individuals against physical declines in old age J Am Geriatr Soc 48: 473–478, 2000

Hydrogen Peroxide– and Peroxynitrite-Induced Mitochondrial DNA Damage and Dysfunction in Vascular Endothelial and Smooth Muscle Cells

Abstract: The mechanisms by which reactive species (RS) participate in the development of atherosclerosis remain incompletely understood. The present study was designed to test the hypothesis that RS produced in the vascular environment cause mitochondrial damage and dysfunction in vitro and, thus, may contribute to the initiating events of atherogenesis. DNA damage was assessed in vascular cells exposed to superoxide, hydrogen peroxide, nitric oxide, and peroxynitrite. In both vascular endothelial and smooth muscle cells, the mitochondrial DNA (mtDNA) was preferentially damaged relative to the transcriptionally inactive nuclear beta-globin gene. Similarly, a dose-dependent decrease in mtDNA-encoded mRNA transcripts was associated with RS treatment. Mitochondrial protein synthesis was also inhibited in a dose-dependent manner by ONOO(-), resulting in decreased cellular ATP levels and mitochondrial redox function. Overall, endothelial cells were more sensitive to RS-mediated damage than were smooth muscle cells. Together, these data link RS-mediated mtDNA damage, altered gene expression, and mitochondrial dysfunction in cell culture and reveal how RS may mediate vascular cell dysfunction in the setting of atherogenesis.

Nucleotide excision repair in yeast.

Abstract: In nucleotide excision repair (NER) in eukaryotes, DNA is incised on both sides of the lesion, resulting in the removal of a fragment approximately 25-30 nucleotides long. This is followed by repair synthesis and ligation. The proteins encoded by the various yeast NER genes have been purified, and the incision reaction reconstituted in vitro. This reaction requires the damage binding factors Rad14, RPA, and the Rad4-Rad23 complex, the transcription factor TFIIH which contains the two DNA helicases Rad3 and Rad25, essential for creating a bubble structure, and the two endonucleases, the Rad1-Rad10 complex and Rad2, which incise the damaged DNA strand on the 5'- and 3'-side of the lesion, respectively. Addition of the Rad7-Rad16 complex to this reconstituted system stimulates the incision reaction many fold. The various NER proteins exist in vivo as part of multiprotein subassemblies which have been named NEFs (nucleotide excision repair factors). Rad14 and Rad1-Rad10 form one subassembly called NEF1, the Rad4-Rad23 complex is named NEF2, Rad2 and TFIIH constitute NEF3, and the Rad7-Rad16 complex is called NEF4. Although much has been learned from yeast about the function of NER genes and proteins in eukaryotes, the underlying mechanisms by which damage is recognized, NEFs are assembled at the damage site, and the DNA is unwound and incised, remain to be elucidated.

Evolutionary Relationships of Endemic/Epidemic and Sylvatic Dengue Viruses

Abstract: Dengue viruses (DEN) (Flaviviridae: Flavivirus) are serious human pathogens that occur nearly throughout the tropics, with ca. 100 million cases annually (16). DEN comprise four serotypes (DEN-1 to DEN-4); although epidemiologically similar, they are genetically and antigenically distinct. Infection with one serotype leads to lifelong protection against homologous reinfection but only brief protection against heterologous challenge (21, 38). DEN cause dengue fever, a self-limited febrile illness lasting 2 to 10 days that has been known in the medical literature for over 200 years. Infrequent epidemics of dengue fever occurred in tropical areas until the 1950s. After War World II, this pattern of disease was disrupted by the emergence of dengue hemorrhagic fever and dengue shock syndrome, more severe diseases characterized by thrombocytopenia, hemorrhage, and excessive plasma leakage (16, 28). Two principal hypotheses have been proposed to explain the hemorrhagic form of disease: (i) the immune enhancement theory maintains that hemorrhage occurs in secondary infections when DEN-specific antibodies and memory T cells resulting from primary infection with another serotype enhance the binding of virus-immunoglobulin G complexes to FcY receptors on monocytic cells, and (ii) certain phenotypes of DEN are more virulent than others. Recent phylogenetic studies suggest that an Asian genotype of DEN-2 recently introduced into the New World may be associated with increased risk for hemorrhagic fever and shock in the presence of heterologous antibody (32). DEN strains of reduced virulence have also been described; endemic transmission on the South Pacific islands of Tonga, involving vectors other than Aedes aegypti, may result in less severe disease because of the lesser selection for high viremia imposed by more susceptible vectors, like Aedes polynesiensis (13). Two distinct DEN transmission cycles occur: (i) endemic and epidemic DEN involving human hosts and transmission by A. aegypti, with Aedes albopictus and other Aedes mosquitoes serving as secondary vectors, and (ii) a zoonotic or sylvatic cycle in sylvatic habitats of Africa and Malaysia, involving nonhuman primate reservoir hosts and several different Aedes mosquitoes (12, 16). Although A. aegypti plays a greater role in urban transmission, A. albopictus and some other secondary Aedes vectors are generally more susceptible to experimental infection (12). Considerable variation in susceptibility and transmission efficiency among geographic populations of both A. aegypti and A. albopictus has also been demonstrated (14, 15). A. aegypti has reinfested most of the neotropics since its partial eradication earlier this century, resulting in reemergence of neotropical dengue (13). The sylvatic transmission cycles of DEN have received little study. In West Africa, nonhuman primate cycles have been identified in several countries. DEN-2 has been isolated from Aedes (S.) africanus, Aedes (S.) leuteocephalus, Aedes (S.) opok, Aedes (D.) taylori, and Aedes (D.) furcifer (5, 33). African DEN-2 sylvatic isolates are genetically distinct from all endemic/epidemic isolates and are believed to be evolutionarily distinct (12, 16, 31). In Malaysia, all four serotypes of DEN are maintained in canopy-dwelling Aedes niveus mosquitoes and nonhuman primates (34–37). DEN-1, -2, and -4 were isolated from sentinel monkeys, and monkey seroconversion was demonstrated against DEN-1, -2, and -3. DEN-4 was also isolated from canopy collections of A. niveus mosquitoes (35). Gubler (13) has hypothesized that endemic/epidemic DEN evolved from sylvatic forms of the viruses that utilize nonhuman primate hosts and gallery forest Aedes vectors (i.e., not A. aegypti or A. albopictus). To test this hypothesis, we have sequenced the complete envelope (E) protein gene of DEN-1, -2, and -4 strains isolated in primary tropical forest habitats in Malaysia by Albert Rudnick and colleagues during the 1960s and 1970s (36, 37), as well as DEN-2 strains from sylvatic locations in West Africa analyzed previously using other, smaller genome regions (31). Phylogenetic analyses indicated that the endemic/epidemic lineages of DEN-1, -2, and -4 evolved independently from sylvatic viruses circulating in the Asian-Oceania region. Estimates of divergence times suggested that emergences of endemic/epidemic DEN occurred on the order of 100 to 1,500 years ago.

Early Maternal and Child Influences on Children's Later Independent Cognitive and Social Functioning

Abstract: The present study examined whether parenting and child characteristics of 2- and 3 Ω -year-old children had common paths of influence on their 4 Ω -year independent cognitive and social functioning. Structural equation modeling was guided by hypotheses that assumed children’s later independence is facilitated by specialized parental support in early social interactions. To address the importance of variability in early development for understanding children’s later independence, we included 104 term and 185 preterm children, as they are known to differ in early skills. As predicted, mothers’ maintaining of children’s interests indirectly supported 4 Ω -year cognitive and social independence through a direct, positive influence on 2- and 3 Ω -year skills. Directiveness positively supported children’s early cognitive and responsiveness skills but by 3 Ω years, high levels of this behavior had a direct, negative influence on their cognitive and social independence at 4 Ω years. Whereas high levels of maintaining interests across these ages support later independence, directiveness needs to decrease in relation to children’s increasing competencies. Results support a theoretical framework that emphasizes the importance of the social context for understanding the origins of children’s later independent functioning.

Acute coronary findings at autopsy in heart failure patients with sudden death: results from the assessment of treatment with lisinopril and survival (ATLAS) trial.

Abstract: Background—Sudden unexpected death frequently occurs in chronic heart failure. The importance of acute coronary events in triggering sudden death (SD) is unclear. Methods and Results—We evaluated at autopsy the prevalence of acute coronary findings (coronary thrombus, ruptured plaque, or myocardial infarction [MI]) and their relation to SD. Autopsy results in 171 patients in the randomized ATLAS trial were reviewed. The prevalence of acute coronary findings was 33%: in 54% of patients with significant coronary artery disease (CAD) who died suddenly, 32% who died of myocardial failure, but in non-CAD patients, they were present in only 5% and 10% respectively. The percentage of patients classified as dying of MI was 28% in the autopsy group versus 4% in the nonautopsied group (P<0.0001). Of the autopsied group with acute MI, 97% (31 of 32 patients) with SD and 40% (6 of 15 patients) with myocardial failure did not have the MI diagnosed during life. When undiagnosed MI was classified as “sudden unexpected” ...

Efficient and accurate replication in the presence of 7,8-dihydro-8-oxoguanine by DNA polymerase η

Abstract: Oxidative damage to DNA has been proposed to have a role in cancer and ageing1. Oxygen-free radicals formed during normal aerobic cellular metabolism attack bases in DNA, and 7,8-dihydro-8-oxoguanine (8-oxoG) is one of the adducts formed2,3. Eukaryotic replicative DNA polymerases replicate DNA containing 8-oxoG by inserting an adenine opposite the lesion4; consequently, 8-oxoG is highly mutagenic and causes G:C to T:A transversions5. Genetic studies in yeast have indicated a role for mismatch repair in minimizing the incidence of these mutations. In Saccharomyces cerevisiae, deletion of OGG1, encoding a DNA glycosylase that functions in the removal of 8-oxoG when paired with C, causes an increase in the rate of G:C to T:A transversions6. The ogg1Δ msh2Δ double mutant displays a higher rate of CAN1S to can1r forward mutations than the ogg1Δ or msh2Δ single mutants, and this enhanced mutagenesis is primarily due to G:C to T:A transversions7. The gene RAD30 of S. cerevisiae encodes a DNA polymerase, Polη, that efficiently replicates DNA containing a cis-syn thymine-thymine (T-T) dimer by inserting two adenines across from the dimer8. In humans, mutations in the yeast RAD30 counterpart, POLH, cause the variant form of xeroderma pigmentosum9,10 (XP-V), and XP-V individuals suffer from a high incidence of sunlight-induced skin cancers. Here we show that yeast and human POLη replicate DNA containing 8-oxoG efficiently and accurately by inserting a cytosine across from the lesion and by proficiently extending from this base pair. Consistent with these biochemical studies, a synergistic increase in the rate of spontaneous mutations occurs in the absence of POLη in the yeast ogg1Δ mutant. Our results suggest an additional role for Polη in the prevention of internal cancers in humans that would otherwise result from the mutagenic replication of 8-oxoG in DNA.