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A Blank

Publications and source records attributed to A Blank.

At least 37 records · Page 2Linked to original sources
PubMed1997

Posttraumatic stress disorder in a community group of former prisoners of war: a normative response to severe trauma.

OBJECTIVE: The goal of this study was to assess and describe the long-term impact of traumatic prisoner of war (POW) experiences within the context of posttraumatic psychopathology. Specifically, the authors attempted to investigate the relative degree of normative response represented by posttraumatic stress disorder (PTSD) in comparison to other DSM axis I disorders often found to be present, either alone or concomitant with other disorders, in survivors of trauma. METHOD: A community group of 262 U.S. World War II and Korean War former POWs was recruited. These men had been exposed to the multiple traumas of combat, capture, and imprisonment, yet few had ever sought mental health treatment. They were assessed for psychopathology with diagnostic interviews and psychodiagnostic testing. Regression analyses were used to assess the contributions of age at capture, war trauma, and postwar social support to PTSD and the other diagnosed disorders. RESULTS: More than half of the men (53%) met criteria for lifetime PTSD, and 29% met criteria for current PTSD. The most severely traumatized group (POWs held by the Japanese) had PTSD lifetime rates of 84% and current rates of 59%. Fifty-five percent of those with current PTSD were free from the other current axis I disorders (uncomplicated PTSD). In addition, 34% of those with lifetime PTSD had PTSD as their only lifetime axis I diagnosis. Regression analyses indicated that age at capture, severity of exposure to trauma, and postmilitary social support were moderately predictive of PTSD and only weakly predictive of other disorders. CONCLUSIONS: These findings indicate that PTSD is a persistent, normative, and primary consequence of exposure to severe trauma.

Age Factors↗
PubMed1996

Lack of the DNA repair protein O6-methylguanine-DNA methyltransferase in histologically normal brain adjacent to primary human brain tumors.

Exposure to exogenous alkylating agents, particularly N-nitroso compounds, has been associated with increased incidence of primary human brain tumors, while intrinsic risk factors are currently unknown. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a major defense against the carcinogenicity of N-nitroso compounds and other alkylators. We report here that in 55% (64/117) of cases, histologically normal brain tissue adjacent to primary human brain tumors lacked detectable MGMT activity [methyl excision repair-defective (Mer-) status]. The incidence of Mer- status in normal brain tissue from brain tumor patients was age-dependent, increasing from 21% in children 0.25-19 years of age to 75% in adults over 50. In contrast, Mer- status was found in 12% (5/43) of normal brain specimens from patients operated for conditions other than primary brain tumors and was not age-dependent. The 4.6-fold elevation in incidence of Mer- status in brain tumor patients is highly significant (chi2 = 24; p < or = 0.001). MGMT activity was independent of age in the lymphocytes of brain tumor patients and was present in lymphocytes from six of nine tumor patients whose normal brain specimen was Mer-. DNA polymerase beta, apurinic/apyrimidinic endonuclease, and lactate dehydrogenase activities were present in all specimens tested, including Mer- specimens from brain tumor patients. Our data are consistent with a model of carcinogenesis in human brain in which epigenetically regulated lack of MGMT is a predisposing factor and alkylation-related mutagenesis is a driving force.

Adolescent↗
PubMed1996

Role of O6-methylguanine-DNA methyltransferase in resistance of human brain tumor cell lines to the clinically relevant methylating agents temozolomide and streptozotocin.

We have analyzed the sensitivity of 14 human medulloblastoma- and glioma-derived cell lines to the clinically used methylating agents temozolomide and streptozotocin. The cell lines responded similarly to these agents, displaying a 3-fold range in cytotoxicity, assessed as the 10% survival dose (LD10). The contribution of O6-methylguanine-DNA methyltransferase (MGMT) to resistance, measured as reduction in the LD10 by O6-benzylguanine (O6-BG), varied among the lines by 1 order of magnitude for both agents. However, in all MGMT-expressing lines, O6-BG eliminated a threshold dose that accounted for up to one-half of the LD10. The effect of O6-BG on the rate of killing varied 13-fold for temozolomide and 14-fold for streptozotocin. Some lines displayed two subpopulations with different rates of killing, with one subpopulation that comprised 20-60% of cells showing essentially no dependence of the rate of killing on MGMT. O6-BG increased the range of the LD10 for both agents. The persistent, heightened variability in cytotoxicity in the absence of MGMT, the lack of correlation between MGMT content of the lines and cytoxicity (LD10), and the lack of correlation between MGMT content and the contribution of MGMT to resistance (O6-BG-mediated reduction of the LD10) reflect the operation of resistance mechanisms other than MGMT. We also analyzed sensitivity to methyl methanesulfonate, observing little dependence of resistance on MGMT and persistent variability in cytotoxicity in the presence of O6-BG. We discuss the implications for clinical use of methylators and O6-BG.

Antineoplastic Agents, Alkylating↗
PubMed1995

Ethnic segregation of HTLV-I and HTLV-II carriers among South American native Indians.

To investigate the genetic background of human T-cell leukemia virus type I (HTLV-I) and II (HTLV-II) carriers among South American native Indians, we analyzed HLA DRB1*-DQB1* haplotypes of the virus carriers from Andes highlands and Orinoco lowlands by the PCR-RFLP genotyping method. It was revealed that the HTLV-I-carrying Andes natives had one of the 5 HLA haplotypes: DRB1*-DQB1* 0403-0302, 0802-0402, 0901-0303, 1406-0302 and 0407-0302, and that the Orinoco HTLV-II carriers had one of the 3 HLA haplotypes: DRB1*-DQB1* 1402-0301, 1602-0301 and 0404-0302. The HLA haplotypes of Andes HTLV-I carriers and Orinoco HTLV-II carriers were mutually exclusive. The haplotypes associated with HTLV-I carriers were commonly found among the Andes Indians and Japanese, which is the known HTLV-I endemic population, while the haplotypes associated with HTLV-II carriers were specifically found among the Orinoco Indians and North American Indians, among whom HTLV-II is endemic. These results suggested that HLA haplotypes might be ethnically segregated among South American natives and might be involved in the susceptibility to HTLV-I and HTLV-II infections.

Alleles↗
PubMed1995

Contribution of O6-methylguanine-DNA methyltransferase to monofunctional alkylating-agent resistance in human brain tumor-derived cell lines.

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) has been implicated in resistance of human brain tumors to alkylating agents. We observed that 14 human medulloblastoma- and glioma-derived cell lines differ in sensitivity to the methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), as shown by their 28-fold range in 10% survival dose (LD10). By using the substrate analogue inhibitor O6-benzylguanine (O6-BG), we showed that the contribution of MGMT to resistance varies widely, as evidenced by 3- to 30-fold reductions in LD10 among the lines, and varies up to 20-fold among subpopulations of individual lines. Importantly, variability in resistance, manifested as a 20-fold range in LD10, persists after measurable MGMT is eliminated, disclosing differential contributions of other resistance mechanisms to survival. Cells exposed to MNNG while suspended in growth medium are more resistant than cells alkylated as subconfluent monolayers, and MGMT accounts for a smaller proportion of their resistance. Notably, the MGMT content of the lines is not statistically correlated with MNNG resistance or with potentiation of killing by O6-BG, even though MGMT is a biochemically demonstrated determinant of resistance. In contrast, the same lines vary less in resistance to the ethylating agent N-ethylnitrosourea (ENU), and MGMT makes only a small contribution to resistance. Our results strongly indicate that resistance to both MNNG and ENU is multifactorial.

Alkylating Agents↗
PubMed1995

Distribution of HLA and haplotypes of Colombian and Jamaican black populations.

To investigate the genetic background of the black populations of Colombia and Jamaica, we determined HLA types of 78 Colombian and 98 Jamaican blacks from 2 different socioeconomic groups (Jamaican #1 and Jamaican #2) and estimated the frequencies of HLA genes and haplotypes. A phylogenetic tree based on the HLA gene frequencies revealed that Jamaican #1 and Jamaican #2 were distinct from each other, Jamaican #1 being closely related to the Colombian blacks and the Jamaican #2 being closely related to Senegalese and Zairean populations. Three-locus HLA haplotypes of Colombian and Jamaican #1 blacks were an admixture between Africans and Caucasians or South American Indians, while Jamaican #2 blacks were relatively homogeneous and appeared to conserve African lineages. The major five-locus HLA haplotypes were not shared among Colombian, Jamaican #1 and Jamaican #2 blacks. These results indicated that the black populations of Colombia and Jamaican were originated from African blacks and admixed variably with Caucasians and South American Indians to make genetic subpopulations in Colombia and Jamaica.

Black People↗
PubMed1994

DNA polymerase delta is required for base excision repair of DNA methylation damage in Saccharomyces cerevisiae.

We present evidence that DNA polymerase delta of Saccharomyces cerevisiae, an enzyme that is essential for viability and chromosomal replication, is also required for base excision repair of exogenous DNA methylation damage. The large catalytic subunit of DNA polymerase delta is encoded by the CDC2(POL3) gene. We find that the mutant allele cdc2-2 confers sensitivity to killing by methyl methanesulfonate (MMS) but allows wild-type levels of UV survival. MMS survival of haploid cdc2-2 strains is lower than wild type at the permissive growth temperature of 20 degrees C. Survival is further decreased relative to wild type by treatment with MMS at 36 degrees C, a nonpermissive temperature for growth of mutant cells. A second DNA polymerase delta allele, cdc2-1, also confers a temperature-sensitive defect in MMS survival while allowing nearly wild-type levels of UV survival. These observations provide an in vivo genetic demonstration that a specific eukaryotic DNA polymerase is required for survival of exogenous methylation damage. MMS sensitivity of a cdc2-2 mutant at 20 degrees C is complemented by expression of mammalian DNA polymerase beta, an enzyme that fills single-strand gaps in duplex DNA in vitro and whose only known catalytic activity is polymerization of deoxyribonucleotides. We conclude, therefore, that the MMS survival deficit in cdc2-2 cells is caused by failure of mutant DNA polymerase delta to fill single-strand gaps arising in base excision repair of methylation damage. We discuss our results in light of current concepts of the physiologic roles of DNA polymerases delta and epsilon in DNA replication and repair.

Alleles↗
PubMed1994

Geographic independence of HTLV-I and HTLV-II foci in the Andes highland, the Atlantic coast, and the Orinoco of Colombia.

To clarify the ethnic specificity of human T cell leukemia virus type I (HTLV-I) and type II (HTLV-II) carriers among Colombian native Indians, we investigated the geographic distribution of HTLV-I and HTLV-II seroprevalence among the isolated ethnic groups of Mongoloid origin in the Andes highlands and the Atlantic coast of Colombia. HTLV-I carriers were found in 1.6% (1/62 samples) of Inga, 8.5% (5/59) of Kamsa, and 0% (0/55) of Cumbal Indians who live in the Andes highlands at 3000 m above sea level. On the other hand, HTLV-II carriers were found in 4.1% (5/123) of Wayuu Indians, who live in the Guajira region of the Atlantic coast of Colombia at a distance of 1000 km from the Andes highlands. This ethnic specificity of HTLV-II was similarly observed among Guahibo Indians in the Orinoco. The seroprevalence of HTLV-I and HTLV-II was mutually exclusive among Inga, Kamsa, and Wayuu Indians. These results suggest that HTLV-I and HTLV-II may have evolved among Mongoloid populations and been independently transmitted among two different lineages of Colombian native Indians, Andes highlanders and Atlantic coast lowlanders.

Adolescent↗
PubMed1994

Maternal and pediatric AIDS in the United States: the current situation and future research directions.

The epidemic of HIV infection and disease in women, adolescents and children represents a complexly intertwined biological and social challenge to health care workers and researchers alike. When considering various issues in confronting this epidemic, women must be viewed as individuals important in their own right, as the primary caretaker of their family members (both infected and uninfected), and as the sexual partners of men who may or may not be infected. Of the myriad of compelling biological questions facing AIDS researchers today, two of the most interesting involve the timing and determinants of vertical transmission and the natural history of HIV infection and disease in women. Scientifically, confronting this epidemic involves research into pathogenesis, epidemiology, natural history, treatment, and prevention of HIV infection. Primary emphasis in the research arena in HIV/AIDS in the United States is focused on therapeutic and prophylactic research. Other research issues are very important, including studies of early diagnostic techniques, behavioral research concerning reproductive choices, the role of breastfeeding in HIV transmission, HIV-specific adolescent issues, and surrogate markers of disease progression.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Increased serum levels of C-terminal parathyroid hormone-related protein in different diseases associated with HTLV-1 infection.

We analyzed the serum levels of C-terminal parathyroid hormone-related protein (C-PTHrP) in asymptomatic carriers of human T lymphotropic virus type 1 (HTLV-1) and patients with three HTLV-1 related diseases; adult T-cell leukemia (ATL), HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and HTLV-1 uveitis (HU). Serum C-PTHrP levels were significantly elevated in HTLV-1-infected individuals, irrespective of whether they were symptomatic or asymptomatic, when compared with that of the seronegative controls. In ATL patients, a good correlation was demonstrated between the serum C-PTHrP level and serum calcium or lactic dehydrogenase (LDH) level. Thus the elevated serum C-PTHrP level could be a characteristic marker of HTLV-1 carrier state, and the determination of its level in ATL patients could be useful for the assessment of the prognosis and as one of the tumor markers. The determination of the serum level of C-PTHrP in various stages of the HTLV-1 carrier state would help to understand the mechanism of the development of hypercalcemia in ATL.

Adult↗
PubMed1993

Mx proteins: GTPases involved in the interferon-induced antiviral state.

Mx proteins have molecular masses between 70 and 80 kDa and their synthesis is tightly regulated by interferons in mammalian and non-mammalian vertebrates. Some Mx proteins function as intracellular mediators of the interferon-induced antiviral state. When suitable cDNA constructs were constitutively expressed in mouse 3T3 cells the mouse nuclear Mx1 protein conferred selective resistance to influenza virus. The human cytoplasmic MxA protein conferred resistance to influenza virus and vesicular stomatitis virus but not to other viruses. Mx1 blocks influenza virus mRNA synthesis within the nucleus of infected cells. Mx1 presumably interacts with the influenza virus polymerase subunit PB2, because overexpression of PB2 titrates out the Mx1 block. MxA does not inhibit mRNA synthesis of influenza virus; it inhibits a subsequent cytoplasmic viral multiplication step. A possible target is the transport of newly synthesized influenza virus polymerase proteins back to the nucleus. Inhibition by MxA of vesicular stomatitis virus, which replicates in the cytoplasm, is at the transcriptional level. Parts of the N-terminal halves of all known Mx proteins are highly conserved. They contain the typical GTP-binding motif and show significant homology to other members of a new family of GTPases that includes rat dynamin, Drosophila Shibire and the yeast proteins Vps1/Spo15 and Mgm1. Purified Mx1 and MxA proteins possess GTPase activity. The GTP/GDP conversion rates are about 40 per min, and Km values about 700 microM. Mx1 and MxA variants with mutations in the GTP-binding sequences that violate the consensus are unable to confer virus resistance in vivo or to hydrolyse GTP in vitro, suggesting that GTPase activity is necessary for antiviral activity of Mx proteins. We hypothesize that the antivirally active Mx proteins (directly or indirectly) bind to polymerase proteins of susceptible viruses, thereby abolishing normal viral polymerase function. Interaction of Mx with viral targets is probably a GTP-dependent process.

Amino Acid Sequence↗
PubMed1993

A functional GTP-binding motif is necessary for antiviral activity of Mx proteins.

Mx proteins are interferon-induced GTPases that inhibit the multiplication of certain negative-stranded RNA viruses. However, it has been unclear whether GTPase activity is necessary for antiviral function. Here, we have introduced mutations into the tripartite GTP-binding consensus elements of the human MxA and mouse Mx1 proteins. The invariant lysine residue of the first consensus motif, which interacts with the beta- and gamma-phosphates of bound GTP in other GTPases, was deleted or replaced by methionine or alanine. These Mx mutants and appropriate controls were then tested for antiviral activity, GTP-binding capacity, and GTPase activity. We found a direct correlation between the GTP-binding capacities and GTP hydrolysis activities of the purified Mx mutants in vitro and their antiviral activities in transfected 3T3 cells, demonstrating that a functional GTP-binding motif is necessary for virus inhibition. Our results, thus, firmly establish antiviral activity as a novel function of a GTPase, emphasizing the enormous functional diversity of GTPase superfamily members.

3T3 Cells↗