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Biomedical subjects

M J Clarke

Publications and source records attributed to M J Clarke.

At least 19 recordsLinked to original sources
PubMed2001

The influence of NO-containing ruthenium complexes on mouse hippocampal evoked potentials in vitro.

The influence of different, nitric oxide-containing ruthenium complexes on the evoked potentials recorded from the CA1 region of the mouse hippocampus in vitro has been investigated. Of the compounds tested, only trans-[(NO)(P(OEt)3)(NH3)4Ru](PF6)3 (1-2.5 mM) exerted a strong facilitatory action on the population spike, the EPSP, and the spontaneous activity. Its activity probably depends upon its ability to release NO following reduction. The phosphito ligand is important both in terms of adjusting the reduction potential of the complex to be biologically accessible and in labilizing the coordinated NO. The effects of this compound could not be reversed by perfusion. Scavenging NO in slices preincubated with oxyhemoglobin prior to the addition of this compound eliminated its neurophysiological effects. The control molecules trans-[(P(OEt)3)2(NH3)4Ru](PF6)2, trans-[(H2O)(P(OEt)3) (NH3)4Ru](PF6)3, and [(NO)(NH3)5Ru]Cl3, which are structurally similar, but unable to generate NO, were ineffective. NaNO2 suppressed neuronal firing. Attempts to induce Long-Term Potentiation (LTP) at the time of maximal effect of trans-[(NO)(P(OEt)3)(NH3)4Ru](PF6)3 were unsuccessful, suggesting that the mechanism of amplification induced by trans-[(NO)(P(OEt)3)(NH3)4Ru](PF6)3 and LTP may share common pathways.

Animals↗
PubMed2001

Terpsichorean movements of pentaammineruthenium on pyrimidine and isocytosine ligands.

Pentaammineruthenium moves on ambidentate nitrogen heterocycles by both rotation and linkage isomerization, which may affect the biological activity of potential ruthenium metallopharmaceuticals. The rapid rotation rates of [(NH3)5RuIII] coordinated to the exocyclic nitrogens of isocytosine (ICyt) and 6-methylisocytosine (6MeICyt) have been determined by 1H NMR. Since these rotamers can be stabilized by hydrogen bonding between the coordinated ammines and the N1 and N3 endocyclic nitrogens, rotamerization is under pH control. Spectrophotometrically (UV-vis) measured pKa values for the two endocyclic sites for the ICyt complex are 2.78 and 9.98, and for 6MeICyt are 3.06 and 10.21, which are probably weighted averages for ionization from N3 and N1, respectively. Activation parameters for the rotamerizations were determined by variable-temperature NMR at pKa1 < pH < pKa2 for the complexes with (ICyt-kappa N2)-, (6MeICyt kappa N2)-, and 2AmPym kappa N2. For [(6MeICyt kappa N2)(-)-(NH3)5RuIII]2+, delta H* = 1.6 kcal/mol, delta S* = -37 cal/mol K, and Ea = 2.2 kcal/mol. Due to strong RuIII-N pi-bonding, the activation enthalpies are approximately 10 kcal lower than the expected values for the free ligands. Rotameric structure is correlated with pKa values, pH-dependent reduction potentials, and 1H NMR parameters. Linkage isomers of [(2AmPym)(NH3)5Ru]n+ are reported in which RuII is coordinated to the endocyclic nitrogen (N1) and RuIII to the exocyclic nitrogen (N2). The rate constant for the kappa N2-->kappa N1 isomerization as part of an ECE mechanism is 3.9 s-1 at pH 3. The pH dependence of the acid-catalyzed hydrolysis of [(2AmPym kappa N1)(NH3)5Ru]2+ is determined.

Catalysis↗
PubMed2001

Cellular effects of transferrin coordinated to.

Estimates of the net equilibrium binding constants for [(H2O)(NH3)5RuII]2+, [Cl(NH3)5RuIII]2+, cis-[(H2O)2(NH3)4RuII]2+ and cis-[Cl2(NH3)4RuIII]+ with apotransferrin (Tf) and holotransferrin (Fe2Tf) suggests that RuIII, but not RuII complexes bind with a higher affinity to the iron binding sites. Several other presumably histidyl imidazole sites bind with approximately the same affinity (Keff = 10(2) to 10(3) M(-1) to both RuII and RuIII. Compared to HeLa cells, an order of magnitude higher level of nuclear DNA binding ([Ru]DNA/[P]DNA) was required to achieve the same level of toxicity in Jurkat Tag cells, which probably relates to the substantially higher levels of cis-[Cl2(NH3)4Ru]+ needed to inhibit 50% of the cell growth in the Jurkat Tag cell line. Against Jurkat Tag cells, the toxicity of the pentaammineruthenium(III) group is enhanced by approximately two orders of magnitude upon binding primarily to the Fe-sites in apotransferrin, whereas the toxicity of the tetraammineruthenium(III) moiety is only marginally increased. Binding to Fe2Tf does not increase the toxicity of either group. Significant dissociation over 24 h of the ammineruthenium(III) ions from apotransferrin requires reduction to RuII.

Antineoplastic Agents↗
PubMed2001

Trends in non-Hodgkin lymphoma (NHL) and HIV-associated NHL deaths in the United States.

Since a significant number of lymphomas have been associated with the human immunodeficiency virus (HIV), the purpose of this study was to describe the impact of HIV infection on non-Hodgkin's lymphoma (NHL) mortality trends and demographics. Multiple-cause-of-death data for the United States from 1979 through 1996 were obtained from the National Center for Health Statistics, Centers for Disease Control and Prevention. Annual NHL deaths rates for the United States were calculated as the number of NHL deaths per 100,000 persons, based on estimates of the U.S. resident population. The time periods 1979-1982, 1986-1989, and 1993-1996 were examined for changes over time. To describe NHL and HIV infection mortality, the characteristics of NHL deaths with HIV infection listed anywhere on the death records were examined beginning in 1987. This study found that despite reports of a lower incidence rate of NHL among blacks with HIV/AIDS, death rates from lymphomas associated with HIV/AIDS have markedly increased in black males and females over time. It was also noted that in agreement with other studies, this study documented a decrease in NHL/HIV mortality in 1996.

Acquired Immunodeficiency Syndrome↗
PubMed2001

The formulation of powder inhalation systems containing a high mass of nedocromil sodium trihydrate.

Nedocromil sodium trihydrate is not amenable to conventional methods of dry powder inhaler formulation, including the preparation of coarse carrier systems and aggregation of the pure drug powder. It is considered that the in vitro aerosol performance of such systems is governed by the cohesive drug-drug interactions. Therefore, alternative powder formulation strategies (novel to nedocromil sodium) were developed. By decreasing the particle size of the lactose carrier, the deaggregation and subsequent fine particle drug deposition were significantly improved. Further improvements were made by selecting and then optimizing high-shear mixing procedures. It was concluded, based on these findings and supportive microscopic studies (low-temperature and environmental scanning electron microscopy together with energy-dispersive X-ray analysis), that the FPL are producing their functional effects by intercalating within the drug self-agglomerates and physically disrupting the cohesive drug-drug interactions. The use of a smaller-sized lactose fraction in conjunction with a blending procedure capable of optimally disrupting the drug self-agglomerates allowed maximal intercalation of the excipient material within the drug self-agglomerates. The adhesive drug-FPL interactions are considered to be weak compared with the cohesive drug-drug particle interactions, cohesive interactions that would normally govern the aerosol performance of powder systems containing a high mass of nedocromil sodium trihydrate.

Aerosols↗
PubMed2001

Effects of HIV infection on age and cause of death for persons with hemophilia A in the United States.

Because of changes in factor replacement therapy and in treatment of human immunodeficiency virus (HIV) infection, we examined death record data for persons with hemophilia A in the United States to evaluate effects of HIV infection on age and causes of death. Multiple cause-of-death data from 1968 through 1998 were examined to assess death rates for persons with hemophilia A. ICD-9 coded causes of death from 1979 through 1998 were examined to assess long-term trends. From 1979 through 1998, 4,781 deaths among persons with hemophilia A were reported, of which 2,254 (47%) had HIV-related disease listed as a cause of death. In the late 1980s, mortality among persons with hemophilia A increased markedly, and the age-adjusted death rate peaked at 1.5 per 1,000,000 population in 1992. Median age at death decreased from 55 years in 1979-1982 to 40.5 years in 1987-1990, and increased to 46 years in 1995-1998. In the period 1995-1998, the median age of hemophilia A decedents with HIV-related disease was 33 years, compared to 72 years for those without HIV-related disease; the most frequently listed causes of death for those without HIV-related disease were hemorrhagic and circulatory phenomena; the most frequently listed for those with HIV-related disease were diseases of liver and the respiratory system. From 1995 to 1998, hemophilia A-associated deaths decreased by 41%, with a 78% decrease among those who had HIV-related disease. Although HIV infection has adversely effected mortality for persons with hemophilia A, the marked recent decrease in the death rate among persons with hemophilia A appears to reflect advances in care for those with HIV-related disease and is consistent with a decline in HIV mortality observed in the general population.

AIDS-Related Opportunistic Infections↗
PubMed2000

Bronchiolitis-associated mortality and estimates of respiratory syncytial virus-associated deaths among US children, 1979-1997.

A 1985 estimate that 4500 respiratory syncytial virus (RSV)-associated deaths occur annually among US children has not been updated using nationally representative data. Thus, 1979-1997 multiple cause-of-death records for children <5 years old listing bronchiolitis, pneumonia, or any respiratory tract disease were examined. Deaths among children associated with any respiratory disease declined from 4631 in 1979 to 2502 in 1997. During the 19-year study period, 1806 bronchiolitis-associated deaths occurred (annual mean, 95 deaths; range, 66-127 deaths). Of these deaths, 1435 (79%) occurred among infants <1 year old. Congenital heart disease, lung disease, or prematurity was listed in death records of 179 (9.9%), 99 (5.5%), and 76 (4.2%) children dying with bronchiolitis, respectively. By applying published proportions of children hospitalized for bronchiolitis or pneumonia who were RSV-infected to bronchiolitis and pneumonia deaths, it was estimated that < or =510 RSV-associated deaths occurred annually during the study period, fewer than previously estimated.

Bronchiolitis↗
PubMed2000

Physicochemical factors governing the performance of nedocromil sodium as a dry powder aerosol.

Previous investigations have found that the in vitro aerosol performance of nedocromil sodium is poor. A study has been undertaken to gain a better understanding of the physicochemical properties of the drug particles together with the factors governing the aerosol performance of inhalation systems containing this drug. Material previously passed through a hammer mill only and particles subsequently passed through a micronizer were characterized, and the information gathered was correlated with the in vitro aerosol performance of the pure drug systems. Optimization of particle sizing procedures revealed that both sets of materials were ultrafine powders with a volume median diameter of approximately 1 microm. It is concluded that the processing stages, employed in the manufacture of these batches of fine particle nedocromil sodium trihydrate, may not in fact be primary particle size reduction stages but instead deaggregation stages and that these govern the aerosol performance. The in vitro aerosol performance of samples of the "micronized" nedocromil sodium stored over a range of relative humidities (RHs) was characterized. Storage RHs in the range 12-76% (where nedocromil sodium is stable as the trihydrate) did not have a dramatic effect on the in vitro aerosol performance of the drug. However, conversion to the heptahemihydrate (following storage of the drug at 86% RH) significantly decreased the deaggregation performance in an in vitro model.

Administration, Inhalation↗
PubMed2000

Bronchiolitis-associated hospitalizations among American Indian and Alaska Native children.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract illness among infants and young children. Respiratory system diseases account for a large proportion of hospitalizations in American Indian and Alaska Native (AI/AN) children; however, aggregate estimates of RSV-associated hospitalizations among AI/AN children have not been made. METHODS: We used Indian Health Service hospitalization data from 1990 through 1995 to describe hospitalizations associated with bronchiolitis, the most characteristic clinical manifestation of RSV infection, among AI/AN children <5 years old. RESULTS: The overall bronchiolitis-associated hospitalization rate among AI/AN infants < 1 year old was considerably higher (61.8 per 1,000) than the 1995 estimated bronchiolitis hospitalization rate among all US infants (34.2 per 1,000). Hospitalization rates were higher among male infants (72.2 per 1,000) than among females infants (51.1 per 1,000). The highest infant hospitalization rate was noted in the Navajo Area (96.3 per 1,000). Hospitalizations peaked annually in January or February, consistent with national peaks for RSV detection. Bronchiolitis hospitalizations accounted for an increasing proportion of hospitalizations for lower respiratory tract illnesses. CONCLUSIONS: Bronchiolitis-associated hospitalization rates are substantially greater for AI/AN infants than those for all US infants. This difference may reflect an increased likelihood of severe RSV-associated disease or a decreased threshold for hospitalization among AI/AN infants with bronchiolitis compared with all US infants. AI/AN children would receive considerable benefit from lower respiratory tract illness prevention programs, including an RSV vaccine, if and when one becomes available.

Age Distribution↗
PubMed2000

The incidence of Kawasaki syndrome in West Coast health maintenance organizations.

BACKGROUND: Kawasaki syndrome (KS) causes an acute vasculitis of unknown etiology. It is a leading cause of acquired heart disease of children in Japan and the United States. METHODS: We examined the incidence of KS in a well-defined population group of children < or =6 years of age, using data collected through the Vaccine Safety Datalink (VSD) project. The VSD database contains information on >1 million children enrolled in four West Coast health maintenance organizations (HMOs). RESULTS: During 1993 through 1996 a total of 234 physician-diagnosed KS patients were reported in the 4 HMOs; 152 (65.0%) were boys and 195 (83.3%) were <5 years of age. The incidence of KS among children <5 years of age in the HMOs ranged from 9.0 to 19.1 per 100,000 person years. KS incidence was higher among boys in 3 of the sites. In the 2 sites with the highest number of KS patients, a seasonal occurrence of KS in winter and early spring was observed. Overall 226 (96.6%) of the KS patients were reported to have been hospitalized; hospitalization rates for children <5 years of age ranged from 9.0 to 16.8 per 100,000 person years. CONCLUSIONS: The incidence of KS in the HMOs was similar to that reported in other population-based studies in the United States and higher than estimates for Australia and several European countries.

Age Factors↗
PubMed1999

Trans-pyridine tetraammine complexes of RuII and RuIII with N7-coordinated purine nucleosides.

The synthesis, spectroscopic, and electrochemical properties of trans-[L(Pyr)(NH3)4RuII/III] (Pyr = py, 3-phpy, 4-phpy, 3-pnpy, or 4-bnpy; L = H2O, Guo, dGuo, 1MeGuo, Gua, Ino, or G7-DNA) are reported. As expected, the Pyr ligand slows DNA binding by trans-[(H2O)(Pyr)(NH3)4RuII]2+ relative to [(H2O)(NH3)5RuII]2+ and favors reduction of RuIII by about 150 mV. The pyridine ligand also promotes the disproportionation of RuIII to afford the corresponding complexes of RuII and, presumably, RuIV. For L = Ino, disproportionation follows the rate law: d[RuII]/dt = k0[RuIII] + k1[OH-][RuIII], k0 = (2.7 +/- 0.7) x 10(-4) s-1 and k1 = 70 +/- 1 M-1 s-1.

Amines↗
PubMed1999

Effects of trans-pyridine ligands on the interactions of RuII and RuIII ammine complexes N7-coordinated to purine nucleosides and DNA.

DNA binding by trans-[(H2O)(Pyr)(NH3)4RuII]2+ (Pyr = py, 3-phpy, 4-phpy, 3-bnpy, 4-bnpy) is highly selective for G7 with KG = 1.1 x 10(4) to 2.8 x 10(4), with the more hydrophobic Pyr ligands exhibiting slightly higher binding. A strong dependence on ionic strength indicates that ion-pairing with DNA occurs prior to binding. At mu = 0.05, d[RuII-DNA]/dt = k[RuII][DNA], where k = 0.17-0.21 M-1 s-1 with the various Pyr ligands. The air oxidation of [(py)(NH3)4RuII]n-DNA to [(py)(NH3)4RuIII]n-DNA at pH 6 occurs with a pseudo-first-order rate constant of kobs = 5.6 x 10(-4) s-1 at mu = 0.1, T = 25 degrees C. Strand cleavage of plasmid DNA appears to occur by both Fenton/Haber-Weiss chemistry and by base-catalyzed routes, some of which are independent of oxygen. Base-catalyzed cleavage is more efficient than O2 activation at neutral pH and involves the disproportionation of covalently bound RuIII and, in the presence of O2, Ru-facilitated autoxidation to 8-oxoguanine. Disproportionation of [py(NH3)4RuIII]n,-DNA occurs according to the rate law: d[RuII-GDNA]/dt = k0[RuIII-GDNA] + k1[RuIII-GDNA][OH-], where k0 = 5.4 x 10(-4) s-1 and k1 = 8.8 M-1 s-1 at 25 degrees C, mu = 0.1. The appearance of [(Gua)(py)(NH3)4RuIII] under argon, which occurs according to the rate law: d[RuIII-G]/dt = k0[RuIII-GDNA] + k1[OH-][RuIII-GDNA] (k0 = 5.74 x 10(-5) s-1, k1 = 1.93 x 10(-2) M-1 s-1 at T = 25 degrees C, mu = 0.1), is consistent with lysis of the N-glycosidic bond by RuIV-induced general acid hydrolysis. In air, the ratio of [Ru-8-OG]/[Ru-G] and their net rates of appearance are 1.7 at pH 11, 25 degrees C. Small amounts of phosphate glycolate indicate a minor oxidative pathway involving C4' of the sugar. In air, a dynamic steady-state system arises in which reduction of RuIV produces additional RuII.

Amines↗
PubMed1999

Trends in hospitalizations associated with gastroenteritis among adults in the United States, 1979-1995.

Gastroenteritis (GE) is among the most common illnesses of humans but the burden of disease, its epidemiology, and the distribution of pathogens in adults have not been fully examined. This information is needed to plan prevention strategies particularly for high-risk groups. This study is a retrospective analysis of data from the National Hospital Discharge Survey for the years 1979 through 1995 which describes the disease burden and epidemiology of hospitalizations associated with GE among adults in the United States. Diarrhoea was listed as a diagnosis on an average of 452,000 hospital discharges per year representing 1.5% of all hospitalizations among adults. The annual number of GE hospitalizations has decreased by 20% from approximately 500,000 in 1979 to 400,000 in 1995. The aetiology of 78% of cases coded as GE was undetermined. Until the aetiology of disease can be better established, specific strategies for prevention cannot be developed.

Adult↗
PubMed1999

Hidden mortality attributable to Rocky Mountain spotted fever: immunohistochemical detection of fatal, serologically unconfirmed disease.

Rocky Mountain spotted fever (RMSF) is the most severe tickborne infection in the United States and is a nationally notifiable disease. Since 1981, the annual case-fatality ratio for RMSF has been determined from laboratory-confirmed cases reported to the Centers for Disease Control and Prevention (CDC). Herein, a description is given of patients with fatal, serologically unconfirmed RMSF for whom a diagnosis of RMSF was established by immunohistochemical (IHC) staining of tissues obtained at autopsy. During 1996-1997, acute-phase serum and tissue samples from patients with fatal disease compatible with RMSF were tested at the CDC. As determined by indirect immunofluorescence assay, no patient serum demonstrated IgG or IgM antibodies reactive with Rickettsia rickettsii at a diagnostic titer (i.e., >/=64); however, IHC staining confirmed diagnosis of RMSF in all patients. Polymerase chain reaction validated the IHC findings for 2 patients for whom appropriate samples were available for testing. These findings suggest that dependence on serologic assays and limited use of IHC staining for confirmation of fatal RMSF results in underestimates of mortality and of case-fatality ratios for this disease.

Adult↗
PubMed1999

Kawasaki syndrome among American Indian and Alaska Native children, 1980 through 1995.

BACKGROUND: Kawasaki syndrome (KS) is a leading cause of acquired heart disease among US children, but the epidemiologic features of KS among American Indian and Alaska Native (AI/AN) children have not been described. METHODS: We examined Indian Health Service computerized records of hospital discharges for AI/AN children <18 years of age with KS during 1980 through 1995. RESULTS: During 1980 through 1995, 85 AI/AN children were reported with a hospitalization for KS; 10 of the children had an additional KS hospitalization record within 5 months. The average annual KS hospitalization rate for children <5 years of age, based on first KS hospitalization only, was 4.3 cases per 100000 children; the rate for children age <1 year (n = 21) was 8.6 per 100000 and for children ages 1 to 4 years was 3.6 per 100000. The annual rates for children < 5 years of age ranged from 0 to 8.5 per 100000 children. KS hospitalizations for children peaked in January and February; 50.6% of the children were hospitalized during January through April. The overall median length of hospital stay was 4 days (range, 1 to 29 days); the median duration decreased from 8 days from 1980 through 1982 to 4 days from 1993 through 1995. CONCLUSIONS: The overall annual hospitalization rate of KS among AI/AN children <5 years of age was slightly lower than rates for several majority white populations in the United States. (4.6 to 15.2 cases per 100000) and much lower than rates for blacks and Asians/Pacific Islanders.

Adolescent↗
PubMed1999

Trends in diarrhea-associated hospitalizations among American Indian and Alaska native children, 1980-1995.

OBJECTIVE: To describe trends in diarrhea- associated hospitalizations among American Indian and Alaska Native (AI/AN) children and to estimate the morbidity from rotavirus. DESIGN: Retrospective analysis of Indian Health Service hospital discharge records. PATIENTS: AI/AN children 1 month through 4 years of age with a diarrhea-associated diagnosis listed on the hospital discharge record. SETTING: Hospitals on or near US Indian reservations from 1980 through 1995. RESULTS: During 1980 through 1995, 21 669 diarrhea-associated hospitalizations were reported among AI/AN children. The annual incidence of diarrhea-associated hospitalizations declined by 76% from 276 per 10 000 in 1980 to 65 per 10 000 in 1995. The median length of hospital stay decreased from 4 days during 1980-1982 to 2 days during 1993-1995. Diarrhea-associated hospitalizations peaked during the winter months (October through March), especially among children 4-35 months of age, with the peaks appearing first in the Southwest during October and moving to the East in March. In the early years of the study (1980-1982), the rate of diarrhea-associated hospitalizations among AI/AN children (236 per 10 000) was greater than the national rate (136 per 10 000). By the end of the study period (1993-1995), the rate for AI/AN children (71 per 10 000) was similar to the national rate (89 per 10 000), although the rate for AI/AN infants remained higher than the national rate for infants. CONCLUSIONS: Diarrhea-associated hospitalization rates for AI/AN children have declined to a level similar to that of the national population. Rotavirus may be an important contributor to diarrheal morbidity among AI/AN children, underscoring the need for vaccines against this pathogen.

Alaska↗