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Biomedical subjects

J Griffith

Publications and source records attributed to J Griffith.

At least 55 records · Page 3Linked to original sources
PubMed1998

Pitfalls to avoid when merging information systems.

When healthcare organizations merge, their goal often is to improve operational efficiencies, with information systems (IS) a common target for cost reduction. These cost reductions usually are achieved by reducing staff, consolidating data centers, establishing standardized systems, and sharing resources throughout the system. During this process, however, several common pitfalls can cause merging organizations to stumble. By carefully evaluating their options, merging organizations can avoid these potential traps and reduce their IS costs.

Contract Services↗
PubMed1997

In vitro reconstruction of the Aspergillus (= Emericella) nidulans genome.

A physical map of the 31-megabase Aspergillus nidulans genome is reported, in which 94% of 5,134 cosmids are assigned to 49 contiguous segments. The physical map is the result of a two-way ordering process, in which clones and probes were ordered simultaneously on a binary DNA/DNA hybridization matrix. Compression by elimination of redundant clones resulted in a minimal map, which is a chromosome walk. Repetitive DNA is nonrandomly dispersed in the A. nidulans genome, reminiscent of heterochromatic banding patterns of higher eukaryotes. We hypothesize gene clusters may arise by horizontal transfer and spread by transposition to explain the nonrandom pattern of repeats along chromosomes.

Aspergillus nidulans↗
PubMed1997

Human p53 binds Holliday junctions strongly and facilitates their cleavage.

Holliday junctions in DNA are generated as a product of homologous recombination events. To test the hypothesis that human p53 may bind to Holliday junctions, synthetic junctions with four approximately 75-base pair (Hol75) or approximately 565-base pair (Hol565) arms were generated. As seen by electron microscopy, under conditions in which 50-61% of the Hol565 DNAs were bound by p53, 80-96% of the p53 was located specifically at the junction with, in the latter case, only 4% of the p53 visualized at the DNA ends or along the arms. Given the large number of potential binding sites, this represents very high specificity for the junctions. Gel retardation assays using the Hol75 DNA confirm these observations, and indicate that the tight junction complexes have a half-life of greater than 4 h. The binding of p53 to three-way junctions is severalfold less than to four-way junctions. Addition of p53 greatly increases the rate of resolution of the Hol75 DNA by T4 endonuclease VII and T7 endonuclease I, two enzymes known to cleave such junctions. This latter finding further confirms the interaction of p53 with Holliday junctions and suggests that p53 binding facilitates their resolution in vivo.

Binding Sites↗
PubMed1997

Effect of cytomegalovirus infection status on first-year mortality rates among orthotopic liver transplant recipients. The Boston Center for Liver Transplantation CMVIG Study Group.

BACKGROUND: To reduce the mortality rate associated with liver transplantation, it is important to identify the risk factors for increased mortality among liver transplant recipients. It has been suggested that cytomegalovirus (CMV) infection is one such risk factor, but no studies have examined mortality rates associated with the CMV serologic status of the donor and recipient by using multivariate techniques. OBJECTIVE: To study the effect of CMV on 1-year mortality rates in orthotopic liver transplant recipients. DESIGN: Intention-to-treat analysis of a cohort. PATIENTS: 146 liver transplant recipients who were enrolled in a multicenter, randomized, placebo-controlled intervention trial. SETTING: Four university-affiliated transplantation centers. RESULTS: 1-year mortality rates for the four strata of donor and recipient CMV serologic status before transplantation were as follows: seronegative donor and recipient, 11%; seronegative donor and seropositive recipient, 22%; seropositive donor and recipient, 30%; and seropositive donor and seronegative recipient, 44% (P = 0.0091). Multivariate analysis using a time-dependent Cox proportional hazards model showed that retransplantation (relative risk, 4.6 [95% CI, 1.9 to 10.7]; P < 0.001); total number of units of blood products administered during transplantation (relative risk, 1.006 per unit [CI, 1.003 to 1.010]; P < 0.001); and presence of CMV disease (relative risk, 3.9 [CI, 1.8 to 8.5]; P < 0.001), invasive fungal disease (relative risk, 3.3 [CI, 1.5 to 7.1]; P = 0.0020), and bacteremia (relative risk, 2.5 [CI, 1.2 to 5.2]; P = 0.0136) were independently associated with higher mortality rates. If post-transplantation variables that were highly correlated with donor and recipient CMV serologic status were restricted from the model, donor and recipient CMV serologic status was the only pretransplantation variable independently associated with higher mortality rates (P = 0.002). CONCLUSION: Donor and recipient CMV serologic status is a significant pretransplantation determinant for death in liver transplant recipients.

Adult↗
PubMed1997

Saccharomyces cerevisiae MSH2, a mispaired base recognition protein, also recognizes Holliday junctions in DNA.

Genetic and biochemical studies have suggested that mismatch repair proteins interact with recombination intermediates to prevent recombination, or to limit the extent of formation of heteroduplex DNA during recombination between divergent DNA sequences. To test the idea that mismatch repair proteins regulate recombination by interacting with recombination intermediates, we investigated whether the Saccharomyces cerevisiae MutS homolog MSH2 could interact with Holliday junctions. Both filter-binding and electron-microscopic analysis showed that MSH2 bound to duplex DNA molecules containing Holliday junctions with a higher affinity than to control duplex DNA, single-stranded DNA or a control duplex DNA containing a mispaired base. The MSH2-Holliday junction complexes were also more stable than MSH2-duplex DNA complexes. This observation suggests that MSH2 protein could directly coordinate the interaction between mismatch repair and genetic recombination observed in genetic studies.

Base Composition↗
PubMed1997

Short-term effectiveness of anticipatory guidance to reduce early childhood risks for subsequent violence.

OBJECTIVE: To determine whether newly developed anticipatory guidance materials designed to teach the use of time-outs and the importance of reductions in childhood television viewing would be recalled by parents and if their use would result in changes in self-reported parental behavior. SUBJECTS AND SETTING: A total of 559 parents of children aged 14 months to 6 years recruited at the time of routine child health maintenance visits at 2 managed care pediatric departments in eastern Massachusetts. METHODS: In-person parent interviews were conducted in the waiting room prior to office visits, with follow-up telephone calls 2 to 3 weeks after the visit. Two groups of families were enrolled: a control group who received usual anticipatory guidance and an intervention group who received written materials. Intervention group providers were trained to include study topics during the office visit and to introduce the written materials. RESULTS: Provider training and the provision of written materials increased the parents' specific recall of anticipatory guidance of at least 2 to 3 weeks following the office visit. This effect was specific to the areas of intervention and did not carry over to other commonly used topics of anticipatory guidance. Among parents who had never used a time-out prior to the office visit, there was a significant increase in the use of time-outs. Parents who received anticipatory guidance regarding the link between exposure to television violence and subsequent violence in children were somewhat more likely to report reductions in weekend television viewing than were parents in the control group, although this change was not statistically significant. CONCLUSIONS: Certain parenting behaviors have been associated with subsequent violence. Brief, inexpensive anticipatory guidance in relevant areas, provided in the context of routine health supervision visits, appears to result in favorable short-term changes in parenting practices.

Child↗
PubMed1997

The independent role of cytomegalovirus as a risk factor for invasive fungal disease in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG-Study Group. Cytogam, MedImmune, Inc. Gaithersburg, Maryland.

PURPOSE: To assess impact of cytomegalovirus (CMV) donor-recipient serostatus, infection, or disease on development of invasive fungal infection in orthotopic liver transplant recipients. PATIENTS AND METHODS: An analysis of prospectively collected data in 146 liver transplant recipients (intention to treat cohort) from 4 tertiary care, university-affiliated transplant centers in Boston (Boston Center for Liver Transplantation). Patients were observed for 1 year after transplantation for the development of CMV infection, CMV disease, CMV pneumonia, as well as for the development of opportunistic fungal infections, graft survival, and mortality. Weekly cultures were taken of urine and throat and every other week of buffy coat for CMV for 2 months, then monthly for 6 months, at 1 year, and at the time of any clinical illness. Pre- and posttransplant variables including CMV-serostatus of donor and recipient, fungal isolation from sterile body sites, fungemia, bacteremia, antibiotic use, immunosuppression, treatment for rejection, and volumes of blood products were measured. RESULTS: Survival analysis demonstrated that 36% of patients with CMV disease developed invasive fungal disease within the first year post-transplant compared with 8% of those without CMV disease (P < 0.0001). One-year mortality in patients with invasive fungal disease was 15 of 22 (68%) compared with 23 of 124 (19%) in those without invasive fungal disease (P < 0.001). A multivariable, time-dependent analysis demonstrated that being a CMV-seronegative recipient of a CMV-seropositive donor organ (P < 0.001), having bacteremia (P = 0.001), UNOS (United Network for Organ Sharing) status 4 (need for life support measures) at transplant (P = 0.002), and volume of platelets (P = 0.002) were independently associated with invasive fungal disease. Restriction of cases of invasive fungal disease to those that occurred more than 2 weeks after transplant demonstrated an association with CMV disease (P = 0.003), bacteremia (P = 0.003), need for life support (P = 0.03), and volume of blood products transfused (P = 0.02). CONCLUSION: CMV disease or being a CMV-seronegative recipient of a CMV-seropositive donor organ is an important predictor for invasive fungal disease following orthotopic liver transplantation.

Adolescent↗
PubMed1997

Clinical and epidemiological predictors of recurrent cytomegalovirus disease in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG Study Group.

Predictors of recurrent cytomegalovirus (CMV) disease after the first episode of successfully treated CMV disease in orthotopic liver transplant recipients were studied. Recurrent CMV disease was defined as disease diagnosed > 14 days after the end of a minimum 8-day course of ganciclovir therapy for the first episode and was classified as early or late if it occurred within or after 90 days, respectively, after completion of ganciclovir treatment. Eleven (27%) of 41 patients had recurrent CMV disease (nine early recurrences and two late recurrences). Death was more likely to occur in patients with recurrent CMV disease than in those without it (55% vs. 13%, respectively; P = .006). Initial episodes of multiorgan CMV disease (P = .001) and CMV pneumonia (P = .012) were associated with early recurrence. Multivariate analysis showed that multiorgan CMV disease was independently associated with early recurrence (P = .003; odds ratio, 13.5; 95% confidence interval, 2.4-76.8). Recognition of risk factors for recurrent CMV disease may help identify patients for whom a more intensive therapeutic or diagnostic approach is needed.

Antiviral Agents↗
PubMed1997

Surveillance cultures of blood, urine, and throat specimens are not valuable for predicting cytomegalovirus disease in liver transplant recipients. Boston Center for Liver Transplantation Cytomegalovirus Immune Globulin Study Group.

The role of markers of cytomegalovirus (CMV) infection, such as the isolation of CMV, the presence of CMV antigenemia, or detection of viral DNA by polymerase chain reaction (PCR) assay, as predictors of subsequent CMV disease has been examined in recent studies. We studied the value of performing surveillance cultures of blood, urine, and throat specimens in a cohort of 156 liver transplant recipients who had participated in clinical trials and had received ganciclovir only for documented CMV disease. Cultures of urine and throat specimens for detection of CMV were performed every week, and cultures of blood specimens were performed every other week for the first 2 months after transplantation, then monthly for 6 months. Eighty-nine (57%) of 156 patients developed CMV infection, 41 (46%) of whom developed clinical CMV disease (36 had organ involvement and five had CMV syndrome). Fifty (32%) of 156 patients had positive blood cultures, 35 (22%) had positive urine cultures, and 41 (26%) had positive throat cultures. The positive and negative predictive values of surveillance cultures for predicting CMV disease were as follows: blood cultures, 46% and 83%, respectively; urine cultures, 26% and 74%, respectively; and throat cultures, 32% and 76%, respectively. These data indicate that such cultures are not useful in predicting CMV disease in liver transplant recipients. Future studies should examine the value of alternative markers, such as CMV antigenemia or the detection of viral DNA by PCR, for predicting CMV disease in this setting.

Adult↗
PubMed1997

Cytomegalovirus immune globulin (CMVIG) prophylaxis is associated with increased survival after orthotopic liver transplantation. The Boston Center for Liver Transplantation CMVIG Study Group.

Cytomegalovirus (CMV) causes considerable morbidity and mortality in orthotopic liver transplant (OLT) recipients. Several prophylactic strategies against CMV have been studied in solid organ transplant recipients, including cytomegalovirus immune globulin (CMVIG). We examined the effect of CMVIG prophylaxis on first-year and long-term survival after liver transplantation. Data were analysed for 162 OLT recipients from four transplant centers in Boston who participated in two CMVIG prophylaxis trials. Ninety patients received CMVIG (median follow-up 5.6 yr), and 72 patients received placebo (median follow-up 5.4 yr). CMVIG prophylaxis was shown to be associated with increased first-year (86% vs. 72%, p = 0.029) and long-term (68% vs. 54%, p = 0.055) survival. The distribution of baseline characteristics including donor and recipient demographics, donor CMV serostatus, United Network for Organ Sharing (UNOS) status, pre-transplant renal and liver function tests, transplantation surgical time, number of units of blood products administered during transplantation, primary immunosuppressive regimen, use of solumedrol or antilymphocyte therapy for induction of immunosuppression or treatment of rejection, and surgical complications was similar for CMVIG and placebo recipients. CMVIG recipients were more likely to have primary biliary cirrhosis than placebo recipients (21% vs. 8%, p = 0.025). Using a Cox proportional hazards multivariate model to control for pre-transplant liver disease, CMVIG was shown to be independently associated with increased first-year survival (p = 0.042); a trend toward association with increased long-term survival (p = 0.098) was also shown. These data support that CMVIG prophylaxis, beyond its proven efficacy in decreasing the incidence of severe CMV-associated disease, is associated with increased survival when used prophylactically in OLT recipients.

Adolescent↗
PubMed1996

Long CCG triplet repeat blocks exclude nucleosomes: a possible mechanism for the nature of fragile sites in chromosomes.

The rare folate-sensitive, fragile sites on chromsomes X, 11, and 16 contain blocks of CCG triplet repeats and large expansions of the CCG block at the FRAXA site produce the fragile X syndrome (FraX). The fragile, poorly staining nature of these sites suggested an altered chromatin structure. Here, repeating CCG DNAs from FraX patients were tested for their ability to assemble into nucleosomes, the basic subunits of chromatin, using in vitro nucleosome reconstitution, electron microscopy and competitive assembly gel retardation assays. CCG blocks of >50 repeats displayed strong nucleosome exclusion, providing a possible explanation for the nature of these sites.

Base Sequence↗
PubMed1996

The tyrosine-based lysosomal targeting signal in lamp-1 mediates sorting into Golgi-derived clathrin-coated vesicles.

Diversion of membrane proteins from the trans-Golgi network (TGN) or the plasma membrane into the endosomal system occurs via clathrin-coated vesicles (CCVs). These sorting events may require the interaction of cytosolic domain signals with clathrin adaptor proteins (APs) at the TGN (AP-1) or the plasma membrane (AP-2). While tyrosine- and di-leucine-based signals in several proteins mediate endocytosis via cell surface CCVs, segregation into Golgi-derived CCVs has so far only been documented for the mannose 6-phosphate receptors, where it is thought to require a casein kinase II phosphorylation site adjacent to a di-leucine motif. Although recently tyrosine-based signals have also been shown to interact with the mu chain of AP-1 in vitro, it is not clear if these signals also bind intact AP-1 adaptors, nor if they can mediate sorting of proteins into AP-1 CCVs. Here we show that the cytosolic domain of the lysosomal membrane glycoprotein lamp-1 binds AP-1 and AP-2. Furthermore, lamp-1 is present in AP-1-positive vesicles and tubules in the trans-region on the Golgi complex. AP-1 binding as well as localization to AP-1 CCVs require the presence of the functional tyrosine-based lysosomal targeting signal of lamp-1. These results indicate that lamp-1 can exit the TGN in CCVs and that tyrosine signals can mediate these sorting events.

Adaptor Protein Complex alpha Subunits↗
PubMed1996

Methylation of expanded CCG triplet repeat DNA from fragile X syndrome patients enhances nucleosome exclusion.

Long tracts of CCG trinucleotide or CCGNN pentanucleotide repeats in DNA have previously been shown to resist assembly into nucleosomes. This may provide a molecular explanation for the nature of certain rare, folate-sensitive fragile sites in human chromosomes that contain expanded CCG triplet tracts. Further, it is known that methylation of CpG dinucleotides at or near these fragile sites enhances the fragile phenotype. Here DNAs containing 76 tandem CCG triplets or 48 CCGNN pentanucleotide repeats were methylated with SssI methylase at three different levels of methylation. Using competitive nucleosome reconstitution/gel shift assays, the ability of these DNAs and a mixed sequence DNA from the pUC19 plasmid were compared in their ability to assemble into nucleosomes. DNA methylation had no significant effect on nucleosome formation over the pUC 19 fragment. However, the highly methylated DNAs containing 76 CCG triplets or 48 CCGNN pentanucleotide repeats were 2.0 +/- 0. 2-fold and 2.1 +/- 0.3-fold less efficient in nucleosome assembly than the respective unmethylated forms, and 4.4 +/- 0.4-fold and 12. 6 +/- 1.6-fold less efficient than a pUC19 fragment of similar length.

Base Sequence↗
PubMed1996

Incidence and predictors of cytomegalovirus pneumonia in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG Study Group.

The incidence, predictors, and outcome of cytomegalovirus pneumonia in OLT recipients have not been well defined. We conducted an analysis of prospectively collected data from 141 OLT recipients who were included as part of a randomized, placebo-controlled trial of CMV immune globulin prophylaxis. Cytomegalovirus pneumonia was diagnosed in 13 of 141 (9.2%) OLT recipients during the first year posttransplant and was associated with a higher 1-year mortality compared with those recipients without CMV pneumonia (84.6 vs. 17.2%, P=0.0001). Univariate analysis demonstrated that CMV viremia (P=0.001), invasive fungal disease (P=0.0001), donor(+)/pretransplant recipient(-) CMV serologic status (P=0.013), abdominal operation (excluding retransplantation) after liver transplantation (P=0.0027), bacteremia (P=0.0105), and advanced United Network of Organ Sharing status (P=0.023) were associated with CMV pneumonia. Cytomegalovirus viremia was diagnosed in 11 of 13 patients with CMV pneumonia at a median of 11 days (range 1-66 days) before diagnosis of CMV pneumonia. In a multivariate analysis using a time-dependent, Cox proportional hazards model, CMV viremia (RR=8.6, 95% CI 1.8-39.7, P=0.0012), invasive fungal disease (RR=6.5, 95% CI 2.1-20.3, P=0.0001), and abdominal reoperation (RR=4.4, 95% CI 1.4-13.1, P=0.0043) were found to be independent predictors of CMV pneumonia. The attributable mortality associated with CMV pneumonia within the first year after liver transplantation for the patients with CMV pneumonia was 67.4%. Intensified measures for prevention of CMV should be considered for patients at high risk of developing CMV pneumonia.

Adult↗
PubMed1996

Risk factors leading to clinical failure in the treatment of intra-abdominal or skin/soft tissue infections.

A study of determinants of outcome in adult patients with intra-abdominal or skin/soft tissue infections treated with cefotetan, cefoxitin, or ampicillin/sulbactam monotherapy was undertaken. Patients were matched for principal infectious process, surgery performed for the management of the infection, year of hospital admission, age, and sex. The criteria for inclusion, exclusion, and matching of patients and assignment of clinical and microbiological outcome were based on the 1992 Infectious Diseases Society of America/Federal Drug Administration guidelines for the evaluation of anti-infective drug products. One hundred and thirty-seven cases of intra-abdominal or skin and soft tissue infections treated with cefotetan (n = 47), cefoxitin (n = 43), or ampicillin/sulbactam (n = 47) monotherapy were selected without knowledge of outcome and analyzed using a single blinded analysis. The baseline characteristics did not differ between the treatment groups, nor did the rates of clinical or microbiological failure. A multivariate analysis showed that isolation of an organism resistant to the treatment regimen, including Pseudomonas spp., [odds ratio (OR) = 14.9, p = 0.001], being on antibiotic therapy at the time of admission (OR = 4.5, p = 0.007), and diagnosis of a complicated intra-abdominal infection (OR = 3.5, p = 0.014) were independently associated with clinical failure. These data support the assertion that antibiotic resistant organisms in mixed anaerobic/aerobic infections are associated with clinical failure and suggest that the antibiotic regimen should be modified to include Pseudomonas spp. in its spectrum when this organism is isolated from patients with such infections.

Abdominal Abscess↗
PubMed1996

Primary cytomegalovirus infection in liver transplant recipients: comparison of infections transmitted via donor organs and via transfusions. Boston Center for Liver Transplantation CMVIG Study Group.

Primary cytomegalovirus (CMV) infection in liver transplant recipients generally occurs following transmission via a CMV-seropositive donor organ. Occasionally primary infection arises in recipients of CMV-seronegative donor organs through blood transfusions. We studied the differences in clinical manifestations of primary CMV infection associated with these two modes of transmission, among 40 liver transplant recipients who had documented primary CMV infection post-transplantation. Thirty-one of 40 patients received a CMV-seropositive donor organ; CMV infection in the other nine patients was transfusion related. Symptomatic CMV disease (22 of 31 vs. 4 of 9; P = .06), CMV hepatitis (20 of 31 vs. 1 of 9; P = .007), invasive fungal disease (13 of 31 vs. 0 of 9; P = .03), and death (16 of 31 vs. 1 of 9; P = .06) were more likely to occur in patients with donor organ-associated primary CMV infection. The incubation period between transplantation and onset of CMV infection, a possible marker for viral load, was shorter in recipients of donor organ-transmitted CMV infection (median, 44 vs. 137 days; P = .004). Controlling for potential confounders such as immunosuppression did not alter these associations. Primary CMV infection associated with the donor organ has a more profound impact than primary infection associated with transfusion. These differences may be due to dissimilarities in the viral load associated with donated livers and transfused blood products.

Adolescent↗
PubMed1996

Exposure to cytomegalovirus from the donated organ is a risk factor for bacteremia in orthotopic liver transplant recipients. Boston Center for Liver Transplantation CMVIG Study Group.

To define predictors of bacteremia and to assess the potential role of exposure to cytomegalovirus (CMV) as a risk factor for bacteremia in liver transplant recipients, an intention-to-treat analysis of data for 146 orthotopic liver transplant recipients who participated in a multicenter, randomized, intervention trial was undertaken. Fifty-eight episodes of bacteremia occurred in 40 (27.4%) of 146 patients within 1 year after transplantation. Bacteremia was diagnosed a median of 39.5 days (range, 1-325 days) after transplantation. One-year mortality rates were higher among patients with bacteremia than among those without bacteremia (47.5% [19 of 40] vs. 18% [19 of 106], respectively; P = .001). A time-dependent multivariate analysis of variables that were significantly (P < or = .05) associated with bacteremia in the univariate analysis showed that donor CMV seropositivity (relative risk [RR], 3.4; 95% confidence interval [CI], 1.6-6.6; P = .0005), age of younger than 16 years (RR, 2.6; 95% CI, 1.3-5.2; P < .0059), and a major abdominal operation after transplantation excluding retransplantation (RR, 3.8; 95% CI, 1.8-8.0; P = .0004) were independently associated with bacteremia. These epidemiologic data suggest that exposure to CMV from the donated organ is an independent risk factor for bacteremia in orthotopic liver transplant recipients.

Bacteremia↗