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Biomedical subjects

N Singh

Publications and source records attributed to N Singh.

At least 19 recordsLinked to original sources
PubMed2000

The chaperone protein BiP binds to a mutant prion protein and mediates its degradation by the proteasome.

Familial prion diseases are thought to result from a change in structure of the mutant prion protein (PrP), which takes a pathogenic conformation. We have examined the role of molecular chaperones in the folding of normal and mutant PrP Q217R (PrP(217)) in transfected neuroblastoma cells. In a previous report we showed that, although most of the PrP(217) forms escape the endoplasmic reticulum quality control system and aggregate in post-Golgi compartments, a significant proportion of PrP(217) retains the C-terminal glycosylphosphatidyl inositol signal peptide (PrP32), and does not exit the endoplasmic reticulum (Singh, N., Zanusso, G., Chen, S. G., Fujioka, H., Richardson, S., Gambetti, P., and Petersen, R. B. (1997) J. Biol. Chem. 272, 28461-28470). We have now studied the folding and turnover of PrP32 to understand the mechanism by which abnormal PrP forms cause cellular toxicity in our cell culture model and in the human brain carrying the Gerstmann-Sträussler-Scheinker disease Q217R mutation. In this report, we show that PrP32 remains associated with the chaperone BiP for an abnormally prolonged period of time and is degraded by the proteasomal pathway. This study is the first demonstration that BiP is chaperoning the folding of PrP and plays a role in maintaining the quality control in the PrP maturation pathway. Our data provide new insight into the diverse pathways of mutant PrP metabolism and neurotoxicity.

Amino Acid Substitution↗
PubMed2000

Type IV collagen of the glomerular basement membrane. Evidence that the chain specificity of network assembly is encoded by the noncollagenous NC1 domains.

The ultrafiltration function of the glomerular basement membrane (GBM) of the kidney is impaired in genetic and acquired diseases that affect type IV collagen. The GBM is composed of five (alpha1 to alpha5) of the six chains of type IV collagen, organized into an alpha1.alpha2(IV) and an alpha3.alpha4.alpha5(IV) network. In Alport syndrome, mutations in any of the genes encoding the alpha3(IV), alpha4(IV), and alpha5(IV) chains cause the absence of the alpha3. alpha4.alpha5 network, which leads to progressive renal failure. In the present study, the molecular mechanism underlying the network defect was explored by further characterization of the chain organization and elucidation of the discriminatory interactions that govern network assembly. The existence of the two networks was further established by analysis of the hexameric complex of the noncollagenous (NC1) domains, and the alpha5 chain was shown to be linked to the alpha3 and alpha4 chains by interaction through their respective NC1 domains. The potential recognition function of the NC1 domains in network assembly was investigated by comparing the composition of native NC1 hexamers with hexamers that were dissociated and reconstituted in vitro and with hexamers assembled in vitro from purified alpha1-alpha5(IV) NC1 monomers. The results showed that NC1 monomers associate to form native-like hexamers characterized by two distinct populations, an alpha1.alpha2 and alpha3.alpha4.alpha5 heterohexamer. These findings indicate that the NC1 monomers contain recognition sequences for selection of chains and protomers that are sufficient to encode the assembly of the alpha1.alpha2 and alpha3.alpha4.alpha5 networks of GBM. Moreover, hexamer formation from the alpha3, alpha4, and alpha5 NC1 monomers required co-assembly of all three monomers, suggesting that mutations in the NC1 domain in Alport syndrome may disrupt the assembly of the alpha3.alpha4.alpha5 network by interfering with the assembly of the alpha3.alpha4.alpha5 NC1 hexamer.

Animals↗
PubMed2000

Cytomegalovirus antigenemia directed pre-emptive prophylaxis with oral versus I.V. ganciclovir for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, controlled trial.

BACKGROUND: The efficacy of pre-emptively administered oral ganciclovir in preventing cytomegalovirus (CMV) disease has not been documented in liver transplant recipients. We sought to compare the efficacy of pre-emptive oral ganciclovir with that of i.v. ganciclovir for the prevention of CMV disease after liver transplantation, and to determine whether withholding prophylaxis in the absence of CMV antigenemia, reliably identified patients in whom no prophylaxis was necessary. METHODS: Surveillance cultures for CMV pp65 antigenemia were performed in all patients at weeks 2, 4, 6, 8, 12, and 16. Patients with CMV antigenemia were randomized into two study groups. The experimental group received oral ganciclovir for 6 weeks (2 g t.i.d. for 2 weeks, then 1 g t.i.d. for 4 weeks), and the control group received i.v. ganciclovir (5 mg/kg q 12 hr) for 7 days. RESULTS: Of 72 consecutive liver transplant recipients studied, CMV antigenemia occurred in 31% (22 of 72). Twenty-two patients with asymptomatic antigenemia were randomized to two study groups. CMV disease (viral syndrome) occurred in 9% (1 of 11) of the patients in the i.v. ganciclovir group and in 0% (0 of 11) of the patients in the oral ganciclovir group. None of the study patients developed tissue invasive CMV disease. The median reduction in antigenemia level with oral ganciclovir was 55% at week 1, and 100% at week 2. Overall, 64% of the patients by week 1, 93% by week 2, and 100% by week 4 had antigenemia levels below the baseline after oral ganciclovir. Of 50 patients without CMV antigenemia, none developed CMV disease. CONCLUSIONS: Pre-emptive prophylaxis based on CMV antigenemia can effectively target the patients for CMV prophylaxis; 69% of the patients never received antiviral prophylaxis and did not develop CMV disease. Antiviral therapy instituted upon detection of antigenemia prevented tissue invasive CMV in both ganciclovir groups. Pre-emptively administered oral ganciclovir was effective as prophylaxis for CMV disease after liver transplantation.

Administration, Oral↗
PubMed2000

Modulation of halofantrine resistance after coadministration of halofantrine with diverse pharmacological agents in a rodent malaria model.

The declining efficacy of antimalarial drugs against Plasmodium falciparum strains has been reported from several endemic regions of the world. Strategic evaluation of several pharmacological agents in combination with chloroquine to enhance the sensitivity of the latter against resistant parasites has been documented in several studies. However no attempts have been directed to monitor the efficacy of such biological response modifiers for reversing the resistance to halofantrine. In the present study the comparative efficacy of a total of 22 pharmacological agents representing diverse categories including antihistamines, antidepressants, calcium channel blockers, neuroleptics etc. has been determined in combination with halofantrine against halofantrine resistant Plasmodium yoelii nigeriensis. Results show significant potentiation of the efficacy of halofantrine when administered concurrently with histamine H1 receptor antagonists cyproheptadine and ketotifen. Combination with pheniramine, amitriptyline, verapamil and penfluridol also produced moderate degree of potentiation which was well marked during the early phase of progression of parasitaemia.

Animals↗
PubMed2000

The alloreactive and self-restricted CD4+ T cell response directed against a single MHC class II/peptide combination.

The cellular basis for allograft rejection derives from the strong T cell response to cells bearing foreign MHC. While it was originally assumed that alloreactive T cells focus their recognition on the polymorphic residues that differ between syngeneic and allogeneic MHC molecules, studies with MHC class I-restricted CTL have shown that MHC-bound peptides play a critical role in allorecognition. It has been suggested that alloreactive T cells depend more strongly on interactions with the MHC molecule than with the associated peptide, but there is little evidence to support this idea. Here we have studied the alloreactive and self-restricted response directed against the class II H2-Ab molecule bound with a single peptide, Ep, derived from the H2-Ealpha chain. This MHC class II-peptide combination was a poor target and stimulator of alloreactive CD4+ T cell responses, indicating that MHC-bound peptides are as important for alloreactive CD4+ T cells as they are for alloreactive CTL. We also generated alloreactive T cells with exquisite specificity for the Ab/Ep complex, and compared their reactivity with self-restricted T cells specific for the same Ab/Ep complex. Our results showed that peptide-specific alloreactive T cells, as compared with self-restricted T cells, were more sensitive to peptide stimulation, but equally sensitive to amino acid substitutions in the peptide. These findings indicate that alloreactive and self-restricted T cells interact similarly with their MHC/peptide ligand.

Amino Acid Sequence↗
PubMed2000

Adherence to protease inhibitor therapy and outcomes in patients with HIV infection.

BACKGROUND: Combination antiretroviral therapy with protease inhibitors has transformed HIV infection from a terminal condition into one that is manageable. However, the complexity of regimens makes adherence to therapy difficult. OBJECTIVE: To assess the effects of different levels of adherence to therapy on virologic, immunologic, and clinical outcome; to determine modifiable conditions associated with suboptimal adherence; and to determine how well clinicians predict patient adherence. DESIGN: Prospective, observational study. SETTING: HIV clinics in a Veterans Affairs medical center and a university medical center. PATIENTS: 99 HIV-infected patients who were prescribed a protease inhibitor and who neither used a medication organizer nor received their medications in an observed setting (such as a jail or nursing home). MEASUREMENTS: Adherence was measured by using a microelectronic monitoring system. The adherence rate was calculated as the number of doses taken divided by the number prescribed. Patients were followed for a median of 6 months (range, 3 to 15 months). RESULTS: During the study period, 45,397 doses of protease inhibitor were monitored in 81 evaluable patients. Adherence was significantly associated with successful virologic outcome (P < 0.001) and increase in CD4 lymphocyte count (P = 0.006). Virologic failure was documented in 22% of patients with adherence of 95% or greater, 61% of those with 80% to 94.9% adherence, and 80% of those with less than 80% adherence. Patients with adherence of 95% or greater had fewer days in the hospital (2.6 days per 1000 days of follow-up) than those with less than 95% adherence (12.9 days per 1000 days of follow-up; P = 0.001). No opportunistic infections or deaths occurred in patients with 95% or greater adherence. Active psychiatric illness was an independent risk factor for adherence less than 95% (P = 0.04). Physicians predicted adherence incorrectly for 41% of patients, and clinic nurses predicted it incorrectly for 30% of patients. CONCLUSIONS: Adherence to protease inhibitor therapy of 95% or greater optimized virologic outcome for patients with HIV infection. Diagnosis and treatment of psychiatric illness should be further investigated as a means to improve adherence to therapy.

Adult↗
PubMed2000

Allele-specific expression patterns of interleukin-2 and Pax-5 revealed by a sensitive single-cell RT-PCR analysis.

Autosomal genes that are subject to random allelic inactivation (RAI), like imprinted genes [1] and genes subject to X-inactivation [2], require mechanisms that dictate the differential transcriptional regulation of two sequence-identical alleles. RAI genes include olfactory receptor genes [3], and the various genes encoding antigen receptors on lymphocytes (immunoglobulin genes, T cell receptor genes and NK receptor genes [4] [5] [6] [7]). These observations raise the possibility that other genes might be similarly regulated. Moreover, an interesting possibility is that certain genes might be monoallelically expressed in some cells and biallelically expressed in others. Recently, reports of monoallelic expression of interleukin-2 (IL-2) [8] [9] and IL-4 [10] [11] have raised the possibility that the cytokine gene family may be subject to monoallelic expression. Another report suggests that the gene encoding the transcription factor Pax-5, which is involved in B-cell (and cerebellar) development [12] [13], is also subject to monoallelic expression [14]. Using a novel single-cell reverse transcription-polymerase chain reaction (RT-PCR) approach, we have analyzed the IL-2 and Pax-5 genes in mice. We found that IL-2 is monoallelically transcribed in some T cells and biallelically transcribed in others, raising interesting questions regarding cytokine gene regulation. Additionally, our analyses suggest that Pax-5 is consistently biallelically transcribed. Thus, the IL-2 gene and other cytokine genes may be regulated in a stochastic manner that results in 0, 1 or 2 alleles of a given cytokine gene expressed in each T cell. This type of regulation could account for the wide variety of different combinations of cytokine genes expressed in individual T cells and therefore plays a role in the generation of T cells with a range of different effector functions.

Alleles↗
PubMed2000

Encephalitis caused by human herpesvirus-6 in transplant recipients: relevance of a novel neurotropic virus.

BACKGROUND: Human herpesvirus-6 (HHV-6) is a neurotropic virus. Encephalitis is a significant clinical manifestation of HHV-6; however, sparse data on this entity exist in transplant recipients. METHODS: Cases of HHV-6 encephalitis reported in the literature (13 bone marrow transplant recipients and 1 liver transplant recipient) were reviewed. The diagnosis was established in all by viral isolation and/or detection of HHV-6 DNA in the cerebrospinal fluid by polymerase chain reaction or histopathologic method. RESULTS: HHV-6 encephalitis occurred a median of 45 days (range 10 days to 15 months) after transplantation. Mental status changes, ranging from confusion to coma (92%), seizures (25%), and headache (25%) were the predominant clinical presentations. Focal neurologic findings occurred in only 17% of the patients. Twenty-five percent of the patients had fever; however, the height of fever (< or =40 degrees C) in febrile patients was striking. Cerebrospinal fluid pleocytosis was generally lacking. Abnormal neuroimaging findings, characterized by low-attenuation lesions in the posterior cerebral lobes, were present only in 17% of the patients. Overall mortality in patients with HHV-6 encephalitis was 58% (7 of 12); 42% (5 of 12) of the deaths were caused by HHV-6. Cure was documented in 7 of 8 patients who received ganciclovir or foscarnet for > or =7 days, compared with 0% (0 of 4) in those who did not receive these drugs or received them for < 7 days (P=.01). CONCLUSIONS: HHV-6 may be associated with encephalitis after transplantation and warrants consideration in transplant recipients with encephalitis of unidentifiable etiology.

Adolescent↗
PubMed2000

Human herpesvirus-6 in liver transplant recipients: role in pathogenesis of fungal infections, neurologic complications, and outcome.

BACKGROUND: The clinical impact and relevance of human herpesvirus-6 (HHV-6) infection in liver transplant recipients, has not been fully discerned. METHODS: A prospective study of 80 consecutive liver transplant recipients was performed using surveillance cultures for HHV-6 at weeks 2, 3, 4, and 6 after transplantation. Viral isolation was used for the detection of HHV-6. RESULTS: HHV-6 infection occurred in 39% (31 of 80) of the patients. Patients with HHV-6 infection were more likely to have hepatocellular carcinoma as underlying liver disease (P=.09). Mental status changes of unidentifiable etiology were significantly more likely to occur in patients with HHV-6 compared with those without (26%, 9 of 31 vs. 6%, 3 of 49, P=.008). HHV-6 infection was an independent predictor of invasive fungal infections (odds ratio 8.3, 95% confidence interval, 1.2-58.0, P=.03). A significant association between HHV-6 infection and CMV infection after transplantation, CMV recipient and donor serostatus, rejection, or fever of unknown origin, could not be documented. Mortality at last follow-up in patients with HHV-6 infection (29%, 9 of 31) was significantly greater than those without HHV-6 (6%, 3 of 49, P=.008). CONCLUSIONS: Central nervous system complications of unknown etiology after liver transplantation may be related to HHV-6 infection. HHV-6 viremia was an independently significant predictor of invasive fungal infections and was associated with late mortality in liver transplantation recipients.

Adult↗
PubMed2000

Effect of calcium carbonate on the absorption of levothyroxine.

CONTEXT: The effect of calcium carbonate on the absorption of levothyroxine has not been studied systematically. Such a potential drug interaction merits investigation because concurrent treatment with both drugs is common, particularly in postmenopausal women. OBJECTIVE: To investigate the potential interference of calcium carbonate in the absorption of levothyroxine. DESIGN: Prospective cohort study conducted from November 1998 to June 1999, supplemented with an in vitro study of thyroxine (T(4)) binding to calcium carbonate. SETTING: Veterans Affairs Medical Center in West Los Angeles, Calif. PATIENTS: Twenty patients (age range, 27-78 years; n=11 men) with hypothyroidism who were taking a stable long-term regimen of levothyroxine were included in the study. All patients had serum free T(4) and thyrotropin values in the normal range before beginning the study. INTERVENTION: Subjects were instructed to take 1200 mg/d of elemental calcium as calcium carbonate, ingested with their levothyroxine, for 3 months. MAIN OUTCOME MEASURES: Levels of free T(4), total T(4), total triiodothyronine (T(3)), and thyrotropin, measured in all subjects at baseline (while taking levothyroxine alone), at 2 and 3 months (while taking calcium carbonate and levothyroxine), and 2 months after calcium carbonate discontinuation (while continuing to take levothyroxine). RESULTS: Mean free T(4) and total T(4) levels were significantly reduced during the calcium period and increased after calcium discontinuation. Mean free T(4) levels were 17 pmol/L (1.3 ng/dL) at baseline, 15 pmol/L (1.2 ng/dL) during the calcium period, and 18 pmol/L (1.4 ng/dL) after calcium discontinuation (overall P<.001); mean total T(4) levels were 118 nmol/L (9.2 microg/dL) at baseline, 111 nmol/L (8.6 microg/dL) during the calcium period, and 120 nmol/L (9.3 microg/dL) after calcium discontinuation (overall P=.03). Mean thyrotropin levels increased significantly, from 1.6 mIU/L at baseline to 2.7 mIU/L during the calcium period, and decreased to 1. 4 mIU/L after calcium discontinuation (P=.008). Twenty percent of patients had serum thyrotropin levels higher than the normal range during the calcium period; the highest observed level was 7.8 mIU/L. Mean T(3) levels did not change during the calcium period. The in vitro study of T(4) binding to calcium showed that adsorption of T(4) to calcium carbonate occurs at acidic pH levels. CONCLUSIONS: This study of 20 patients receiving long-term levothyroxine replacement therapy indicates that calcium carbonate reduces T(4) absorption and increases serum thyrotropin levels. Levothyroxine adsorbs to calcium carbonate in an acidic environment, which may reduce its bioavailability. JAMA. 2000;283:2822-2825

Absorption↗
PubMed2000

Immunosuppressive-associated leukoencephalopathy in organ transplant recipients.

Immunosuppressive-associated leukoencephalopathy is a significant complication of cyclosporine (CsA) or tacrolimus therapy. However, the precise time of onset, role of putative risk factors, differences, if any, in presentation in various types of organ transplantation and outcome of this entity, remain poorly defined. Fifty cases of immunosuppressive-associated leukoencephalopathy reported in the literature in organ transplant recipients, were reviewed. Of 50 cases, 31 occurred in liver, 8 in renal, 6 in lung, and 5 in heart transplant recipients. Median time to onset was 28 days (range 3-1512 days); 82% occurred within 90 days of transplantation. Lesions tended to occur earlier in the liver transplant recipients, compared with other organ transplant recipients (median 9 vs. 29 days, P=.19). Seizures 74%, altered mental status 50%, and visual abnormalities 28% were the most frequently presenting features. Ten percent of the patients had fever with no documented source of infection. Systemic hypertension (P=.001), and lesions in the presence of therapeutic drug levels (P=.11) were more likely to occur with CsA than tacrolimus. Neuroimaging and clinical abnormalities were reversible on cessation or reduction of CsA or tacrolimus in all but two cases. Resolution of neurologic signs/symptoms occurred a median of 4 days and neuroimaging abnormalities in a median of 20 days on reduction/cessation of the drug. Immunosuppressive-associated leukoencephalopathy is a unique entity that can usually be diagnosed on the basis of its distinctive time of onset, and clinical and neuroimaging characteristics, and it is potentially reversible if promptly diagnosed. Despite identical clinical presentation of this syndrome in the recipients of CsA and tacrolimus, above noted variations in risk factors suggest that a difference in pathophysiologic mechanism may exist.

Cyclosporine↗
PubMed2000

Late-onset renal failure after liver transplantation: role of posttransplant alcohol use.

BACKGROUND: Late-onset renal failure is being increasingly recognized as a complication in patients undergoing liver transplantation for hepatitis C virus (HCV). However, its precise incidence, predisposing risk factors, and impact on outcome after liver transplantation, have not been defined. METHODS: The development of late-onset renal failure (defined as serum creatinine persistently >2.0 mg/dl, occurring more than 6 months posttransplant) was assessed in 120 consecutive liver transplant recipients who survived at least 6 months after transplantation. Fifty-seven percent (68/120) of the patients had undergone transplantation for liver disease due to HCV. The median follow-up was 5 years. RESULTS: Late-onset renal failure developed in 28% (33/120)of the patients. Posttransplant alcohol use (P=0.0001), posttransplant diabetes (P=0.0042), and recurrent HCV hepatitis (P=0.019) were significantly associated with late onset renal failure. In multivariate analysis, alcohol use (O.R. 10.7, 95%; CI 2.4-35.9, P=0.001) and diabetes (O.R. 2.1, 95%; CI 1.1-9.9, P=.03) were independently significant predictors of late onset renal failure. When only patients transplanted for HCV were analyzed, posttransplant alcohol use (P=0.004) was the only significant independent predictor of late-onset renal failure. HCV genotype 1b, as compared with other HCV genotypes, was associated with a higher rate of late-onset renal failure in patients with HCV; 70% of the patients with genotype 1b versus 32% of those with 1a and 33% of those with 2b, developed late onset renal failure (P=0.03). At a median follow up of 5 years, mortality in patients with HCV with late-onset renal failure was 52% as compared with 2% in those without renal failure (P=.0001). CONCLUSION: Late-onset renal failure in patients with HCV portended a grave outcome. Alcohol use was an independent predictor of late-onset renal failure in patients with HCV and represents a potentially modifiable risk factor for late-onset renal failure in these patients.

Adult↗
PubMed2000

Comparison of the mutations at Hprt exon 3 of T-lymphocytes from B6C3F1 mice and F344 rats exposed by inhalation to 1,3-butadiene or the racemic mixture of 1,2:3,4-diepoxybutane.

Experiments were conducted to define the spectra of mutations occurring in Hprt exon 3 of T-cells isolated from spleens of female B6C3F1 mice and F344 rats exposed by inhalation to 1,3-butadiene (BD) or its reactive metabolite, (+/-)-diepoxybutane (DEB). Hprt mutant frequencies (Mfs) in BD-exposed (1250 ppm for 2 weeks or 625 ppm for 4 weeks; 6 h/day, 5 days/week) and DEB-exposed (2 or 4 ppm for 4 weeks or 5 ppm for 6 weeks; 6 h/day, 5 days/week) mice and rats were significantly increased over concurrent control values. Mutant T-cell colonies from control and treated animals were screened for mutations in Hprt exon 3 using PCR amplification of genomic DNA and denaturing gradient gel electrophoresis, followed by sequence analysis. Exon 3 mutations were found at the following frequencies: 20/394 (5%) in control mice, 56/712 (8%) in BD-exposed mice, 59/1178 (5%) in BD-exposed rats, 66/642 (10%) in DEB-exposed mice, and 51/732 (7%) in DEB-exposed rats. Mutations in exposed animals included base substitutions, small deletions (1 to 74 bp), and small insertions (1 to 8 bp), with base substitutions predominating. Among the types of base substitutions observed in mice, the proportions of G.C-->A.T transitions (p=0.035, Fisher's Exact Test) and G.C-->C.G transversions (p=0.05) were significantly different in control vs. BD-exposed animals. Given the small number of exon 3 mutants analyzed, there was a high degree of overlap in the mutational spectra between BD-exposed mice and rats, between BD- and DEB-exposed mice, and between BD- and DEB-exposed rats in terms of the sites with base substitutions, the mutations found at those mutated sites, the relative occurrence of the most frequently observed base substitutions, and the occurrence of a consistent strand bias for the most frequently observed base substitutions. The spectra data suggest that adduction of both G.C and A.T bps is important in the induction of in vivo mutations by BD metabolites in exposed mice and rats.

Administration, Inhalation↗
PubMed2000

Thrombocytopenia in liver transplant recipients: predictors, impact on fungal infections, and role of endogenous thrombopoietin.

BACKGROUND: Thrombocytopenia is a frequent and potentially serious complication in liver transplant recipients. The role of endogenous thrombopoietin level in posttransplant thrombocytopenia, has not been fully defined in liver transplant recipients. Additionally, there is accumulating evidence to suggest that platelets play a important role in antimicrobial host defense. METHODS: There were 50 consecutive liver transplant recipients studied. Variables predictive of thrombocytopenia, its impact on infectious morbidity and outcome, and serial thrombopoietin (TPO) serum concentration were assessed. RESULTS: The median pretransplant platelet count was 67 x 10(3)/cmm. After the liver transplantation, the median nadir platelet count was 33 x 10(3)/cmm and was reached a mean of 6 days after the transplant. A lower pretransplant platelet count (r= +.068, P=.0001), lower serum albumin before the transplants (r=+0.39, P=.014), longer operation time (r=0.27, P=.05), higher intraoperative packed red cells (r=0.28, P=.049) and fresh frozen plasma transfusions (r=0.42, P=.004), higher bilirubin at Day 7 (r=-.386, P=.005), and higher serum creatinine at Day 7 after the transplants (r=-.031, P=.025) correlated significantly with a lower nadir in platelets after the transplant. Nadir in platelet count was significantly lower in nonsurvivors compared with survivors (16 vs. 36 x 10(3)/cmm, P=.0001). Forty-three percent (9 of 21) of the patients with nadir platelet counts of < or =30 x 10(3)/cmm had a major infection within 30 days of the transplant compared with 17% (5 of 29) with nadir platelet counts > 30 x 10(3)/cmm (P=.04). Fungal infections occurred in 14% of the patients with nadir platelet counts of < or =30 x 10(3)/cmm versus 0% in those with nadir platelet counts of > 30 x 10(3)/cmm (P=.06); all patients with fungal infections had nadir platelet counts of < or =30 x 10(3)/cmm before fungal infection. Nadir in platelet count preceded the first major infection by a median of 7 days. Pretransplant TPO level did not differ between survivors (mean 103 pg/ml) or nonsurvivors (mean 144 pg/ml). After the transplantation, TPO levels increased in both groups. TPO level peaked at Day 7 and subsequently declined in survivors. Nonsurvivors had persistent thrombocytopenia despite a progressive rise in TPO level; TPO level was significantly higher at Day 7 (P=.02), Day 9 (P=.0019), and Day 14 (P=.04) in nonsurvivors compared with survivors. CONCLUSION: Persistent thrombocytopenia portended a poor outcome in liver transplant recipients and was not related to low TPO levels. Thrombocytopenia preceded infections and identified a subgroup of liver transplant patients susceptible to early major infections; its precise role in fungal infections warrants validation in larger studies.

Adult↗
PubMed2000

Predicting bacteremia and bacteremic mortality in liver transplant recipients.

Predictors of bacteremia and mortality in bacteremic liver transplant recipients were prospectively assessed. One hundred eleven consecutive episodes of fever or infections were documented in 59 patients over a 4-year period. Forty-nine percent (29 of 59 patients) of the patients had bacteremia, 39% (23 of 59 patients) had nonbacteremic infections, and 12% (7 of 59 patients) had fever of noninfectious cause. Primary (catheter-related) bacteremia (31%; 9 of 29 patients), pneumonia (24%; 7 of 29 patients), abdominal and/or biliary infections (14%; 4 of 29 patients), and wound infections (10%; 3 of 29 patients) were the predominant sources of bacteremia. Diabetes mellitus (odds ratio, 6.9; P =.03) and serum albumin level less than 3.0 mg/dL (odds ratio, 0.14; P =.02) were independently significant predictors of bacteremia compared with nonbacteremic infections. Mortality at 14 days was 28% (8 of 29 patients) in those with bacteremia compared with 4% (1 of 23 patients) in those with nonbacteremic infections and 0% (0 of 7) in patients with fever of noninfectious cause (P =.03). Intensive care unit stay at the time of bacteremia (100% v 47%; P =.005), absence of chills (0% v 53%; P =.005), lower temperature at the onset of bacteremia (99.2 degrees F v 101.5 degrees F; P =.009), lower maximum temperature during the course of bacteremia (99.3 degrees F v 102 degrees F, P =.008), greater serum bilirubin level (7.6 v 1.5 mg/dL; P =.024), presence of abnormal blood pressure (80% v 16%; P =. 0013), and greater prothrombin time (15.6 v 13.3 seconds; P =.013) were significantly predictive of greater mortality in the bacteremic patients. These data have implications for discerning the likelihood of bacteremia and initiation of empiric antibiotics pending cultures. Lack of febrile response in bacteremic liver transplant recipients portended a poorer outcome.

Antibiotic Prophylaxis↗