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Biomedical subjects

R H Rubin

Publications and source records attributed to R H Rubin.

At least 127 records · Page 7Linked to original sources
PubMed1993

Renal transplantation and related infections.

Although patient survival 1 year after kidney transplantation is greater than 90%, infection remains a leading cause of morbidity and death. The risk of infection is related to exposures to potential pathogens in the patient's environment (epidemiological exposures) and the patient's endogenous net state of immunosuppression. Approximately 70% of severe bacterial, fungal, and viral infections occur within 3 months of transplantation. Cytomegalovirus (CMV) infection is still the most important infectious agent following renal transplantation because of its direct effects-morbidity and mortality caused by CMV syndrome and disease, and its indirect effects-contribution to the net state of immunosuppression, which independently increases the risk of opportunistic superinfection. Management of infection in the renal-transplant recipient focuses on preventative strategies. In addition to traditional prophylactic strategies, transplant recipients may benefit from preemptive therapy, ie, therapy directed at patients who are at the greatest risk of developing clinically significant disease, at a time when the risk is maximal. Use of preemptive ganciclovir therapy for the prevention of CMV disease in CMV seropositive renal-transplant recipients during therapy with antilymphocyte antibody is an example of such a strategy. The therapeutic prescription for the transplant recipient is an effective immunosuppressive regimen combined with an anti-infective strategy to ensure its safety.

Humans↗
PubMed1993

Technetium-99m-labeled hydrazino nicotinamide derivatized chemotactic peptide analogs for imaging focal sites of bacterial infection.

We synthesized and evaluated four hydrazino nicotinamide (HYNIC) derivatized chemotactic peptide analogs: For-NleLFK-HYNIC (HP1), For-MLFK-HYNIC (HP2), For-MLFNH(CH2)6NH-HYNIC (HP3), and For-MLF-(D)-K-HYNIC (HP4), for in vitro bioactivity and receptor binding. The peptides were radiolabeled with 99mTc via a glucoheptonate co-ligand and their biodistribution determined in rats (n = 6/time point) at 5, 30, 60 and 120 min after injection. Localization of the peptides at sites of deep thigh Escherichia coli infection was determined by radioactivity measurements on excised tissues in rats (n = 6/time point) and rabbits as well as scintillation camera imaging in rabbits (n = 6). All peptides maintained biological activity (EC50s for O2 production by human PMNs: 12-500 nM) and the ability to bind to the oligopeptide chemoattractant receptor on human PMNs (EC50s for binding: 0.12-40 nM). After incubation with 99mTc-glucoheptonate, radiolabeled peptides were isolated by HPLC at specific activities of > 10,000 mCi/microM. Technetium-99m-labeled peptides retained receptor binding with EC50s < 10 nM. Blood clearance of all four peptides was rapid. Biodistributions of the individual peptides were similar, with low levels of accumulation in most normal tissues. In rats, all of the peptides concentrated at the infection sites (T/B ratio: 2.5-3:1) within 1 hr of injection. In rabbits, outstanding images of the infection sites were obtained, with T/B ratios of > 20:1 at 15 hr after injection. This study demonstrates that 99mTc-labeled chemotactic peptide analogs are effective agents for the external imaging of focal sites of infection.

Animals↗
PubMed1993

Localization of indium-111-immunoglobulin G, technetium-99m-immunoglobulin G and indium-111-labeled white blood cells at sites of acute bacterial infection in rabbits.

Biodistribution and infection imaging properties of 111In-DTPA-IgG, 99mTc-hydrazino nicotinamide-IgG and 111In-WBC were compared in rabbits with E. coli infection. Groups of six rabbits were injected with 10 mCi of 99mTc-IgG plus 0.5 mCi of 111In-IgG or 1 mCi of 99mTc-IgG plus 0.05 mCi of 111In-WBC. At 4-5 and 18-20 hr, dual photon scintigrams were acquired. At both times, the distributions of 99mTc and 111In-IgG were nearly identical. The sites of infection were well visualized with all three radiopharmaceuticals. In the early images, the target-to-background ratios (T/B) for 111In and 99mTc-IgG determined by ROI analysis were 1.95 +/- 0.26 and 2.57 +/- 0.38 (p = NS). In the delayed images, the T/B ratios increased (p < 0.01) to 3.56 +/- 0.49 and 4.90 +/- 0.98. At both times, the T/B ratios for 111In-WBC were higher (p < 0.01); 4.17 +/- 0.78 at 4-5 hr and 8.52 +/- 1.52 at 18-20 hr. These results indicate that all three agents yield excellent images of infection sites. Although 111In-WBC had higher T/B ratios, the ease of preparation of the radiolabeled proteins makes them attractive alternatives for infection imaging.

Acute Disease↗
PubMed1993

In vivo bioactivity and biodistribution of chemotactic peptide analogs in nonhuman primates.

The dose dependence of the effect of chemotactic peptide on peripheral leukocyte levels was measured in normal Rhesus monkeys. A 99mTc-labeled hydrazino nicotinamide (HYNIC) derivatized chemotactic peptide analog was used to study biodistribution and inflammation imaging in Rhesus monkeys. In normal animals the studies demonstrated that chemotactic peptide induced a clear dose-dependent reduction in peripheral leukocyte levels. The decrease in leukocyte number occurred almost immediately after injection and rapidly returned to baseline. Significant effects on differential WBC count, blood pressure, pulse rate or respiration rate were not detected. The lowest dose of peptide tested (10 ng/kg) had minimal effect on leukocyte level. The HYNIC derivatized peptide was prepared in excellent yield and purity, had biological activity similar to the native peptide and was readily labeled at specific activity of > 20,000 mCi/mumole. When approximately 0.5 mCi (< 2.0 ng/kg) of radiolabeled peptide was injected in monkeys with focal sites of mild sterile inflammation, a pattern of biodistribution similar to radiolabeled WBCs was observed and reductions in leukocyte levels were not detected. At 3 hr after injection, the site of inflammation was readily apparent with a target-to-background ratio of approximately 3:1. These studies demonstrate that radiolabeled chemotactic peptide analogs are effective agents for imaging sites of inflammation in monkeys. By radiolabeling at high specific activity, the effect of these reagents on peripheral leukocyte levels can be avoided.

Animals↗
PubMed1993

Technetium-99m-labeled chemotactic peptides: comparison with indium-111-labeled white blood cells for localizing acute bacterial infection in the rabbit.

The biodistribution and infection imaging properties of 99mTc-labeled formyl-methionyl-leucyl-phenylalanyl-lysyl-hydrazinonicotinamide (99mTc-HP) were compared with 111In-labeled leukocytes (111In-WBCs) in rabbits with E. coli infections. Groups of six animals were co-injected with 1 mCi of 99mTc-HP plus 0.05 mCi of 111In-WBCs and serial scintigrams were acquired from 3 to 6 hr and 18 hr postinjection. After acquiring the final images, the animals were killed and biodistribution was determined. At all imaging times, the distributions of 99mTc-HP and 111In-WBCs were similar and the sites of infection were well visualized with both radiopharmaceuticals. The target (infected muscle) to background (contralateral normal muscle) ratios (T/B) were: 3.38 +/- 0.46, 3.80 +/- 0.37 and 10.87 +/- 1.44 for 99mTc-HP and 1.71 +/- 0.04, 1.81 +/- 0.26 and 3.79 +/- 0.83, for 111In-WBCs at 3, 6 and 18 hr postinjection, respectively. The average ratio of T/B ratios (99mTc-HP-to-111In-WBCs) was 2.99 +/- 1.88, with no value less than unity. T/B ratios calculated from direct tissue sampling were significantly higher for 99mTc-HP than for 111In-WBCs (33.6:1 versus 8.1:1, p < 0.01). These differences were primarily due to increased absolute accumulation of 99mTc-HP (0.102%ID/g versus 0.024%ID/g, p < 0.01) in infected muscle rather than a difference in accumulation in normal skeletal muscle. These results indicate that 99mTc-HP yields target-to-background ratios greater than or equal to those achievable with 111In-WBCs probably as a result of an increase in absolute accumulation at the site of infection.

Acute Disease↗
PubMed1993

Understanding and diagnosing infectious complications in the immunocompromised host. Current issues and trends.

The number of patients who are at an increased risk of life-threatening infection has expanded greatly during the past decade. This expansion is because of two events, one terrible in its consequences, the other very positive. The first is the unprecedented epidemic of opportunistic infection that follows infection with the human immunodeficiency virus or the acquired immunodeficiency syndrome. The second is a direct consequence of the successes of the transplant surgeon, the cancer chemotherapist, the hematologist, and the rheumatologist. The authors review the current issues and trends in understanding and diagnosing infectious complications in the immunocompromised host.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Trimethoprim-sulfamethoxazole compared with ciprofloxacin for the prevention of urinary tract infection in renal transplant recipients. A double-blind, randomized controlled trial.

BACKGROUND: Prophylaxis with low-dose trimethoprim-sulfamethoxazole has been shown to be cost-effective in the prevention of urinary tract infections, pyelonephritis, urosepsis, and pneumocystis pneumonia in renal transplant recipients. Ciprofloxacin, effective against almost all urinary tract pathogens in this patient population, represents a promising alternative prophylactic agent for patients unable to tolerate trimethoprim-sulfamethoxazole due to toxicity. METHODS: We conducted a randomized, double-blind trial to compare low-dose trimethoprim-sulfamethoxazole with ciprofloxacin for the prevention of urinary tract infections in renal transplant recipients. Patients received either ciprofloxacin (250 mg) or trimethoprim-sulfamethoxazole (80 mg trimethoprim, 400 mg sulfamethoxazole) daily for 6 months following transplantation. Treatment was considered successful if patients completed the 6-month course and 3-month follow-up period without evidence of urinary tract infection or drug-related toxicities. RESULTS: Of 103 eligible patients, 51 received ciprofloxacin and 52 received trimethoprim-sulfamethoxazole. At 6 months, treatment was successful in 75% (38 of 51) receiving ciprofloxacin and 71% (37 of 52) treated with trimethoprim-sulfamethoxazole (P = 0.87, relative risk 1.04, 95% confidence limits 0.83 to 1.33). Thirteen patients (25%) receiving trimethoprim-sulfamethoxazole withdrew from the study-4 for resistant urinary tract infection and 9 for drug-related toxicity, while 3 (6%) of the patients receiving ciprofloxacin withdrew because of drug-related toxicity (P = 0.016, relative risk of urinary tract infection or adverse event 0.24, 95% confidence limits 0.07 to 0.78). At 9 months, all 38 patients who completed the 6-month course of ciprofloxacin remained free of urinary tract infection, while an additional 4 patients who had received trimethoprim-sulfamethoxazole prophylaxis (total of 8 patients over the 9 months) developed urinary tract infections (P = 0.006, Fisher's exact test for urinary tract infection alone). Pneumocystis pneumonia occurred in a total of 7 (14%) patients who were randomized to ciprofloxacin, but 2 of the 7 had withdrawn from the study at least 2 weeks prior to the diagnosis of pneumocystis pneumonia. There were no cases of pneumocystis pneumonia in patients receiving trimethoprim-sulfamethoxazole (P = 0.006). Following completion of the study, monthly aerosolized pentamidine administered in conjunction with ciprofloxacin has provided complete protection against urinary tract infection and pneumocystis pneumonia in 30 transplant recipients unable to tolerate trimethoprim-sulfamethoxazole therapy. CONCLUSIONS: Ciprofloxacin is at least as effective as trimethoprim-sulfamethoxazole in the prevention of urinary tract infection in renal transplant recipients, and is better tolerated. Ciprofloxacin prophylaxis is associated with a higher incidence of pneumocystis pneumonia than is trimethoprim-sulfamethoxazole therapy. An uncontrolled follow-up study suggests that ciprofloxacin prophylaxis combined with monthly aerosolized pentamidine may be efficacious in preventing both urinary tract infection and pneumocystis pneumonia in renal transplant recipients.

Adult↗
PubMed1992

Accumulation of immunoglobulin G at focal sites of inflammation.

To evaluate the factors responsible for the accumulation of indium-111 immunoglobulin G (111In-IgG) at sites of inflammation, sequential measurements of tissue blood volume, interstitial fluid volume and accumulation of radiolabelled albumin and IgG were made in rats following Escherichia coli infection in the thigh. Compared with normal thigh muscle, there was approximately two-fold increase in interstitial fluid volume and approximately 1.5-fold increase in plasma and red blood cell volumes in infected muscle. For both proteins, there was a fivefold increase in influx rate constant (kin) in infected muscle. In normal muscle, the interstitial fluid concentration of labelled human serum albumin (111In-HSA) was significantly higher than that of 111In-IgG (P less than 0.01). In contrast, the concentrations in infected muscle were nearly identical. The concentration ratios (infected to normal muscle) were 1.7:1 for HSA and 3:1 for IgG. These data suggest that the infection imaging properties of 111In-IgG are related to expansion of the space available to macromolecules in infected tissue and increased transport into this space. At clinically important imaging times (24-48 h after injection), the higher target-to-background ratio of 111In-IgG compared with 111In-HSA is not due to the higher accumulation IgG in infected tissue but rather to the higher accumulation of HSA in normal tissue.

Animals↗
PubMed1992

Regional perfusion, oxygen metabolism, blood volume and immunoglobulin G accumulation at focal sites of infection in rabbits.

Infection causes remarkable changes in extracellular fluid volume, blood flow and oxygen consumption in the region of the lesion. To determine the sequence and magnitude of these changes, we performed serial scintigraphic measurements in 10 rabbits with experimental Escherichia coli abscesses. Positron emission tomography with C15O2, 15O2 and 11CO was used to measure regional blood flow, oxygen extraction (OEF) and blood volume; extracellular fluid volume was evaluated by single photon scintigraphy with indium-111 immunoglobulin G (IgG). Images were recorded following tracer administration at 1 and 7-10 days after infection. At the first imaging time, blood flow to infected muscle had increased by 40% compared with control sites (7.4 +/- 0.6 to 10.8 +/- 3.8 ml/min.100 g), OEF had decreased from 55% +/- 34% to 45% +/- 14%, and the infected-to-contralateral (I/C) ratio of IgG had increased to 3.34 +/- 1.85. At the later imaging time, flow had increased by almost threefold compared with day 1 (29.4 +/- 9.8 ml/min.100 g), OEF had decreased to 29% +/- 14%, and the I/C ratio for IgG had remained constant. Although OEF fell, oxygen delivery (OEF x flow) increased from 4.07 ml/min (control value) to 4.86 ml/min on day 1 and 8.64 ml/min on days 7-9. The infected-to-contralateral (IC) ratio of 15O2/C15O2 was 0.74 +/- 0.15 on day 1 and 0.77 +/- 0.10 at 7-9 days. These studies indicate that expansion of the extracellular fluid volume increases early in the evolution of the infection and exceeds changes in regional perfusion and oxygen delivery.

Animals↗
PubMed1992

Evaluation of new anti-infective drugs for the treatment of urinary tract infection. Infectious Diseases Society of America and the Food and Drug Administration.

The term urinary tract infection (UTI) encompasses a broad range of clinical entities that share one characteristic: a positive urine culture. Clinical manifestations and responses to therapy are diverse even when comparable numbers of a particular bacterial species are identified on urine culture. These guidelines include discussion of acute uncomplicated cystitis, acute uncomplicated pyelonephritis, and complicated infections of the urinary tract. It is proposed that the finding of > or = 10(3) cfu/mL of urine defines significant bacteriuria in acute uncomplicated cystitis, > or = 10(4) cfu/mL in acute uncomplicated pyelonephritis and UTI in men, and > or = 10(5) cfu/mL in complicated UTI. The preferred clinical study design is prospective, randomized, and controlled with an active agent. Ideally, treatment with antimicrobial agents should eradicate the infecting organism, bring about the resolution of clinical signs and symptoms, have few adverse effects, and prevent reinfection.

Adult↗
PubMed1992

Indium-111-labeled human nonspecific immunoglobulin G: a new radiopharmaceutical for imaging infectious and inflammatory foci.

Indium-111-labeled human nonspecific immunoglobulin G (111In-IgG) is a newly developed radiopharmaceutical for imaging infectious and inflammatory foci. This article presents an overview of the literature concerning 111In-IgG scintigraphy. The current theory about the mechanism of accumulation suggests that 111In-IgG accumulates in lesions as a result of enhanced vascular permeability and subsequent entrapment of the radiolabeled protein. Human studies show excellent results in imaging bone and joint, abdominal, and intravascular infection. Of special interest is the ability to depict infectious foci in granulocytopenic patients. The value of 111In-IgG scintigraphy for detection of infection is compared with that of gallium-67, labeled-leukocyte, and technetium-99m (99mTc) nanocolloid scintigraphy. The significance of differences between 111In-IgG scintigraphy and two other new scintigraphic techniques, 99mTc-labeled IgG and 99mTc-labeled murine monoclonal anti-granulocyte antibody BW 250/183, are discussed.

Animals↗
PubMed1992

An approach to evaluating antibacterial agents in the treatment of urinary tract infection.

The evaluation of antibacterial therapy for urinary tract infection (UTI) is based on the results of randomized, controlled comparative studies (preferably double-blinded) in which sufficient numbers of patients are entered into both arms to ensure statistical validity. Since the term UTI encompasses a broad array of clinical syndromes (acute uncomplicated UTI; acute uncomplicated pyelonephritis; complicated UTI; and asymptomatic bacteriuria), the design of clinical studies should include a careful definition of the clinical syndromes being studied, the course of therapy prescribed, and the microbiological characterization necessary for evaluability. End points to be considered in the evaluation of new therapies include the effect of therapy on clinical symptoms; the ability of the therapy to eradicate the original infecting organism; the incidence of reinfection posttherapy; the number of instances of primary drug resistance of the infecting inoculum; and the incidence of adverse effects with a particular regimen.

Acute Disease↗
PubMed1992

Symptomatic cytomegalovirus disease in the cytomegalovirus antibody seropositive renal transplant recipient treated with OKT3.

A prospective study to investigate risk factors for CMV disease was conducted in 94 renal transplant recipients. CMV disease was defined as either unexplained fever for greater than 3 days with viremia or unexplained fever for greater than 3 days with isolation of CMV from the urine or throat wash and at least one of the following: leukopenia, elevated serum alanine aminotransferase, or biopsy-proved invasive tissue infection of the lung or gastrointestinal tract. Fifty-three patients received immunosuppressive regimens consisting of prednisone and cyclosporine, with or without azathioprine. The remaining 41 patients were treated with these agents plus OKT3 (21 received OKT3 to treat rejection, 20 received OKT3 prophylactically). Thirty-seven patients were at minimal risk of CMV disease (donor and recipient seronegative for CMV); 12 patients were at risk of primary disease (donor seropositive, recipient seronegative), and 45 were at risk of reactivation disease (recipient seropositive at the time of transplantation). The incidences of CMV disease in the 3 groups were 0%, 58%, and 36%, respectively. Although the incidence of CMV disease in patients at risk of primary disease was not influenced by the immunosuppressive regimen, immunosuppression had a profound effect on the occurrence of CMV disease in CMV-seropositive transplant recipients. The incidence of CMV disease in those receiving OKT3 was 59%; but only 21% in those who did not receive OKT3. OKT3 increased the risk of CMV disease five-fold (odds ratio 5.2 (95% confidence limits 1.4-17.5)). In the CMV-seropositive patient, OKT3 was also the most important predictor of CMV disease by multivariate analysis (P less than 0.002). A pilot study of preemptive therapy with ganciclovir (2.5 mg/kg daily during OKT3 therapy) in 17 patients decreased the incidence of CMV disease without appreciable toxicity.

Adult↗
PubMed1992

Viral infection in the renal transplant recipient.

The viral infections with greatest impact on the renal transplant recipient are those due to cytomegalovirus, Epstein-Barr virus, and the two hepatitis viruses, hepatitis B and C. All of these are modulated by the administered immunosuppressive therapy, and all have both direct and indirect effects on the transplant patient. The direct effects are the infectious disease clinical syndromes that are produced (fever and malaise, pneumonia, hepatitis, and so forth). The indirect effects are several--all of these viruses contribute to the patient's net state of immunosuppression, predisposing him or her to the development of opportunistic superinfection with a variety of pathogens. In addition, both Epstein-Barr virus and hepatitis B virus have been clearly linked to the development of certain malignancies (lymphoproliferative disease and hepatocellular carcinoma, respectively). Finally, cytomegalovirus has been linked to allograft injury. Although antiviral strategies effective for cytomegalovirus and Epstein-Barr virus infection are being developed, similar programs are not yet available for the hepatitis viruses.

Cytomegalovirus Infections↗
PubMed1992

Opportunistic fungal and bacterial infection in the renal transplant recipient.

The risk of opportunistic infection in the renal transplant recipient is determined by the interaction between two factors: the epidemiologic exposures the individual encounters within the community and the hospital and a complex function termed the net state of immunosuppression. There are two general categories of opportunistic fungal infection in this patient population: (1) disseminated primary or reactivation infection with one of the geographically restricted systemic mycoses (histoplasmosis, coccidioidomycosis, blastomycosis, and paracoccidioidomycosis) and (2) opportunistic infection with fungal species that rarely cause invasive infection in the normal host (Aspergillus species, Candida species, Cryptococcus neoformans, and the Mucoraceae), with these last usually being acquired within the hospital environment. Newly available azole compounds, fluconazole and itraconazole, are exciting new alternatives to amphotericin in the treatment of at least some of these infections. The three most important forms of opportunistic bacterial infections are those due to Listeria monocytogenes, Nocardia asteroides, and a variety of mycobacterial species. Clinical diseases with these first two are effectively prevented by low-dose trimethoprim-sulfamethoxazole prophylaxis. There are two cardinal therapeutic rules to be followed by clinicians in dealing with these infections: prevention is better than treatment; when treatment is required, however, the major determinant of the success of therapy is the rapidity with which the diagnosis is made and effective therapy is initiated.

Anti-Bacterial Agents↗
PubMed1992

Varicella in pediatric renal transplant recipients.

As of November 1991, 8 of 83 children who had received renal transplants at Massachusetts General Hospital since January 1979 required admission for primary varicella. All 8 had cutaneous manifestations of disease, and 4 had evidence of visceral disease. Three of these 8 children received varicella zoster immune globulin (VZIG) after exposure to varicella; in the remaining children, exposure was not revealed until symptoms were present. All 8 children were treated with high-dose intravenous acyclovir. Two children died of complications of varicella infection, including 1 child who received VZIG on the day of exposure to varicella. Neither VZIG prophylaxis nor treatment with intravenous acyclovir offers complete protection against severe varicella infection to immunosuppressed children who have received organ transplants. A high priority should be given to the evaluation of alternative treatments, such as vaccination to the varicella virus, which could be administered to susceptible transplant candidates, preferably prior to transplantation.

Acyclovir↗
PubMed1992

Effect of carbohydrate modification on the localization of human polyclonal IgG at focal sites of bacterial infection.

Radiolabeled human polyclonal IgG localizes at focal sites of infection/inflammation. Previous studies have sought to identify the mechanism of localization, but the relative importance of specific antigen recognition by individual antibody molecules, binding to Fc receptors on inflammatory cells and nonspecific processes such as increased tissue permeability remains uncertain. This study was performed to evaluate the specific role of Fc receptor binding as a mechanism of localization. The Fc region of IgG was modified by endoglycosidase-F digestion and periodate oxidation to reduce the binding of IgG to Fc receptors. In-vitro binding was tested in an Fc receptor binding assay using the human monocyte-like cell line, U937. The in-vivo ability of the modified antibodies to localize at focal sites of E. coli infection was tested by biodistribution studied with the 111In-labeled proteins. Modification of the carbohydrate moiety of the Fc region of IgG resulted in a marked decrease in Fc receptor binding in vitro; with antibody concentrations of 1 micrograms/ml (which is presumed to exist at infected sites) showing no binding for endoglycosidase modified IgG and 50% binding for periodate modified IgG. In contrast, in-vivo infection localization as measured by level of accumulation or target-to-background ratio was not significantly effected by carbohydrate modification. These studies suggest that the contribution of Fc receptor binding to IgG localization at sites of infection is minimal.

Animals↗