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Rationale and Objectives The role of transthoracic needle biopsy (TTNB) in patients with hematologic malignancies, particularly in discriminating between malignant and benign etiologies, has not been well studied. Hence, the diagnostic efficacy and safety of computed tomography–guided TTNB were retrospectively evaluated in this population. Materials and Methods The records of 53 patients with hematologic malignancies who underwent TTNB from August 1, 1999, to July 31, 2007, were reviewed. Potential factors for increased diagnostic yield and risk for complications were collected and analyzed, including the status of neutropenia, thrombocytopenia, chemotherapy, and transplant as well as lesion size and location. Both cytopathologic and microbiologic results were assessed. Results The most common underlying hematologic malignancy was non-Hodgkin lymphoma, in 20 patients (37.7%). Lesions were most frequently located in the left upper lobe (16 [30.2%]); 33 lesions were pleural based (63.5%), and nine had cavitation (17.0%). TTNB established specific diagnoses in 22 patients (41.5%): malignancies was found in 12 (22.6%) and infections in 10 (18.9%). Sensitivity for detecting malignancy was 50.0%, and sensitivity for the detection of a specific infection was 40.0%. There were no false-positive results. Complications occurred in nine patients (17.0%): self-limited small-volume hemoptysis in one patient (1.9%) and pneumothorax in eight patients (15.1%), one requiring chest tube placement. The results of TTNB led to changes in antimicrobial therapy for eight of the 22 patients with specific diagnoses (36.4%). Conclusions TTNB is a safe diagnostic procedure in patients with hematologic malignancies and has the potential of making specific diagnoses with minimal morbidity.

Item does not contain fulltext BACKGROUND: Computed tomography (CT) of the chest may be used to identify the halo sign, a macronodule surrounded by a perimeter of ground-glass opacity, which is an early sign of invasive pulmonary aspergillosis (IPA). This study analyzed chest CT findings at presentation from a large series of patients with IPA, to assess the prevalence of these imaging findings and to evaluate the clinical utility of the halo sign for early identification of this potentially life-threatening infection. METHODS: Baseline chest CT imaging findings from 235 patients with IPA who participated in a previously published study were systematically analyzed. To evaluate the clinical utility of the halo sign for the early identification and treatment of IPA, we compared response to treatment and survival after 12 weeks of treatment in 143 patients who presented with a halo sign and in 79 patients with other imaging findings. RESULTS: At presentation, most patients (94%) had > or =1 macronodules, and many (61%) also had halo signs. Other imaging findings at presentation, including consolidations (30%), infarct-shaped nodules (27%), cavitary lesions (20%), and air-crescent signs (10%), were less common. Patients presenting with a halo sign had significantly better responses to treatment (52% vs. 29%; P

Received 6 September 2006; accepted 6 September 2006;electronically published 13 September 2006.Author affiliations are listed at the end of the text.Reprints or correspondence: Dr. Elias J. Anaissie, MyelomaInstitute for Research and Therapy, University of Arkansasfor Medical Sciences, 4301 W. Markham, Slot 816, LittleRock, AR 72205 (anaissieeliasj@uams.edu).

The close linkage of infection with the nature and intensity of the transplant immunosuppressive program has led to the concept of the therapeutic prescription. This has two components: an immunosuppressive one to prevent or treat rejection and graft-versus-host disease and an antimicrobial one to make it safe. This review provides a conceptual framework to approach the risk and risk periods for infection in solid organ and hematopoietic stem cell transplant recipients as well as an approach to antimicrobial use in this population.

Background. In a previous randomized trial of voriconazole versus amphotericin B deoxycholate for primary therapy of invasive aspergillosis, voriconazole demonstrated superior efficacy and better survival. In that trial, treatment with voriconazole or amphotericin B deoxycholate could be followed with other licensed antifungal therapies (OLAT). Here, we report the impact of OLAT on the outcome of patients with invasive aspergillosis. Methods. Data on dose, duration, and the reason for switching to the first OLAT were analyzed, and outcome at week 12 was assessed. Results. Fewer patients in the voriconazole group (52 [36%] of 144) switched to OLAT, compared with patients in the amphotericin B deoxycholate group (107 [80%] of 133). Lipid formulations of amphotericin B were the most common OLAT (38% of patients). Switches were made because of intolerance or insufficient response in 70% for patients in the amphotericin B deoxycholate group, compared with 24% of patients in the voriconazole group. Favorable responses to OLAT in the amphotericin B deoxycholate group occurred in only 19% of patients with initial insufficient response and 38% of patients with intolerance. Salvage therapy with a lipid formulation of amphotericin B after initial treatment with amphotericin B deoxycholate was successful for only 30% of patients (14 of 47). Treatment success among patients randomized to receive amphotericin B, including those whose treatment was switched to OLAT, was 32%, compared with 55% among patients who received voriconazole alone (P

Background. Invasive fungal infections (IFI), particularly those caused by Aspergillus and other angioinvasive molds, are associated with an excessive mortality despite therapy. Methods. Voriconazole was prescribed on a compassionate basis to patients with IFI who were intolerant to or who had progressed despite standard therapy. Outcome was determined by protocol-based criteria as established by the consensus definitions (complete response [CR], partial response [PR], stable disease, failure, and intolerance). Results. Forty-five patients were enrolled in a compassionate release program (29 [64%] because of failure of response to standard therapy), between 1998 and 2002. Of the 45 patients enrolled, 35 (78%) had invasive Aspergillus, 3 (7%) had Fusarium, and 2 (4%) had Scedosporium infections. Underlying illnesses were as follows: 13 (29%) solid-organ transplant (SOT), 11 (24%) BMT, and 7 (13%) hematologic malignancy. Site of infection was as follows: 26 (58%) pulmonary, 9 (20%) disseminated, 5 (11%) central nervous system (CNS), and 3 (7%) sinus. Overall response rates were as follows: 9 (20%) CR, 17 (38%) PR, 15 (33%) failure, and 4 (9%) intolerant. Seven of the eight (88%) patients with sinus or CNS disease demonstrated stabilization of the IFI. The median duration of voriconazole therapy was 79 days with 9 (20%) patients receiving over 1 year of therapy. Nine thousand one hundred twenty-eight days of therapy were given with only four serious adverse events in two cases considered possibly or probably drug related. Conclusions. In this population of severely immuno-compromised patients with life-threatening IFI who have failed or were intolerant to standard antifungal therapy, voriconazole demonstrated substantial efficacy and an acceptable level of toxicity.

A randomized, blinded, multicenter trial was conducted to compare fluconazole (800 mg per day) plus placebo with fluconazole plus amphotericin B (AmB) deoxycholate (0.7 mg/kg per day, with the placebo/AmB component given only for the first 5-6 days) as therapy for candidemia due to species other than Candida krusei in adults without neutropenia. A total of 219 patients met criteria for a modified intent-to-treat analysis. The groups were similar except that those who were treated with fluconazole plus placebo had a higher mean (+/- standard error) Acute Physiology and Chronic Health Evaluation II score (16.8+/-0.6 vs. 15.0+/-0.7; P=.039). Success rates on study day 30 by Kaplan-Meier time-to-failure analysis were 57% for fluconazole plus placebo and 69% for fluconazole plus AmB (P=.08). Overall success rates were 56% (60 of 107 patients) and 69% (77 of 112 patients; P=.043), respectively; the bloodstream infection failed to clear in 17% and 6% of subjects, respectively (P=.02). In nonneutropenic subjects, the combination of fluconazole plus AmB was not antagonistic compared with fluconazole alone, and the combination trended toward improved success and more-rapid clearance from the bloodstream.

Background. Pseudomonas aeruginosa is an uncommon cause of infection in the female genital tract. We report a case of postmenopausal tubo-ovarian abscess (TOA) due to P. aeruginosa in a renal transplant recipient. The presentation included mild abdominal symptoms with rapid progression of peritonitis and surgical abscess drainage. This is the first such case in an organ transplant recipient described in the English literature. Methods and Results. Published reports of 1040 cases of TOA were reviewed. The most common features were a history of sexually transmitted disease or pelvic inflammatory disease, and symptoms including abdominal pain and fever. Escherichia coli, Bacteroides spp., and Klebsiella pneumoniae were the most frequently encountered pathogens. Neisseria gonorrhoeae and Chlamydia trachomatis, which are frequently isolated from cervical cultures, are uncommonly isolated from tubo-ovarian abscesses. Forty percent of patients were treated with antibiotics alone, 18.8% with abdominal surgery, and 32% with surgery and antimicrobial therapy. Conclusion. This report illustrates the muted presentation and atypical microbiology of gynecologic infection in an organ transplant recipient.

It is often very difficult to distinguish between infection-related and immunosuppression-related gastrointestinal (GI) complications after transplantation. The risk of infection itself is determined by the patient's net state of immunosuppression as well as the presence of anatomic or technical abnormalities and the patient's epidemiological exposures. Of the anatomic abnormalities, diverticulitis is a particular problem in transplant patients, with a high rate of perforation and abscess formation. The causes of infectious disease syndromes are very different immediately after, early after, and late after transplantation. Infection during the first month may result from a pre-existing infection in the donor or recipient, or from the surgical wound, endotracheal tube, vascular access or drainage. During 1-6 months after transplantation, viruses attack and, with sustained immunosuppression, make opportunistic infections possible. Beyond 6 months after transplantation, the 80% of patients with good result from the transplant are at risk primarily for community-acquired microbes, including such enteric pathogens as Salmonella. Of the remaining patients, 10% have chronic viral infections and the 10% who have poor allograft function are at greatest risk for opportunistic infection. This time line is helpful in determining whether a GI complication is likely to be related to infection rather than a specific effect of an immunosuppressant drug. Fever, inflammatory cells in the stool, abnormalities on endoscopy or computed tomography and leukocytosis can be useful in the diagnosis but are inconsistent markers for an infectious cause.

Infectious complications are still a significant cause of morbidity and death in solid-organ transplant patients, with significant infection being found in up to two-thirds of these individuals. The risk of infection in the organ transplant patient, particularly of opportunistic infection, is largely determined by 3 factors: the net state of immunosuppression, the epidemiologic exposures the patient encounters, and the consequences of the invasive procedures to which the patient is subjected. The most important principles of patient treatment are prevention, early diagnosis, and specific therapy. This issue is designed as a position paper by a group of experts on epidemiology, prevention, diagnosis, and management of infections in solid-organ transplant patients. We feel that our efforts may serve as an important first step in the development of guidelines in this area.

This review presents evidence-based guidelines for the prevention of infection after blood and marrow transplantation. Recommendations apply to all myeloablative transplants regardless of recipient (adult or child), type (allogeneic or autologous) or source (peripheral blood, marrow or cord blood) of transplant.In Section I, Dr. Dykewicz describes the methods used to rate the strength and quality of published evidence supporting these recommendations and details the two dozen scholarly societies and federal agencies involved in the genesis and review of the guidelines.In Section II, Dr. Longworth presents recommendations for hospital infection control. Hand hygiene, room ventilation, health care worker and visitor policies are detailed along with guidelines for control of specific nosocomial and community-acquired pathogens.In Section III, Dr. Boeckh details effective practices to prevent viral diseases. Leukocyte-depleted blood is recommended for cytomegalovirus (CMV) seronegative allografts, while ganciclovir given as prophylaxis or preemptive therapy based on pp65 antigenemia or DNA assays is advised for individuals at risk for CMV. Guidelines for preventing varicella-zoster virus (VZV), herpes simplex virus (HSV) and community respiratory virus infections are also presented.In Section IV, Drs. Baden and Rubin review means to prevent invasive fungal infections. Hospital design and policy can reduce exposure to air contaminated with fungal spores and fluconazole prophylaxis at 400 mg/day reduces invasive yeast infection.In Section V, Dr. Sepkowitz details effective clinical practices to reduce or prevent bacterial or protozoal disease after transplantation. In Section VI, Dr. Sullivan reviews vaccine-preventable infections and guidelines for active and passive immunizations for stem cell transplant recipients, family members and health care workers.

Cytomegalovirus (CMV) remains the most important infection affecting heart-transplant recipients. Treatment of clinical disease is with a two to three-week course of intravenous ganciclovir, which is effective in more than 90% of individuals. However, relapsing disease, particularly in those with primary infection, is an increasing problem, occasionally with the development of ganciclovir-resistant infection. In those instances, foscarnet is needed, despite its nephro- and neurotoxicities. Increasingly, in order to prevent relapse, more prolonged oral courses of anti-viral therapy are being added to the standard two to three-week course of intravenous treatment. In the prevention of CMV disease, those at risk of primary disease (donor seropositive, recipient seronegative) should receive prophylaxis; for seropositive transplant patients, preemptive strategies linked to immunosuppression or viremia monitoring are becoming increasingly prevalent. In the future, as new drugs become available, the essential question will be whether chronic allograft injury (i.e., accelerated coronary artery atherosclerosis) can be prevented with an anti-viral strategy.

The purpose of this study was to examine the neural activity underlying an implicit motor learning task. In particular, our goals were to determine whether initial phases of procedural learning of a motor task involve areas of the brain distinct from those involved in later phases of learning the task, and what changes in neural activity coincide with performance improvement. We describe a novel integration of robotic technology with functional brain imaging and its use in this study of implicit motor learning. A portable robotic device was used to generate forces that disturbed the subjects' arm movements, thereby generating a “virtual mechanical environment” that the subjects learned to manipulate. Positron emission tomography (PET) was used to measure indices of neural activity underlying learning of the motor task. Eight healthy, right‐handed male subjects participated in the study. Results support the hypothesis that different stages of implicit learning (early and late implicit learning) occur in an orderly fashion, and that distinct neural structures may be involved in these different stages. In particular, neuroimaging results indicate that the cortico‐striatal loop may play a significant role during early learning, and that the cortico‐cerebellar loop may play a significant role during late learning. Hum. Brain Mapping 6:59–72, 1998. © 1998 Wiley‐Liss, Inc.

The physiological and biochemical measurements that can be performed noninvasively in humans with modern imaging techniques offer great promise for defining the precise state of a patient's disease and its response to therapy. In general, there are two critical points in drug development when PET measurements are likely to be particularly useful: (1) In preclinical studies, a new drug can be precisely compared to standard therapies or a series of analogs can be screened for further development on the basis of performance in appropriate animal models. (2) In phase I-II human studies, classic pharmacokinetic measurements can be coupled with imaging measurements (a) to define optimal dosing schedule; (b) to define the potential utility of interventions in particular clinical situations; and (c) to formulate the design of phase III studies that are crucial for drug licensure. In general, the types of measurements that are possible can be grouped into the following categories: 1. In those situations in which the drug can be radiolabeled, the time course of tissue delivery can be determined noninvasively in vivo in health and disease. Such information should be useful for determining dosing schedules, establishing efficacy, and predicting possible toxicity. 2. Ligand-receptor binding can be assessed in vivo in two ways. The ability of the drug to displace standard radiolabeled ligands from their receptors can be determined; alternatively, labeled drug can be used to more directly assess the distribution and time course of binding. These measurements are particularly useful for studying drugs that are active in the central nervous and cardiovascular systems. 3. Measurements of tissue metabolism will be useful in determining the effects of therapies aimed at particular metabolic abnormalities. In addition, these measurements may be useful in defining viability and function of tissues in such widely disparate clinical situations as cancer chemotherapy and cardiology. For example, effects of CNS or cardiovascular drugs can be monitored by observing 18FDG metabolism in brain and heart. We suggest that the joining of classic clinical pharmacology to exquisite imaging measurements will help form the basis for 21st-century clinical drug development.

To quantify the activity of joint inflammation with magnetic resonance (MR) imaging and positron emission tomography (PET).Gadolinium-enhanced MR imaging and 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) PET of the wrist were performed prospectively in 12 patients receiving antiinflammatory therapy. Patients were studied three times: off medications for 2 weeks, after 2 weeks of treatment with prednisone or nonsteroid antiinflammatory drugs, and after 12 weeks of treatment with methotrexate. Volume of enhancing pannus (VEP) was determined from fat-suppressed MR images (12 patients). FDG uptake was calculated from PET images (11 patients).VEP and FDG uptake were closely correlated (r.86, P.0001), as were changes in VEP and standardized uptake volume (r.91, P.0002). VEP and FDG uptake were strongly associated with clinical findings in wrists (P.002) but not with treatment outcomes (P.05).Contrast material-enhanced MR imaging and PET allow quantification of volumetric and metabolic changes in joint inflammation and comparison of efficacies of antiinflammatory drugs.

Fungal infections following solid organ transplantation remain a major cause of morbidity and mortality. Candida species and Aspergillus fumigatus continue to account for the majority of these infections, although the attack rate is higher among recipients of organs other than kidneys because those patients receive more immunosuppressive therapy. Although amphotericin B remains the drug of choice for treatment of invasive aspergillosis, its toxicity profile limits its widespread use. Recent experience suggests that fluconazole may be a safe and effective alternative for the treatment of fungal infections caused by Candida species or Cryptococcus neoformans. Prevention of fungal infections remains one of the most important goals in the field of transplantation. New approaches--such as the use of "preemptive therapy," or prophylaxis, for patients at greatest risk of developing infection--may assist in attainment of this goal.

The serendipitous discovery that radiolabeled nonspecific immunoglobulin G (IgG) accumulates at a site of focal inflammation has led to the development of a new radiopharmaceutical for inflammation scanning, 111 In-IgG. This reagent has been extensively studied in humans with focal infection and has been shown to be both safe and effective. It has been especially useful in the evaluation of patients with possible abdominal and skeletal infection, with the ability to perform serial scans being an important attribute in terms of determining "proof of cure". Preliminary data suggest that this approach may be particularly useful in immunocompromised patients and may find a role in the quantitative assessment of patietns with such nonfectious inflammatory processes as rheumatoid arthritis and inflammatory bowel disease. A new method of labeling IgG with technetium, via the hydrazino nicotinamide derivative, holds promise, in terms of substituting this more practical radionuclide for indium. However, caution must be directed against total substitution, because such processes as suspected vascular or skeletal prosthesis infection may required the longer half-life of 111 In for satisfactory diagnosis. When one compares the results obtained with radiolabeled IgG against the ideal specifications for a radiopharmaceutical to be used for inflammation imaging, most of the requirements are met. The major weakness of this approach is that even with, the technetium-labeled reagent, a minimum of, 6 to 12 hours is necessary for a scant to become positive, which is not acceptable in the evaluation of acutely evolving processes. Development of other radiopharmaceuticals for this purpose remains to be accomplished.

The biological behavior of human polyclonal immunoglobulin G (IgG) radiolabeled with 99mTc via a nicotinyl hydrazine derivative, was evaluated in Rhesus monkeys. 99mTc-IgG and 111In-MACROSCINT DTPA-IgG were co-administered to Rhesus monkeys with focal sites of sterile inflammation and scintillation camera images were acquired at 6 and 19 h after injection. The biodistribution of the two antibody preparations were similar, however, small differences were detected: 99mTc-IgG > 111In-IgG in spleen and lung; 99mTc-IgG in bone and skeletal muscle. A linear correlation of the tissue-to-blood ratios of 99mTc- and 111In-labeled IgG was observed at both times (r2 > 0.98). The slopes of the regression lines were not significantly different from unity: 6 h-0.982 +/- 0.018; 19 h 1.0334 +/- 0.0226. Also, at both 6 and 19 h after injection, the target-to-background ratios (T/B) for the sites of inflammation were remarkably similar for 111In and 99mTc. These studies establish that human polyclonal IgG labeled with 99mTc via a nicotinyl hydrazine modified intermediate is equivalent to 111In-MACROSCINT DTPA-IgG for imaging focal sites of inflammation in monkeys.

Patient 1. A 24-year-old woman with chronic renal failure secondary to membranoproliferative glomerulonephritis underwent living-related renal transplantation from her 56-year-old mother. Other than her renal disease, she had no significant medical problems. She received cyclosporine, prednisone, and azathioprine as immunosuppressive therapy post transplant. The allograft functioned immediately, and the serum creatinine concentration fell to I . I mg/dl 3 days after transplantation. Because the donor was seropositive for cytomegalovirus (CMV), the patient received CMV hyperimmune globin, 150 mg/kg intravenously every 2 weeks, beginning on the first post-transplant day and continuing until she presented with CMV infection on the 38th post-transplant day. On the 10th day post transplant, the patient's temperature rose to 100.6° F and she felt sick. Physical examination revealed no site of infection, a chest radiograph was normal, and all cultures were negative; the serum creatinine, however, had risen to 1.6 mg/dl. Ultrasound examination of the allograft revealed no fluid collection or evidence of hydronephrosis. A clinical diagnosis of allograft rejection was made, and 500 mg of methylprednisolone was administered intravenously on 2 consecutive days. Although the patient became afebrile, she became increasingly oliguric, and her serum creatinine continued to rise (to 3.2 mg/dl). A percutaneous renal biopsy revealed acute allograft rejection without evidence of cyclosporine toxicity; anti-rejection therapy with OKT3 was initiated at a dose of 5 mg/kg for a total of 14 days. By the end of this course of OKT3, the serum creatinine had returned to normal. The therapeutic program then consisted of cyclosporine, 450 mg/day; prednisone, 20 mg/day; azathioprine, 100 mg/day; one single

Since the early days of transplantation, infection has been a major consequence of antirejection immunosuppressive therapy. Increasingly effective prophylactic and preemptive strategies are being developed to prevent the infectious consequences of immunosuppressive therapy. Although the data base is incomplete and there remains a compelling need for well-designed, randomized, comparative trials, the potential for controlling life-threatening viral, bacterial, fungal, and protozoal infections exists. The cornerstone of this effort is the recognition that effective immunosuppressive strategies require an antimicrobial program to make them safe and that such an antimicrobial program needs to be individualized in order to be appropriately matched with the needs of the antirejection program. Thus, escalation and de-escalation of the antimicrobial program should be carried out to match the immunosuppressive program. Infection and rejection remain closely intertwined, linked by the immunosuppressive program that is prescribed.

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.

We studied the in vivo antifungal activity of azoles in humans and in a murine model of disseminated trichosporonosis. Eight patients infected with Trichosporon species were treated with fluconazole, SCH 39304, or miconazole for 2-26 weeks. Four patients had fungemia, two patients had disseminated trichosporonosis, and one patient each had soft-tissue infection and cystitis. Response of trichosporonosis to azoles was seen in all eight patients, although one patient died with disseminated aspergillosis while still receiving SCH 39304. A literature review indicated that responses to ketoconazole or miconazole were noted in four patients with trichosporonosis. In the experimental infection, amphotericin B, SCH 39304, and fluconazole were effective in prolonging survival and reducing fungal counts in the kidneys of mice infected with a clinical strain of Trichosporon beigelii. Fluconazole but not amphotericin B prolonged survival of mice infected with a clinical strain of Trichosporon capitatum. We conclude that azoles represent effective therapy for infection with Trichosporon species.

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.

Aims: Heparin-induced antibody formation and thrombocytopenia are well-established complications of heparin use and may be associated with thromboembolic events. Our study aimed to establish the prevalence of heparin-induced antibodies (HIA), otherwise known as platelet factor 4 (PF4) antibodies, and their relationship to thrombocytopenia and thrombotic events in a group of predominantly African-American hemodialysis patients over 12 months. For comparison, the prevalence of HIA in thrombocytopenic patients with serum creatinine of less than 2.0 mg/dl tested for the antibody in the same period was evaluated. Methods: 36 hemodialysis patients on thrice-weekly, in-center treatments receiving heparin on dialysis were selected to have blood drawn pre-dialysis for PF4 heparin antibodies (HIA). Complete blood counts (CBC) were also checked that day and monthly for the next 3 months. Outpatient records were reviewed for thromboembolic events, including thrombosis of dialysis access lines, grafts and fistulas. The HIA results for the dialysis patients were compared with HIA performed at the same lab for non-dialysis thrombocytopenic patients during the same period. Results: 17 out of 36 (47%) hemodialysis patients had detectable HIA. There were no differences in gender, ethnicity, disease states, or duration of hemodialysis. None of the patients had thrombocytopenia, and the incidence of thromboembolic events was statistically not different from patients without HIA. The non-CKD thrombocytopenic group had a lower incidence, 16/88 (18%) of positive HIA. Conclusions: Heparin-induced antibodies are relatively common in patients receiving hemodialysis. However, their presence does not appear to be associated with clinical consequences. Therefore, testing for HIA should be done only if a clinical indication is present.

Electrostatic effects play an important role in protein interactions and may alter the biodistribution of antibodies. To study the effect of molecular charge of the biodistribution and infection imaging properties of human polyclonal immunoglobulin G (IgG), its isoelectric point was varied by changing the level of diethylene triamine penta-acetic acid (DTPA) substitution: 0.8, 0.9, 3.7, 5.1 and 5.9 DTPA/IgG. Biodistributions of the different IgG preparations were determined at 10 min, 1, 6, 24, and 48 h post injection in normal rats, and infection imaging properties were determined in rats with Escherichia coli thigh infections. The biodistribution was significantly affected by pI. The immunoglobulin preparations with 0.9 and 3.7 DTPA/IgG showed faster clearance from the circulation and generally lower accumulation in most organs. The images had a target-to-background ratio of approximately 1.3-2.3:1. These results suggest that even though targeting is not affected by the level of DTPA substitutions, preparations with 0.9 and 3.7 DTPA/IgG may be superior imaging agents because of reduced accumulation by background organs.

Cytomegalovirus infection is initiated when tumor necrosis factor binds to the cytomegalovirus receptors of latently infected cells, resulting in the reactivation of the virus and the production of clinical disease of two types: direct infection causing pneumonia, mononucleosis, colitis and other viral-related syndromes, and indirect infection in which an array of cytokines are released by the host that produce much the same effect as does the rejection process.These effects fall into three categories: allograft injury, an increase in superinfection with opportunistic pathogens and an increase in the incidence of B cell lymphoproliferative disease. Other factors that modulate the clinical impact of reactivated cytomegalovirus in the transplant patient include the past experience of the host with the virus (primary infection, donor seropositive and recipient seronegative), the degree of major histocompatibility complex mismatch, the viral burden and the amount of calcineurin inhibitor the patient receives.Optimal therapy for diagnosing, treating and preventing these indirect effects still remains to be defined; the direct effects, in contrast, are well managed with valganciclovir.

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Surgical wound infection remains a significant problem following an operation, although surveillance for such infections remains a challenge exacerbated by early discharge and outpatient surgery. The riskof such infections isdetermined by technical problems with the operation, particularly bleeding, the amount of devitalized tissue created, and the need for drains within the wound, as well as such metabolic factors as obesity and diabetes. Perioperative antibiotic prophylaxis can decrease the incidence of such infections further, but a technically perfect operation is even more important.

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Altered fat distribution is associated with insulin resistance in HIV, but little is known about regional glucose metabolism in fat and muscle depots in this patient population. The aim of the present study was to quantify regional fat, muscle, and whole body glucose disposal in HIV-infected men with lipoatrophy. Whole body glucose disposal was determined by hyperinsulinemic clamp technique (80 mU·m−2·min−1) in 6 HIV-infected men and 5 age/weight-matched healthy volunteers. Regional glucose uptake in muscle and subcutaneous (SAT) and visceral adipose tissue (VAT) was quantified in fasting and insulin-stimulated states using 2-deoxy-[18F]fluoro-d-glucose positron emission tomography. HIV-infected subjects with lipoatrophy had significantly increased glucose uptake into SAT (3.8 ± 0.4 vs. 2.3 ± 0.5 μmol·kg tissue−1·min−1, P < 0.05) in the fasted state. Glucose uptake into VAT did not differ between groups. VAT area was inversely related with whole body glucose disposal, insulin sensitivity, and muscle glucose uptake during insulin stimulation. VAT area was highly predictive of whole body glucose disposal ( r2= 0.94, P < 0.0001). This may be mediated by adiponectin, which was significantly associated with VAT area ( r = −0.75, P = 0.008), and whole body glucose disposal ( r = 0.80, P = 0.003). This is the first study to directly demonstrate increased glucose uptake in subcutaneous fat of lipoatrophic patients, which may partially compensate for loss of SAT. Furthermore, we demonstrate a clear relationship between VAT and glucose metabolism in multiple fat and muscle depots, suggesting the critical importance of this depot in the regulation of glucose and highlighting the significant potential role of adiponectin in this process.

Background. Systemic antifungal medications can be lifesaving but can also have important toxicities. With a number of new antifungal drugs being introduced, there is a compelling need to define the toxicities associated with existing therapies. Methods. We identified cases of hepatotoxicity among patients who underwent bone marrow transplantation and selected matched control subjects from the same population. Multivariable logistic regression modeling was used to control for patient characteristics in evaluating the relationship between hepatotoxicity and exposure to antifungal medications. Follow-up analyses were performed for patients who continued receiving antifungal medications after developing hepatotoxicity. Results. The unadjusted incidence of hepatotoxicity was 0.78 cases per 100 patient-days of exposure to amphotericin deoxycholate, 0.98 for fluconazole, and 1.50 for liposomal amphotericin B. Case-control analyses found that liposomal amphotericin B was associated with a substantial increase in the risk of hepatotoxicity in these patients (odds ratio [OR], 3.33; 95% confidence interval [CI], 1.61-6.88); a smaller increase in risk was found for fluconazole (OR, 1.99; 95% CI, 1.21-3.26). There was no statistically significant association between amphotericin B deoxycholate and the development of hepatotoxicity. Patients had greater elevations of serum transaminase values associated with exposure to larger cumulative doses of liposomal amphotericin B. In the follow-up analysis of patients who developed hepatotoxicity and who continued receiving antifungal medication, one-third of those receiving liposomal amphotericin B had marked increases in bilirubin levels, as opposed to 8% of patients treated with fluconazole. Conclusions. In these bone marrow transplant recipients, liposomal amphotericin B and fluconazole were both associated with increased risk of hepatotoxicity, independent of other treatments received or patient characteristics; the magnitude of the risk was larger for liposomal amphotericin B. Patients who develop hepatotoxicity appear to tolerate continued therapy with fluconazole, but a large fraction of those who received liposomal amphotericin B have worsening conditions with continued treatment.

Cytomegalovirus remains the single most important pathogen affecting solid organ transplant recipients. Its importance lies both in its effects and as a model for deciphering the clinical impact and management of other agents such as hepatitis C virus and other herpes viruses such as human herpes virus-6 and 7. The effects of cytomegalovirus infection in these patients can be divided into two categories: the direct causation of a wide variety of infectious disease syndromes; and the indirect effects, which include contributing to the net state of immunosuppression, allograft injury, and potentiating posttransplant lymphoproliferative disease.The advent of valganciclovir, with its excellent oral bioavailability, combined with intravenous ganciclovir have provided powerful tools for controlling the direct effects of cytomegalovirus, particularly with the recognition that the intensity of the antiviral therapy has to be linked to the intensity of the immunosuppression required.Unfortunately, far less is known about the efficacy of antiviral therapy in managing the indirect effects of cytomegalovirus. Preliminary data suggest antiviral prophylaxis protects against acute allograft injury, as well as decreasing the incidence of some opportunistic infection.A great deal of progress has been made in the prevention and treatment of the infectious disease syndromes caused by cytomegalovirus, with the development of the concept of the therapeutic prescription. This has two components: an immunosuppressive component to prevent and treat rejection and an antimicrobial component to make it safe. Much more information, however, is required.

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after hematopoietic stem cell transplantation. Significant progress has been made in the prevention of CMV disease over the past decade, but prevention of late CMV disease continues to be a challenge in selected high-risk populations. The pretransplantation CMV serostatus of the donor and/or recipient remains an important risk factor for posttransplantation outcome despite the use of antiviral prophylaxis and preemptive therapy; CMV-seropositive recipients of T cell-depleted grafts in particular continue to have a survival disadvantage compared with seronegative recipients with seronegative donors. The risk of developing antiviral drug resistance remains low in most patients; however, in a setting of intense immunosuppression (eg, after transplantation from a haploidentical donor), the incidence may be as high as 8%. Primary CMV infection via blood transfusion can be reduced by the provision of seronegative or leukocyte-depleted blood products; however, a small risk of 1% to 2% of CMV disease remains. Surveillance and preemptive therapy are effective in preventing the sequelae of transfusion-related CMV infection. Indirect immunomodulatory effects of CMV are increasingly recognized in hematopoietic stem cell transplant recipients. Strategies currently being investigated include long-term suppression of CMV with valganciclovir for the prevention of late CMV infection and disease, adoptive transfer of CMV-specific T cells, and donor and recipient vaccination strategies.

Organ transplant recipients are vulnerable to a variety of infections because of the immunosuppressed state required to prevent organ rejection. We review the recommendations of the Centers for Disease Control and Prevention (Atlanta, Georgia) for smallpox vaccination and the possible complications of vaccination in the population with organ transplants. The risk of these complications is presumably dependent on the extent of deficient cell-mediated immunity.

Advances in positron emission tomography (PET), single photon emission computed tomography (SPECT) and magnetic resonance spectroscopy (MRS), and the ability to label a wide variety of compounds for in vivo use in humans, have created a new technology for making precise physiological and pharmacological measurements. Due to the noninvasive nature of these approaches, repetitive and/or continuous measurements have become possible. Thus far, these techniques have been primarily used for one-time assessments of individuals. However, experience suggests that a major use of this technology will be in the evaluation of new drug therapies. Already, these techniques have been used to measure precisely and noninvasively the pharmacokinetics of a variety of antimicrobial, antineoplastic and CNS agents. In the case of CNS drugs, imaging techniques (particularly PET) have been used to define the classes of neuroreceptors with which the drug interacts. The physiological, pharmacological and biochemical measurements that can be performed noninvasively using modern imaging techniques can greatly facilitate the evaluation of new therapies. These measurements are most likely to be useful during drug development in preclinical studies and in phase I/II human studies. Preclinically, new drugs can be precisely compared with standard therapies, or a series of analogues can be screened for further development on the basis of performance in animal models. In Phase I/II, imaging measurements can be combined with classical pharmacokinetic data to establish optimal administration schedules, evaluate the utility of interventions in specific clinical situations, and aid in the design of Phase III trials.

We developed a noninvasive method for the mapping of regional renal blood flow in humans using PET and H(2)(15)O.Fifteen subjects participated in the study, 5 with normal renal function and 10 with renal disease. The protocol used a whole-body PET scanner, intravenous bolus injection of 1,110-1,850 MBq H(2)(15)O and sequential imaging at 3 s per frame. (131)I-Iodohippuran was used to independently assess effective renal plasma flow in each subject. Hippuran clearance and renal blood flow (RBF) were measured twice, before and after treatment with probenecid, to verify that RBF is not affected. Flow analysis was based on the Kety model, according to the operational equation: C(t) = F integral C(a)(u)du - k integral C(u)du, where F is the RBF, k is the tissue-to-blood clearance rate, C is the PET concentration, and C(a) is the tracer concentration in the abdominal aorta. F and k were estimated by linear least squares on a pixel-by-pixel basis to produce quantitative maps (parametric images) of RBF. The flow maps were analyzed by regions of interest (largely excluding the medulla and collecting system) for each kidney on each slice and pooled to yield mean RBF.In the 5 healthy subjects, mean RBF was 3.4 +/- 0.4 mL/min/g. There was no difference in flow between kidneys (t = -0.59; n = 11; P0.95). Before treatment with probenecid, RBF was linearly related to hippuran clearance (r(2) = 0.92). Probenecid treatment significantly reduced hippuran clearance (P0.003), but RBF was unchanged (P0.17). Compared with healthy control subjects, RBF was significantly decreased in patients with renal disease (P0.002). Flow maps were of good quality in all subjects, exhibiting characteristic patterns, with higher values in regions composed largely of renal cortex.Parametric mapping of RBF with PET and H(2)(15)O provides a straightforward, noninvasive method for quantitative mapping of RBF, which may prove useful in research applications and in the management of patients whose therapy alters renal tubular transport.