Hybrid MR-PET of brain tumours using amino acid PET and chemical exchange saturation transfer MRI.

PURPOSE: PET using radiolabelled amino acids has become a promising tool in the diagnostics of gliomas and brain metastasis. Current research is focused on the evaluation of amide proton transfer (APT) chemical exchange saturation transfer (CEST) MR imaging for brain tumour imaging. In this hybrid MR-PET study, brain tumours were compared using 3D data derived from APT-CEST MRI and amino acid PET using O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). METHODS: Eight patients with gliomas were investigated simultaneously with 18F-FET PET and APT-CEST MRI using a 3-T MR-BrainPET scanner. CEST imaging was based on a steady-state approach using a B1 average power of 1µT. B0 field inhomogeneities were corrected a Prametric images of magnetisation transfer ratio asymmetry (MTRasym) and differences to the extrapolated semi-solid magnetisation transfer reference method, APT# and nuclear Overhauser effect (NOE#), were calculated. Statistical analysis of the tumour-to-brain ratio of the CEST data was performed against PET data using the non-parametric Wilcoxon test. RESULTS: A tumour-to-brain ratio derived from APT# and 18F-FET presented no significant differences, and no correlation was found between APT# and 18F-FET PET data. The distance between local hot spot APT# and 18F-FET were different (average 20 ± 13 mm, range 4-45 mm). CONCLUSION: For the first time, CEST images were compared with 18F-FET in a simultaneous MR-PET measurement. Imaging findings derived from18F-FET PET and APT CEST MRI seem to provide different biological information. The validation of these imaging findings by histological confirmation is necessary, ideally using stereotactic biopsy.

Malaria among United States troops in Somalia.

PURPOSE: United States military personnel deployed to Somalia were at risk for malaria, including chloroquine-resistant Plasmodium falciparum malaria. This report details laboratory, clinical, preventive, and therapeutic aspects of malaria in this cohort. PATIENTS AND METHODS: The study took place in US military field hospitals in Somalia, with US troops deployed to Somalia between December 1992 and May 1993. Centralized clinical care and country-wide disease surveillance facilitated standardized laboratory diagnosis, clinical records, epidemiologic studies, and assessment of chemoprophylactic efficacy. RESULTS: Forty-eight cases of malaria occurred among US troops while in Somalia; 41 of these cases were P falciparum. Risk factors associated with malaria included: noncompliance with recommended chemoprophylaxis (odds ratio [OR] 2.4); failure to use bed nets (OR 2.6); and failure to keep sleeves rolled down (OR 2.2). Some patients developed malaria in spite of mefloquine (n = 8) or doxycycline (n = 5) levels of compatible with chemoprophylactic compliance. Five mefloquine failures had both serum levels > or = 650 ng/mL and metabolite:mefloquine ratios over 2, indicating chemoprophylactic failure. All cases were successfully treated, including 1 patient who developed cerebral malaria. CONCLUSIONS: P falciparum malaria attack rates were substantial in the first several weeks of Operation Restore Hope. While most cases occurred because of noncompliance with personal protective measures or chemoprophylaxis, both mefloquine and doxycycline chemoprophylactic failures occurred. Military or civilian travelers to East Africa must be scrupulous in their attention to both chemoprophylaxis and personal protection measures.

Fever in the returned traveler.

The most important cause of fever in the returned traveler is malaria. All febrile patients in which malaria is epidemiologically possible require urgent evaluation for P. falciparum malaria, which can be rapidly fatal in the nonimmune patient. Early diagnosis and therapy can prevent severe morbidity and mortality. Other less common causes of undifferentiated fever include acute schistosomiasis, the enteric fevers, rickettsial diseases, leptospirosis, and dengue fever. Early empiric therapy for suspected leptospirosis and the rickettsial infections is encouraged to decrease morbidity and mortality. About a quarter of febrile patients do not have an etiologic agent determined for their illness but recover without sequelae. Patients with fever and hemorrhagic manifestations within 3 weeks of their return need to be isolated for the remote possibility of a highly transmissible agent. Although the febrile traveler is always a challenge, the real world differential diagnosis is limited and a systematic approach via the history, physical examination, and selected laboratory tests is usually sufficient to confirm the diagnosis or eliminate potentially serious infections.

Survivability and infectivity of viscerotropic Leishmania tropica from Operation Desert Storm participants in human blood products maintained under blood bank conditions.

To assess the potential for leishmaniasis being transmitted through blood transfusion, we studied the survival of Leishmania in blood products under blood bank storage conditions. We report that L. tropica- or L. donovani-contaminated transfusable blood products are a risk to the blood supply for at least 25 days postdonation under blood bank general conditions. The blood components that have been implicated are whole blood, packed red blood cells, platelet concentrate, and frozen-deglycerolized red blood cells, but not, as would be expected, fresh frozen plasma. Blood units containing four infected monocytes per milliliter of blood with a mean of three amastigotes per monocyte contain viable parasites for 15 days under blood bank storage conditions. Furthermore, animal studies showed the presence of parasites in the blood of cutaneously infected animals and the possibility of transmitting the disease to healthy experimental animals by blood transfusion from infected animal donors. Three of three BALB/C mice showed metastasis to the lower extremities and face after they received 0.25 ml of blood from a CPDA-1 bag seeded with 1.5 x 10(5) amastigotes per ml of blood kept under blood bank conditions for 30 days. This proves that Leishmania not only survives blood banking procedures and storage conditions but that the parasite retains its infectivity. The results of this study and the recent demonstration of L. tropica-infected monocytes in the blood of a patient returning from Southwest Asia suggests that transfusion-associated leishmaniasis can occur.

Plasmodium vivax infections in U.S. Army troops: failure of primaquine to prevent relapse in studies from Somalia.

Different strains of Plasmodium vivax vary in their sensitivity to primaquine, the only drug that prevents relapses. Described are the clinical data and relapse pattern for 75 soldiers treated for vivax malaria since returning from Somalia. Following their initial attack of malaria, 60 of the 75 cases received a standard course of primaquine (15 mg base daily for 14 days). Twenty-six of the 60 soldiers subsequently relapsed for a failure rate of 43%. Eight soldiers had a second relapse following primaquine therapy after both the primary attack and first relapse. Three of these soldiers had received a higher dosage of primaquine (30 mg base daily for 14 days) after their second attack. The apparent ineffectiveness of primaquine therapy in preventing relapses suggests the presence of primaquine-resistant P. vivax strains in Somalia.

Identification and genetic comparison of leishmanial parasites causing viscerotropic and cutaneous disease in soldiers returning from Operation Desert Storm.

Six Leishmania major and seven L. tropica parasites were isolated and identified from participants in Operation Desert Shield/Storm. A complete enzyme analysis (21 enzymes) revealed that there was enzyme polymorphism among the isolates of each species group. Any one Desert Storm L. major isolate could differ from any other for 1-3 enzymes, and any L. tropica isolate could differ from any one other for up to eight enzymes. Enzyme polymorphism data from other L. major and L. tropica isolates from Africa and the Middle East region were obtained and combined with the Desert Storm data to produce population enzyme polymorphism estimates. Results from these population data indicated that L. major parasites could be expected to differ from each other for as many as eight enzymes and still be L. major, and similarly, L. tropica isolates could differ for as many as 14 enzymes. These expected isolate variation extremes have not been observed among the isolates studied. All L. major and most L. tropica isolates were from patients who, as expected, presented with cutaneous disease, but the Desert Storm and two Kenyan patients infected with L. tropica presented with a viscerotropic disease, the symptoms of which are unlike those of classic visceral leishmaniasis. Such unrecognized presentation for these L. tropica-infected patients indicates that both parasite and patient can play critical roles in disease manifestations. The Desert Storm isolates are, as indicated, either L. major or L. tropica.

The epidemiology of malaria in an epidemic area of the Peruvian Amazon.

A longitudinal study of malariometric indicators and their association with potential risk factors was conducted during August 1997-July 1998 at Padre Cocha, a village of 1,400 residents in the Peruvian Amazon. The incidence of Plasmodium falciparum infections during the study year was 166/1,000 persons; that of P. vivax was 826/1,000 persons. The mean duration of symptoms prior to diagnosis was 2 days; presenting geometric mean parasite densities were 3,976 parasites/microl for P. falciparum infections and 2,282 parasites/microl for P. vivax. There were no malaria-associated deaths. Consistent with the epidemic nature of malaria in the area, the incidence of both parasite species increased with age and there were no age-specific differences in mean parasite densities. No specific occupational risks for malaria were identified. Activities significantly associated with malaria risk reflected local vector behavior and included strolling outdoors after 6:00 PM and arising before 6:00 AM for adults, and attending evening church services for children.

Short report: detection of Leishmaniavirus in human biopsy samples of leishmaniasis from Peru.

Leishmaniavirus is a double-stranded RNA virus that persistently infects some strains of the protozoan parasite Leishmania. There is considerable interest in the possibility that the presence of this virus alters parasite phenotype and may affect disease pathogenesis. If so, the virus marker could provide a valuable prognostic indicator for human leishmaniasis, particularly in those cases caused by New World parasite strains. The virus has been detected in cultured L. braziliensis, L. b. guyanensis, and L. major. To date there has been no information as to the extent of infection in samples prior to culturing in the laboratory. This study demonstrates, through the reverse transcription-polymerase chain reaction, that Leishmaniavirus exists in human biopsy samples of leishmaniasis prior to manipulation in culture.

Comparative CD4 T-cell responses of reverse transcriptase inhibitor therapy with or without nelfinavir matched for viral exposure.

BACKGROUND: Therapy of HIV infection with protease inhibitors (PIs) may be associated with improvements in CD4 T-cell number via a mechanism that is independent of effects on plasma viral load (VL). PURPOSE: To compare CD4 responses of patients who receive reverse transcriptase inhibitor (RTI) therapies with or without a PI, matched for viral exposure. METHODS: Patient data were analyzed from two prospective randomized trials of antiviral therapy with or without nelfinavir. Total viral exposure over 24 weeks was estimated by viral area under the curve (AUC), which reflects baseline viral load, slope of virologic decay, viral nadir, and duration of suppression. Patients were stratified into quartiles on the basis of viral AUC, and CD4 T-cell responses were evaluated between PI-containing and RTI-only treatment groups within each quartile. RESULTS: In both trials, patients receiving nelfinavir had greater CD4 T-cell increases than patients receiving RTI alone. Analysis of variance modeling revealed increased CD4 T-cell responses in PI-treated groups at all time points after the second week. These differences were significant (p <.05) at weeks 12, 24, 28, 32, 36, 40, and 48 in one study, and weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, and 44 in the other. Within quartiles matched for viral AUC, absolute CD4 T-cell change from baseline was greater in the PI-treated patients at 84% (101/120) of time points analyzed. CONCLUSION: Nelfinavir-containing therapy is associated with enhanced increases in CD4 T-cell number compared to RTI therapy alone with equivalent antiviral effect. These data suggest that PIs influence CD4 T-cell number through a nonvirologic effect.

Use of secretin in the roentgenologic and biochemical diagnosis of duodenal gastrinoma.

The use of secretin in the biochemical and roentgenologic diagnoses of a duodenal gastrinoma has been described. Preoperatively, the secretin test indicated that a gastrinoma and not a retained antrum was the cause of hypergastrinemia in a patient who had previously undergone Billroth II gastrectomy. Intravenous infusion of secretin during selective angiography resulted in greatly enhanced visualization of the tumor which allowed it to be localized to the duodenal stump. Several months postoperatively, the secretin test result had become negative, which presumably suggested that the tumor had been excised completely. Our experience has revealed that intravenous secretin might improve the diagnostic usefulness of selective angiography.

Spectrophotometric method for quantitation of peroxides in sorbitan monooleate and monostearate.

A rapid and sensitive spectrophotometric method has been developed to quantitate the peroxides present in sorbitan monooleate and monostearate. The method relies on the peroxide conversion of iodide to iodine. The method has also been found to work for polysorbate 60.

Approaches for improving the stability of ketorolac in powder blends.

Methods for improving the stability of ketorolac powder blends under elevated humidity and temperature conditions were investigated. The approaches that were examined for potentially increasing the stability of ketorolac were varying the ketorolac salt form, altering the excipient ratios, and adding antioxidants or pH modifiers to the formulation. The ketorolac powder blends were stored for 3 months at 75% relative humidity (RH) and 40, 50, and 60 degrees C. The results showed that the salt form of ketorolac had a large impact on stability after 3 months of storage at 50 degrees C/75% RH. The calcium salt powder blend and the free acid powder blend exhibited only 0.2% and 0.5% drug loss, respectively, whereas the tromethamine salt powder blend showed a 10.2% drug loss. Varying the ratios of lactose, microcrystalline cellulose, and croscarmellose sodium in the powder blends of ketorolac tromethamine showed that croscarmellose sodium and microcrystalline cellulose destabilized ketorolac. Addition of propyl gallate (1% w:w) to ketorolac tromethamine powder blends increased the stability of the ketorolac significantly. Addition of pH modifiers caused a modest improvement in the stability of ketorolac.

Epidemiology of the leishmaniases.

The leishmaniases are a group of zoonotic infections caused by protozoan parasites of the genus Leishmania. These infections produce a variety of different clinical diseases depending on the virulence or tropism of the parasite and differential host immune responses. Newly recognized clinical presentations, such as viscerotropic leishmaniasis in American military veterans of Operation Desert Storm, continue to challenge clinicians. Epidemics of classic visceral leishmaniasis leading to thousands of deaths are ongoing in Brazil, India, and the Sudan. Epidemics of localized cutaneous leishmaniasis are ongoing in many areas of South America, North Africa, and Central Asia. A marked increase in cases is often associated with an influx of nonimmune populations into newly cleared agricultural populations into newly cleared agricultural areas or population expansion into previously unsettled areas surrounding cities. The emergence of leishmaniasis as an important opportunistic infection in AIDS patients portends an ominous future as the HIV pandemic sweeps into the hyperendemic areas of South America, Africa, and the Indian subcontinent. Parenteral transmission via needle sharing in HIV coinfected individuals in Spain is an epidemiologically significant new mode of transmission. Finally, recent work has elucidated an enzootic transmission cycle involving L. mexicana in Texas.

Leishmaniasis in the United States military.

Leishmaniasis is a recurrent health problem for the U.S. and other militaries. Health care workers may be unfamiliar with the risk factors, transmission, clinical features, diagnosis, and treatment of this disease. A team of highly trained specialists is required to properly manage service members with leishmaniasis. Such care is available only in a few medical centers. Although there are no prophylactic drugs to prevent this disease, control of insect populations and use of personal protection measures can minimize arthropod-related casualties. The impact of leishmaniasis on military operations and research initiatives to better prevent, diagnose, and treat infection are discussed.

The effect of clozapine on preexisting tardive dyskinesia.

Since the 1950s, the main treatment for schizophrenia has been the use of neuroleptic therapy. However, these medications may produce tardive dyskinesia in those patients who require prolonged neuroleptic treatment. With the advent of clozapine, patients with preexisting tardive dyskinesia began therapy and their symptoms did not worsen--and, in many cases, their symptoms improved dramatically. In this study, the mean Abnormal Involuntary Movement Scale (AIMS) scores from baseline to 6 months are compared for 12 patients in a private partial hospitalization program for schizophrenia. The findings reveal a drastic decrease in AIMS scores after 1 month of clozapine therapy and a steady decrease in scores throughout the 6 months of analysis.

Long-term stability studies using radiopharmaceuticals: consequence of using multiply tritiated compounds, with an application to fluocinolone acetonide.

The use of multiply tritiated radiopharmaceutical compounds for long-term stability studies should be avoided because different radiolabeled products are produced by radioactive decay than by chemical degradation. This is demonstrated by showing that doubly tritiated fluocinolone acetonide and (14)C-labeled fluocinolone acetonide have different shelf lives and that the tritiated compound affords additional degradation products not seen in reaction of the (14)C-labeled drug after 26 months.

Stability of prostacyclin analogues: an unusual lack of reactivity in acid-catalyzed alkene hydration.

Prostacyclin analogue 5 undergoes specific acid-catalyzed hydration (kH+ = 1.9 x 10(-7)M-1 sec-1 at 25 degrees C) and a pH-independent oxidation reaction (k0 = 1.2 x 10(-10) sec-1 at 25 degrees C) above pH approximately 5. The hydration reaction for 5 is much slower than for other structurally similar exocyclic alkenes, even though the rate-determining step is proton transfer. This slowness of reaction and an analysis of the pH-rate profile show that 5 does not exhibit significant intramolecular general acid catalysis, as does prostacyclin.

Starting patients on clozapine in a partial hospitalization program.

OBJECTIVE: The authors' aim was to assess the safety and efficacy of starting clozapine in a structured, long-term, partial hospitalization program that included protocols for detecting and managing side effects and adverse reactions to the drug as well as therapeutic programming to enhance patients' reintegration into community life. METHODS: Medical records of 47 patients with schizophrenia or schizoaffective disorder who were started on clozapine in the partial hospitalization program were analyzed. Data on incidence and management of adverse reactions, number of hospitalizations, status of symptoms, and changes in patients' social functioning for periods up to 12 months after initiation of clozapine were collected. RESULTS: Although adverse reactions were common in the first weeks of treatment, they were managed with dosing strategies, monitoring, and concomitant medication so that no patient had to discontinue the medication. Psychotic symptoms and symptoms of tardive dyskinesia decreased significantly during the study period. At 12-month follow-up, most patients were able to attend school, hold paying or volunteer jobs, and live independently. CONCLUSIONS: Clozapine can be safely initiated outside an inpatient setting. Partial hospitalization programs can enhance patients' reintegration into the community through a combination of treatment with clozapine and rehabilitative and psychotherapeutic programming.