The MAPK pathway functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma.

Stimulation of the c-Kit receptor tyrosine kinase has a critical role in the development and migration of melanocytes, and oncogenic c-Kit mutants contribute to the progression of some melanomas. c-Kit signalling activates the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways and their relative contribution to the activities of oncogenic and ligand-dependent c-Kit remains uncertain. We show that PI3K is a major regulator of MAPK activation in response to c-Kit activity and the dominant effector of c-Kit-driven melanocyte proliferation and melanoma survival. Nevertheless, inhibition of the PI3K pathway in c-Kit mutant melanoma cells did not replicate the apoptotic efficacy of the c-Kit inhibitor, imatinib mesylate. Instead, the simultaneous suppression of the PI3K and MAPK pathways promoted a strong synergistic apoptotic effect. These data indicate that MAPK functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma. Thus, the concurrent inhibition of PI3K and MAPK signalling is required to suppress oncogenic c-Kit activity and may provide an effective therapeutic strategy in c-Kit mutant melanomas.

Possible clinically significant interaction of itraconazole plus rifampin.

We report two patients treated with the combination of itraconazole plus rifampin for more than 4 months. While on itraconazole plus rifampin, patient 1 lost weight at a rate of 30 g/d. After stopping rifampin, he gained 14 g/d. While on itraconazole plus rifampin, patient 2 lost 41 grams/day. After stopping rifampin, he gained 33 g/d. Weight loss while taking the combination of itraconazole plus rifampin, followed by weight gain after stopping rifampin, suggests the possibility of a clinically significant drug interaction between itraconazole and rifampin.

Glioblastoma multiforme in a case of acquired immunodeficiency syndrome: investigation a possible oncogenic influence of human immunodeficiency virus on glial cells. Case report and review of the literature.

Malignant glioma is the most common primary brain neoplasm, but generally it is not included in the differential diagnosis of enhancing lesions of the central nervous system (CNS) in patients suffering from acquired immunodeficiency syndrome. We report a case of glioblastoma multiforme (GBM) in a 29-year-old man with human immunodeficiency virus (HIV). Primary CNS lymphoma was suspected, making a definitive histological diagnosis crucial. An initial stereotactic biopsy sample was insufficient to establish a diagnosis and a second biopsy of the lesion was obtained. The histopathological investigation confirmed GBM and adjuvant external radiation treatment was given to the patient, who survived for 4 months after the initial biopsy. A decline in the rate of Toxoplasma infection and the changing diseases observed in HIV infection indicate the importance of obtaining a biopsy in cases of CNS mass lesions.

Disparate prognosis of thrombotic microangiopathy in HIV-infected patients with and without AIDS.

Thrombotic microangiopathy (TMA) is more common in HIV-infected individuals than in the normal population. In idiopathic TMA, plasmapheresis with or without prednisone decreases the mortality rate from almost 100 to 10%. Patients with HIV-associated TMA, who do not have AIDS, have a similar favorable outcome when treated with plasmapheresis. However, all 12 patients previously reported with AIDS-associated TMA have died. We report another patient with AIDS-associated TMA, who had a fulminant hospital course and died despite plasmapheresis. None of the reported AIDS-associated TMA patients had evidence of opportunistic infections, sepsis or disseminated malignancies at the time of their death. Since many infections and malignancies can be associated with TMA, it is possible that TMA can be an association of the terminal illness rather than an independent cause of death in AIDS patients. To examine this possibility, we reviewed the charts of all the patients who were hospitalized and died of AIDS at our medical centers from 1987 to 1994. Of the 214 patients reviewed, 15 patients (7%) had evidence of TMA at the time of their death. Seven of the 15 patients (47%) had no direct cause of death other than TMA. The remaining 8 patients had evidence of sepsis and other overwhelming infections. In conclusion, TMA is common in AIDS patients. While HIV-associated TMA has a good prognosis similar to that of idiopathic TMA, AIDS-associated TMA has a grave prognosis. The etiology of the higher mortality in AIDS-associated TMA as compared to HIV-associated TMA remains unclear.

Non-neoplastic chorioretinal enhancement patterns in magnetic resonance imaging of the eye.

OBJECTIVE: To define the role of contrast-enhanced magnetic resonance imaging (MRI) as a possible adjunct to funduscopy and ultrasonography in a selected sample of non-neoplastic disorders of the chorioretina. PATIENTS AND METHODS: The study group consisted of five patients (ranging in age from 3 to 78 years) with one of the following diagnoses: ocular toxocariasis, staphyloma, glaucoma, or ocular involvement of cytomegalovirus (CMV) infection or AIDS. All of the patients underwent MRI, and the findings were correlated with those of funduscopy and ultrasonography when possible. RESULTS: There were two abnormal MRI enhancement patterns, one with and the other without major distortion of the chorioretina. Areas of abnormal enhancement correlated well with the funduscopic findings. For the patient with CMV infection and the one with AIDS, who were not examined with ultrasonography, MRI showed subtle chorioretinal abnormalities. In the other three cases, for which both ultrasonography and MRI were performed, the findings of the two methods correlated well. CONCLUSIONS: Ultrasonography remains the imaging modality of choice in the work-up of most ocular abnormalities. Ultrasonography, MRI and computed tomography are recommended when funduscopy is technically not possible. Because contrast-enhanced MRI is often performed to define the remainder of the orbit, as well as extra-orbital structures, and because of its capability to demonstrate abnormalities of the chorioretina, this modality may serve as a useful adjunct to ultrasonography. Further studies are needed to compare the efficacy of contrast-enhanced MRI and ultrasonography in the evaluation of small, nonneoplastic lesions of the chorioretina.

Alterations in the microbial flora and in the incidence of bacteremia at a university hospital after adoption of amikacin as the sole formulary aminoglycoside.

Because of the rapid emergence of resistance to gentamicin and tobramycin among isolates of aerobic and facultative gram-negative bacteria at our university hospital, we designed a prospective study to track aminoglycoside resistance, bacteremic episodes, and bacteremia-associated deaths before and after the institution of amikacin as the sole formulary aminoglycoside. From June 1984 through June 1987 (immediately before this policy change), amikacin accounted for only 20% of patient-days of aminoglycoside therapy, and rates of resistance to gentamicin, tobramycin, and amikacin among aerobic and facultative gram-negative bacterial isolates were 12.8%, 10.8%, and 5.9%, respectively. During the next 30 months (immediately after the change in policy), amikacin accounted for 98% of patient-days of aminoglycoside therapy, and rates of resistance to gentamicin, tobramycin, and amikacin were 6.3%, 5.0%, and 3.3%, respectively. Furthermore, during the latter 30 months, the incidence of both bacteremia and bacteremia-associated death decreased significantly. Hospitals at which resistance to gentamicin or tobramycin is increasing among the gram-negative flora may benefit from the use of amikacin as the principal aminoglycoside.

Comparison of the immunogenicity of hepatitis B vaccine administered intradermally and intramuscularly.

Although hepatitis B vaccine reliably induces immunity to hepatitis B virus, the expense of intramuscular (im) vaccination with this product has limited its use. To determine if a smaller, less expensive, intradermal (id) dose of hepatitis B vaccine would be an effective alternative, we compared the response of antibody to hepatitis B surface antigen (anti-HBs) following im vaccination to that following id vaccination. Volunteers who were seronegative for antibody to hepatitis B core antigen were enrolled in the study and received either im or id vaccine. A total of 108 subjects received three 1-mL im injections of hepatitis B vaccine, and another 110 subjects received four 0.1-mL id injections of the vaccine. Similar rates of seroconversion occurred; greater than or equal to 10 mIU of anti-HBs/mL was noted following either three im or three id vaccinations. Furthermore, 2 years after initiation of vaccination, the serum concentration of anti-HBs for id vaccine recipients was similar to that for im vaccine recipients.

Human leukocyte antigen and leprosy: study in northern Louisiana and review.

We examined the relationship of human leukocyte antigen (HLA) phenotype to leprosy in six sporadic cases in northern Louisiana and in the world literature through pooling of the results of several studies. We found that HLA antigens DR2 and DQwl were associated with leprosy in the six cases in northern Louisiana (relative risks, 4.57 for DR2 and 4.53 for DQwl), but the results are not statistically significant. We pooled the Louisiana study and other population studies of HLA and leprosy. The results of the pooling show DR2 and DQwl to be associated with leprosy (relative risks, 2.65 for DR2 and 2.73 for DQwl), and these associations are highly statistically significant (P less than 1 x 10(-8) for DR2 and P = 3.6 x 10(-8) for DQwl). Further, we pooled studies of lepromatous leprosy patients vs. controls and studies of tuberculoid leprosy patients vs. controls and found that DR2 and DQwl are associated with both the lepromatous and the tuberculoid forms of leprosy and that these associations are statistically significant. We consider the associations of DR2 and DQwl in these population studies to be evidence for an HLA-associated genetic influence on susceptibility to leprosy.

Earthworms near leprosy patients' homes are negative for acid-fast bacilli by fite stain, providing no link between leprous armadillos (Dasypus novemcinctus) and human leprosy.

Enzootic leprosy has been recognized in armadillos in Louisiana since 1975. Contact with armadillos is being assessed as a risk factor for leprosy in three white women, lifelong residents of separate rural areas in northern Louisiana, which is a region without endemic leprosy. None has had any known exposure to human leprosy. Each was aware of armadillos (Dasypus novemcinctus) near or under her home for decades. In considering Possible environmental sources forMycobacterium leprae, we observed that all three had earthworm growth areas for fishing bait where soil was kept moist near their homes. The worms attracted armadillos. Since armadillos subsist on worms, grubs, and insects and because of the common feature of a "worm farm" near each home, we reasoned that earthworms might containM. leprae and be part of a cycle involving the armadillo and human beings. Worms from each home worm farm were studied. One site was sampled twice at patient 1's home, five sites were sampled once at patient 2's home, and three sites were sampled once at patient 3's home. A sample consisted of 3-4 worms, which were washed, purged, fixed live in 10% formalin, embedded in paraffin, sectioned, and stained with the Fite stain. Each was sagittally sectioned and examined by three independent observers. No acid-fast bacilli or other acid-fast structures were identified. We conclude that it is unlikely that earthworms are an environmental source or reservoir ofM. leprae.

Leprosy in six isolated residents of northern Louisiana. Time-clustered cases in an essentially nonendemic area.

Northern Louisiana has been essentially free of indigenous leprosy, and now it is not. Six new cases of leprosy have been diagnosed: three in 1986, the other three in 1985, 1983, and 1982, respectively. The patients had been lifelong residents of six scattered rural parishes. Leprosy had never been reported from five of them. No patient had had contact with human leprosy. The patients were white; four were women; the mean +/- SD age at onset was 60.3 +/- 16.4 years (age range, 31 to 80 years); and the mean +/- SD interval to diagnosis was 1.2 +/- 1.4 years. One patient had Hodgkin's disease at the age of 25 years and leprosy at the age of 31 years; another patient had cervical carcinoma. All rural northern Louisiana residents coexist with armadillos (Dasypus novemcinctus), some of which are infected with Mycobacterium leprae, the significance of which is unknown. Hypothetically, exposure to an unknown human case, reactivation of "asymptomatic" leprosy through immunosenescence or immunosuppression, or infection from an environmental source might have occurred. Because the patients lacked contact, travel, residence, and exposure risk factors, the origin of leprosy in the new indigenous cases is noteworthy and is not understood.

Wegener granulomatosis and trimethoprim-sulfamethoxazole. Complete remission after a twenty-year course.

Wegener granulomatosis was diagnosed in a 42-year-old woman in 1965. Although a regimen of azathioprine and prednisone was helpful, the disease progressed. Cyclophosphamide was added to this regimen in 1969. On three separate occasions her disease relapsed when cyclophosphamide therapy was discontinued. In 1984, she developed cyclophosphamide-resistant disease and drug toxicity. We were able to discontinue cyclophosphamide therapy after a trimethoprim-sulfamethoxazole regimen that was begun in February 1985 led to rapid improvement, a fall in the erythrocyte sedimentation rate, and a complete remission. Her 22-year survival is the longest one reported. Because patients with Wegener granulomatosis sometimes respond to trimethoprim-sulfamethoxazole, this therapy deserves careful study and implies that Wegener granulomatosis is an as yet unidentified infection.

Environmental nonhuman sources of leprosy.

Leprosy has been considered to occur only after exposure to a human case. However, evidence has been accumulating that this conventional view is wrong and that an environmental nonhuman source is critical to some human infections with Mycobacterium leprae. Observations, some of which date back to the nineteenth century, support soil, vegetation, water, arthropods, and armadillos (Dasypus novemcinctus) as environmental sources of leprosy. Disparate clinical, epidemiologic, and microbiologic evidence has been critically reviewed in light of the fact that 50%-70% of sporadic cases of leprosy in well-studied populations occur in persons who have had no known contact with human leprosy. Historical data and current information alike substantiate the concept of nonhuman sources of the disease; recent observations with monoclonal antibody have shown that phenolic glycolipid-I antigen, which is unique to the M. leprae cell wall, is present in soil. In the absence of a technique for in vitro cultivation, indirect methods and the body of observations reviewed here persuasively favor but do not prove the existence of environmental nonhuman sources of M. leprae.

The copper status of beef cattle in Northern Ireland.

1. Serum caeruloplasmin (ferroxidase I;EC 1.16.3.1) activity has been used as an indicator of copper status of cattle to survey beef herds in Northern Ireland. 2. The main survey covered some 20 000 cows on 1200 farms. 3. The results are reported in the form of a map showing area where herds of low and very-low Cu status predominate. Clinical signs of Cu deficiency in calves were encountered in only two areas.

Role of pentose-phosphate pathway in haemolytic crisis of chronic copper toxicity of sheep.

Although the rise in blood copper is associated with onset of the acute haemolytic crisis of chronic copper poisoning in sheep, the sudden fall in erythrocyte glutathione is apparently not due to a direct action of the copper. Moreover the reduced glutathione of the red cells is converted to some form that is not capable of regeneration by the pentose-phosphate mechanism. Only negligible inhibition of the pentose-phosphate enzymes occurs. As the haemolysis proceeds, there is a rapid recovery of erythrocyte glutathione levels, and a marked increase in pentose-phosphate enzyme activity, consistent with influx of young red cells. It seems that the release of copper into blood from liver at the haemolytic crisis is associated with an increase of the oxidative state of the blood, possibly by simultaneous release of other components from the liver.