Antitumor effects of two polyamine antimetabolites combined with mitomycin C on human stomach cancer cells xenotransplanted into nude mice

The antitumor effects of alpha-difluoromethylornithine (DFMO), methylglyoxal-bis-guanylhydrazone (MGBG) and mitomycin C (MMC), administered separately or in various combinations, on human stomach cancer cells xenotransplanted into BALB/c nude mice were studied using the protocol of Battelle's Columbus Laboratories (Ovejera et al., 1978). DFMO (1,000 mg/kg in 2 divided doses) and MGBG (50 mg/kg) were given intraperitoneally (i.p.) for 7 consecutive days from the time when the tumor weighed about 100 mg. MMC (2 mg/kg) was given i.p. every other day from the same time. Animals treated with either DFMO or MGBG alone displayed tumor growth comparable to that seen in untreated controls. In mice treated with DFMO plus MGBG with or without MMC, or in mice treated only with MMC, tumor growth was significantly lower than in untreated mice. In the group which received only combined DFMO/MGBG there was a rapid regrowth of the tumor after termination of therapy. Tumor putrescine levels decreased within 4 days following the administration of DFMO; however, spermidine levels did not decline with either DFMO or MGBG treatment even after 7 days. When combined DFMO/MGBG was given, there was a significant decline in spermidine levels 7 days after the initiation of treatment. In contrast, when MMC alone was administered, putrescine and spermidine levels in the tumor did not differ from those in control mice. Spermine decreased markedly in tumor with the combined administration of DFMO/MGBG as well as with combined DFMO/MGBG/MMC, but decreased only slightly when MMC alone or MMC plus either DFMO or MGBG was administered. By the 7th treatment day, DNA biosynthesis in the tumor had dropped markedly in all groups except those receiving DFMO or MGBG alone.     

Melioidosis imported into Nepal

This is a report of the first recognized case of melioidosis in Nepal. Illness began 1 month after returning from Malaysia after a 1 y stay. The case highlights the importance of ascertaining the travel history in any patient with a suspected infectious disease in this age of global travel.     

Rheumatic complications of human immunodeficiency virus infection in the era of highly active antiretroviral therapy: emergence of a new syndrome of immune reconstitution and changing patterns of disease

OBJECTIVE: To describe the impact of the introduction of highly active antiretroviral therapy (HAART) on the nature and frequency of rheumatic complications in human immunodeficiency virus (HIV)-infected patients. METHODS: Case report and systematic review of a newly described syndrome of rheumatic immune reconstitution syndrome and prospective longitudinal cohort study analyzing the frequency and nature of rheumatic complications in the setting of HIV infection from 1989 through 2000. RESULTS: A newly described syndrome of either the de novo appearance or the exacerbation of clinically occult autoimmunity following immune reconstitution from HAART is described. Including the present case report, 32 cases have been individually described with sarcoidosis and autoimmune thyroid disease being most common with arthritis and various forms of connective tissue disease making up the rest. The mean onset to their appearance following HAART was nearly 9 months and most resolved with little or no therapy. In addition, a longitudinal analysis of 395 HIV-infected patients from 1989 to 2000 designed to detect the appearance of rheumatic complications has revealed a dramatic decline in certain problems such as reactive arthritis, psoriatic arthritis, and various forms of connective tissue disease. New rheumatic complications possibly due to the effects of longer survival and metabolic derangements associated with this form of therapy are now being described and may become more formidable problems in this population in the future. CONCLUSIONS: HAART has had a profound beneficial effect on survival in HIV-infected patients but has also contributed to both an altered frequency and a different nature of rheumatic complications now being observed in this population. Rheumatologists need to be aware of these changes to provide optimal diagnosis and treatment for this group.     

MR imaging findings in autoimmune hepatitis: correlation with clinical staging

PURPOSE: To retrospectively evaluate the morphologic and enhancement features of the liver on magnetic resonance (MR) images obtained in patients with autoimmune hepatitis (AIH) and to determine if there is a correlation between MR imaging findings and severity of clinical disease as measured with the Mayo end-stage liver disease (MELD) score. MATERIALS AND METHODS: This study was compliant with the Health Insurance Portability and Accountability Act and approved by the institutional review board. The need for informed consent was waived. Thirty-two patients (29 female and three male patients; mean age, 44 years; age range, 14-69 years) undergoing treatment for AIH underwent unenhanced and gadolinium-enhanced MR imaging. Two radiologists reviewed all cases independently to determine the presence of patchy or heterogeneous liver enhancement, biliary duct changes, lymphadenopathy, and findings of portal hypertension. Fibrosis was graded as mild, moderate, or severe reticular (corresponding to a grading scale of 1-3) or as confluent. Agreement between radiologists was assessed by using kappa coefficients. Mean MELD scores were compared across fibrosis categories by using the Kruskal-Wallis analysis of variance. RESULTS: Of the 32 patients, two (6%) had no imaging findings of cirrhosis. Thirty patients (94%) had reticular fibrosis with a mean grade of 1.8. Six patients had confluent fibrosis, and all six had associated reticular fibrosis. Mild intrahepatic biliary duct dilatation involving the right and left lobes was observed in four patients (12%). Lymphadenopathy was observed in 12% of patients. None of the patients had hepatocellular carcinoma. There was no significant overall association between fibrosis grade and MELD score (P = .36). CONCLUSION: Although fibrosis is a common feature in AIH and is often moderate to severe, no significant correlation between fibrosis grade and MELD score was found.     

Extremely rapid formation of mitral valve ring abscess in infective endocarditis

A patient with infective endocarditis (IE) due to methicillin-resistant staphylococcus aureus (MRSA) was found to have conversion of the hypoechoic region of the posterior mitral valve ring apparatus into a clearly delineated echolucent space by repeating transthoracic echocardiography at an interval of 1 week. Color Doppler showed features of blood entry into this space. Abscess formation in IE due to MRSA may be quick and repeated echocardiography may help detect the complications of IE. Semiurgent mitral valve plasty was performed for the associated prolapse of the posterior mitral leaflet using a hand-made, rolled, twisted autologous pericardial ring.     

Action of MT-II on ghrelin-induced feeding in the paraventricular nucleus of the hypothalamus

Ghrelin is a 28 amino-acid peptide that has been shown to induce positive energy balance when administered both peripherally and centrally. This effect appears to occur by increasing food intake and by reducing fat utilization. Ghrelin injected into the PVN increases food intake dose-dependently. The NPY receptor has been implicated in the orexigenic effect of ghrelin, but until now, the role of melanocortins on the effect of ghrelin in the PVN has not been reported. Sprague-Dawley rats were stimulated to eat by PVN ghrelin. Pre-injection of 10 pmol of MT II into the PVN caused a significant decrease in ghrelin-induced feeding in both 0-1 h and 0-4 h food intake studies. This finding indicates that MC 3/4-R signaling appears to be recruited by ghrelin, in the PVN, in its role to induce feeding.     

Molecular investigation of hepatitis E virus infection in patients with acute hepatitis in Kathmandu,Nepal

One hundred fifty-four consecutive patients with sporadic acute hepatitis, who were seen at a city hospital in the Kathmandu valley of Nepal in 1997, were studied. IgM antibodies to hepatitis A virus were detected in four patients (3%), IgM antibodies to hepatitis B core in four patients (3%), hepatitis B surface antigen in 20 (13%), and hepatitis C virus RNA in four patients (3%). IgM antibodies to hepatitis E virus (HEV) (anti-HEV IgM) and HEV RNA were detected in 77 (50%) and 48 (31%), respectively. Consequently, 86 patients (56%) including nine HEV-viremic patients without anti-HEV IgM, were diagnosed with hepatitis E. The cause of hepatitis was not known in 53 patients (34%). All 48 HEV RNA-positive samples were genotyped as 1, and subtyped further as 1a in 17 (35%), 1c in 29 (60%), and mixed infection of 1a and 1c in 2 (4%). A seasonal difference in the prevalence of HEV subtypes was recognized. Before the rainy season (January to July), both 1a and 1c isolates were found: the intrasubtypic difference was up to 9.0% and 1.7%, respectively, in the 412-nucleotide sequence of open reading frame 2. During the rainy season (August), only 1c isolates (n = 17) with 99.5-100% identity were found; 13 of 17 isolates had the same sequence, being identical to the 3 isolates that emerged at the end of July. These results suggest that a particular HEV 1c strain spread widely during the rainy season and was implicated in a small epidemic in the Kathmandu valley in August 1997.     

A critical role for induced IgM in the protection against West Nile virus infection

In humans, the elderly and immunocompromised are at greatest risk for disseminated West Nile virus (WNV) infection, yet the immunologic basis for this remains unclear. We demonstrated previously that B cells and IgG contributed to the defense against disseminated WNV infection (Diamond, M.S., B. Shrestha, A. Marri, D. Mahan, and M. Engle. 2003. J. Virol. 77:2578-2586). In this paper, we addressed the function of IgM in controlling WNV infection. C57BL/6J mice (sIgM-/-) that were deficient in the production of secreted IgM but capable of expressing surface IgM and secreting other immunoglobulin isotypes were vulnerable to lethal infection, even after inoculation with low doses of WNV. Within 96 h, markedly higher levels of infectious virus were detected in the serum of sIgM-/- mice compared with wild-type mice. The enhanced viremia correlated with higher WNV burdens in the central nervous system, and was also associated with a blunted anti-WNV IgG response. Passive transfer of polyclonal anti-WNV IgM or IgG protected sIgM-/- mice against mortality, although administration of comparable amounts of a nonneutralizing monoclonal anti-WNV IgM provided no protection. In a prospective analysis, a low titer of anti-WNV IgM antibodies at day 4 uniformly predicted mortality in wild-type mice. Thus, the induction of a specific, neutralizing IgM response early in the course of WNV infection limits viremia and dissemination into the central nervous system, and protects against lethal infection.     

The Bhaktapur eye study: ocular trauma and antibiotic prophylaxis for the prevention of corneal ulceration in Nepal

AIMS: To determine the incidence of ocular trauma and corneal ulceration in the district of Bhaktapur in Kathmandu Valley, and to determine whether or not topical antibiotic prophylaxis can prevent the development of ulceration after corneal abrasion. METHODS: A defined population of 34 902 individuals was closely followed prospectively for 2 years by 81 primary eye care workers who referred all cases of ocular trauma and/or infection to one of the three local secondary eye study centres in Bhaktapur for examination, treatment, and follow up by an ophthalmologist. All cases of ocular trauma were documented and treated at the centres. Individuals with corneal abrasion confirmed by clinical examination who presented within 48 hours of the injury without signs of corneal infection were enrolled in the study and treated with 1% chloramphenicol ophthalmic ointment to the injured eye three times a day for 3 days. RESULTS: Over the 2 year period there were 1248 cases of ocular trauma reported in the population of 34 902 (1788/100 000 annual incidence) and 551 cases of corneal abrasion (789/100 000 annual incidence). The number of clinically documented corneal ulcers was 558 (799/100 000 annual incidence). Of the 442 eligible patients with corneal abrasion enrolled in the prophylaxis study, 424 (96%) healed without infection, and none of the 284 patients who were started on treatment within 18 hours after the injury developed ulcers. Four of the 109 patients (3.7%) who presented 18-24 hours after injury developed infections, and 14 (28.6%) of the 49 patients who presented 24-48 hours subsequently developed corneal ulceration. CONCLUSIONS: Ocular trauma and corneal ulceration are serious public health problems that are occurring in epidemic proportions in Nepal. This study conclusively shows that post-traumatic corneal ulceration can be prevented by topical application of 1% chloramphenicol ophthalmic ointment in a timely fashion to the eyes of individuals who have suffered a corneal abrasion in a rural setting. Maximum benefit is obtained if prophylaxis is started within 18 hours after injury.