The potential role of lonidamine (LND) in the treatment of malignant glioma

Summary Up-to-date unsatisfactory results obtained in multimodality treatments of malignant glioma have prompted the research of new therapeutic modalities with unconventional modes of action. Lonidamine (LND) is a drug which reduces aerobic glycolytic activity in both human and experimental tumors. This effect mainly depends on the inhibition of mitochondrially-bound hexokinase (HK) which is present in large amounts in malignant cells. A Phase II study was conducted on patients with recurrent glioma; 12 patients were admitted to the study. Clinical side effects were moderate, necessitating a reduction of the dosage in only 1 case. The objective results were evaluated according to the indications of Levin. 2 responders and 3 cases of stable disease were observed out of 10 evaluable patients. The potential value of this new drug is discussed.     

Study of antigen HBs and antivirus antibodies of hepatitis C during hepatopathies in Mali

A prospective study carried out in Bamako, Mali between July 1998 and January 1999 has assessed the seroprevalence of hepatitis C virus (HCV) in 91 carrier patients of chronic hepatopathy at a cirrhrosis stage (53) or of hepato-cellular carcinoma (38) and to compare with in 92 blood donors as a control population. Only seroprevalence confirmed by a complementary test has been taken into account (RIBA). HCV seroprevalence reached 25% including all hepatopathies, 24% in cirrhrosis and 26% in hepato-cellular carcinomae (HCC) versus 4% in blood donors. Antigen HBs of hepatitis B virus has been found in 55% of patients, versus 25% of the control cases (p = 0.0006). On the whole, the two markers have been notified a little more often in HCC than in cirrhosis and the combination of the two markers has been more frequent during cirrhosis as well. The role of HCV played in cirrhosis and HCC onset in Mali appears to be important.     

Predominance of a single genotype of Mycobacterium tuberculosis in countries of east Asia.

Analysis of the population structure of Mycobacterium tuberculosis strains from the People's Republic of China showed that the vast majority belong to a genetically closely related group. These strains shared the majority of their IS6110 DNA-containing restriction fragments, and also, the DNA polymorphism associated with other repetitive DNA elements, like the polymorphic GC-rich sequence and the direct repeat, was very limited. Because the majority of these strains originated from the province of Beijing, we designated this grouping the "Beijing family" of M. tuberculosis strains. Strains of this family were also found to dominate in neighboring countries such as Mongolia, South Korea, and Thailand, whereas a low prevalence of such strains was observed in countries on other continents. These data indicate that strains of the Beijing family recently expanded from a single ancestor which had a selective advantage. It is speculated that long-term Mycobacterium bovis BCG vaccination may be one of the selective forces implicated in the successful spread of the Beijing genotype.     

Dysautonomia in early Parkinson disease: a window into the determinants of functional disability and an opportunity for early intervention

Clinical Autonomic Research -     

Autocrine insulin-like growth factor 1 and stem cell factor but not interleukin 6 support self-renewal of human myeloma cells

In this study, we have identified the growth factors supporting myeloma self-renewal in eight myeloma cell lines. All cell lines able to form self-colonies displayed constitutive P-AKT and P-ERK1,2 but not P-STAT3 and did not express CD45, suggesting the presence of an insulin-like growth factor 1 (IGF1) loop. We showed that a blocking anti-insulin-like growth factor 1 receptor (IGF1R) monoclonal antibody (mAb) inhibited colony formation in correlation with IGF1R expression and decreased P-AKT. Imatinib or a blocking anti-stem cell factor (SCF) mAb also inhibited colony formation of two cell lines expressing C-KIT and SCF, and decreased P-AKT. Moreover, the PI3K/AKT pathway inhibitor wortmannin inhibited colony formation. Blocking interleukin (IL)6R did not inhibit colony formation in good agreement with a lack of constitutive P-STAT3. We showed that primary cells frequently co-expressed IGF1R/IGF1 but not C-KIT/SCF or IL6R/IL6, suggesting that in vivo autonomous growth could be possible via IGF1R. Despite their similar role in clonogenic growth and shared signaling pathway, IGF1R and C-KIT had opposite prognostic values, suggesting that they were surrogate markers. Indeed, we showed that both C-KIT and IGF1R prognostic values were not independent of MMSET expression. This study highlights the autocrine role of IGF1 in myeloma cells and reinforces the interest in targeting IGF1R in IGFR1⁺ CD45^+/− patients, such as MMSET⁺ patients.     

Short-term trial of clofazimine in previously untreated lepromatous leprosy.

Forty-five previously untreated lepromatous leprosy patients were allocated randomly to three groups and treated, respectively, with Regimen A, standard dosage of clofazimine (CLO) in multidrug therapy (MDT) regimen; Regimen B, CLO 600 mg once every 4 weeks; and Regimen C, CLO 1200 mg once every 4 weeks. The duration of the trial was 24 weeks. By the end of the trial, although a few patients in each group did not improve at all clinically, the majority of patients showed clinical amelioration but the responses were slow. While the mean morphological index dropped to the baseline after 24 weeks of treatment, the mean bacterial index did not change significantly. About 80% of the patients in each group remained nasal-smear positive at the end of the trial, but the bacterial loads steadily declined. No significant difference has been detected in these parameters among the three groups. The patients tolerated the regimens very well and the side effects were mild. The results of serial mouse foot pad inoculation demonstrated that the positivity rates of multiplication of Mycobacterium leprae in mice and the proportions of viable organisms reduced gradually in all groups. Because the positivity rate at week 24 in Group C did not differ significantly from Group A, but was significantly smaller than that of Group B, we conclude that Regimen C was as active as Regimen A and could be applied for monthly supervised treatment along with rifampin; Regimen B is less effective and should not be used for the treatment of leprosy.