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Cryptococcal meningitis is being increasingly described in immunocompetent adults. We describe here a young immuncompetent adult of Indian origin from Ghana, West Africa with cryptococcal meningitis who had several ups and downs during his treatment. First he developed neurologic worsening due to premature transition from intensive to consolidation phase therapy. Subsequently he deteriorated due to “immune reconstitution inflammatory syndrome (IRIS)” like phenomenon that necessitated the prolonged use of steroids. Additionally he suffered serious adverse effects due to antifungal drugs including liposomal amphotericin B and flucytosine. He recovered after 16 months of treatment. The case highlights the possible difficulties in management of cryptococcal meningitis in immunocompetent host including ‘immune reconstitution like syndrome’. There is need for new trial data and guidelines about treatment of cryptococcosis in the non HIV host. Keywords: Cryptococcus, Meningitis, Immunocompetent, Paradoxical upgrading reaction

Mutations in the copper (Cu) transporter gene ATP7B, the primary cause of Wilson disease (WD), result in high liver Cu and death of hepatocytes. Cu chelators and zinc salts are the two most important drugs used in the treatment of WD patients; however, the molecular mechanisms of the drugs with regard to ATP7B expression have not been determined. A targeted knockout of ATP7B (KO) was established in the most widely used human hepatoma cell line, HepG2 for molecular studies of the pathogenesis and treatment of the disease. KO cells showed similar growth, Cu uptake, release, and gene expression as compared to parental cells. However, in the presence of Cu, morphological changes, oxidative stress, apoptosis, and loss of viability were observed. Induction of metallothionein (MT1X) after Cu exposure was significantly reduced in KO cells. Following zinc treatment, MT1X expression was strongly induced and a high percentage of KO cells could be rescued from Cu induced toxicity. D-penicillamine treatment had a minor effect on the viability of KO cells whereas the parental cell line showed a pronounced improvement. Combined treatment displayed a highly synergistic effect in KO cells. The data suggest that zinc has a previously unrecognized effect on the viability of hepatocytes that lack ATP7B due to a high induction of MT1X expression that compensates low gene expression after Cu exposure. A combination therapy that simultaneously targets at MT1X induction and Cu chelation improves the overall survival of hepatocytes for most efficient therapy of patients having WD. [ABSTRACT FROM AUTHOR]

Aim: To study the effect of anti-copper treatment for survival of hepatic cells expressing different ATP7B mutations in cell culture., Methods: The most common Wilson disease (WD) mutations p.H1069Q, p.R778L and p.C271*, found in the ATP7B gene encoding a liver copper transporter, were studied. The mutations represent major genotypes of the United States and Europe, China, and India, respectively. A human hepatoma cell line previously established to carry a knockout of ATP7B was used to stably express WD mutants. mRNA and protein expression of mutant ATP7B, survival of cells, apoptosis, and protein trafficking were determined., Results: Low temperature increased ATP7B protein expression in several mutants. Intracellular ATP7B localization was significantly impaired in the mutants. Mutants were classified as high, moderate, and no survival based on their viability on exposure to toxic copper. Survival of mutant p.H1069Q and to a lesser extent p.C271* improved by D-penicillamine (DPA) treatment, while mutant p.R778L showed a pronounced response to zinc (Zn) treatment. Overall, DPA treatment resulted in higher cell survival as compared to Zn treatment; however, only combined Zn + DPA treatment fully restored cell viability., Conclusion: The data indicate that the basic impact of a genotype might be characterized by analysis of mutant hepatic cell lines.