BACKGROUND: Many polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are causal, mediated by a direct effect of the polymorphism on the gene product itself. However, the supporting evidence is not always clear. METHODS: We conducted systematic reviews and meta-analyses to assess the empirical evidence for functional polymorphisms in genes encoding dopaminergic enzymes (COMT, DBH, DDC, MAOA, MAOB, and TH), dopamine receptors (DRD1, DRD2, DRD3, DRD4, and DRD5), the dopamine transporter (DAT), and vesicular transporters (VMAT1 and VMAT2). We defined functionality as an effect of the polymorphism on the expression, abundance, activity, or affinity of the gene product. RESULTS: We screened 22,728 articles and identified 255 eligible studies. We found robust and medium to large effects for polymorphisms in 4 genes. For catechol-O-methyltransferase (COMT), the Val 158 Met polymorphism (rs4680) markedly affected enzyme activity, protein abundance, and protein stability. Dopamine b-hydroxylase (DBH) activity was associated with rs1611115, rs2519152, and the DBH-STR polymorphism. Monoamine oxidase A (MAOA) activity was associated with a 5 0 VNTR polymorphism. Dopamine D 2 receptor (DRD2) binding was influenced by the Taq1A (rs1800497) polymorphism, and rs1076560 affected DRD2 splicing. CONCLUSIONS: Some widely studied dopaminergic polymorphisms clearly and substantially affect the abundance or activity of the encoded gene product. However, for other polymorphisms, evidence of such an association is negative, inconclusive, or lacking. These findings are relevant when selecting polymorphisms as "markers" of dopamine function, and for interpreting the biological plausibility of associations between these polymorphisms and aspects of brain function or dysfunction.

We describe a case of disseminated Beauveria bassiana infection in a patient with acute lymphoblastic leukemia. Her infection was successfully treated with amphotericin B and itraconazole. B. bassiana is rarely reported as a human pathogen. It is commonly found in soil and because of its pathogenicity to many insect species is incorporated into several pesticides. CASE REPORTA 44-year-old Caucasian woman was diagnosed with acute lymphoblastic leukemia. She had a history of recurrent sinusitis but was otherwise well. She lived in a rural area of the South Island of New Zealand and owned a garden center.At presentation she had a neutrophil count of 0.36 ϫ 10 9 / liter but was clinically well with no signs of infection and commenced treatment with prophylactic ciprofloxacin and fluconazole. She was nursed in a positive-pressure single room and given a low-bacteria diet. At day 1 of induction chemotherapy (United Kingdom Acute Lymphoblastic Leukemia 12 protocol), ciprofloxacin and fluconazole were stopped, and co-trimoxazole and nystatin were started. At day 15 of treatment the patient became febrile, and Streptococcus viridans was isolated from blood cultures. She was treated with piperacillin and gentamicin, and her temperature stabilized. She remained neutropenic, and at day 20, small (Ͻ1-cm) purple macular "cigarette burn " lesions were noted on her left upper arm (Fig. 1A). An aspirate sent for bacteriology and skin scrapings sent for fungal culture yielded no microorganisms. Four days after the skin lesions developed, she complained of symptoms of sinusitis, headache, and facial pain and had percussion tenderness over her maxillary sinuses. Paranasal sinus disease was not identified by computed tomography scanning, and in view of her persisting neutropenia further invasive investigations were not performed. Serum transaminases were elevated on day 21, but an abdominal ultrasound scan was normal.Fluconazole was restarted on day 28, and an excision biopsy of one of the skin lesions was performed the next day. Histopathological examination of the biopsy specimen revealed sharply demarcated areas of necrosis with lack of cellular reaction at the interface. The necrotic tissue was heavily permeated by fungal hyphae, which also invaded the local blood vessels (Fig. 2). Cultures of the tissue biopsy sample on blood agar and Sabouraud glucose agar plates at 30°C produced a pure growth of a white mould identified preliminarily as a Beauveria sp. No recovery of the mould was obtained on plates incubated at 35°C. The susceptibility of the isolate was assessed using Sensititre Yeast One susceptibility plates (Trek Diagnostic Systems, West Sussex, England). Testing was performed at 30°C, and the MIC was read after 72 h of incubation. The susceptibility results were as follows: the amphotericin B MIC was 2.0 mg/liter, the itraconazole MIC was 0.06 mg/liter, the fluconazole MIC was 8.0 mg/liter, the ketoconazole MIC was 0.125 mg/liter, and the 5-flucytosine MIC was Ͼ64 mg/liter.Prednisone was stopped on day 37 of phase 1 in...

Antithrombin Glasgow is a hereditary abnormal antithrombin that has lost thrombin inhibitory activity. It was isolated from the plasma of a 41‐year‐old male with a history of thrombotic events. Antithrombin Glasgow was purified from plasma using heparin‐Sepharose chromatography at pH 7.4 eluting with increasing concentrations of NaCl. The normal protein eluted with 0.9 mol/l NaCl and Glasgow with 1.05 mol/l NaCl. Electrophoresis in agarose at pH 8.6 showed the variant to migrate more anodally than normal. The C‐terminal small fragment resulting from catalytic cleavage with elastase between P3 and P4 of the reactive loop was isolated and sequenced. This showed the replacement of the arginine at residue 3 by a histidine. This is residue 393 in the intact molecule. The findings suggest that heparin, on binding, interacts indirectly with the reactive centre region of antithrombin.

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