Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease

Recently targeted disruption of Omi/HtrA2 has been found to cause neurodegeneration and a parkinsonian phenotype in mice. Using a candidate gene approach, we performed a mutation screening of the Omi/HtrA2 gene in German Parkinson's disease (PD) patients. In four patients, we identified a novel heterozygous G399S mutation, which was absent in healthy controls. Moreover, we identified a novel A141S polymorphism that was associated with PD (P<0.05). Both mutations resulted in defective activation of the protease activity of Omi/HtrA2. Immunohistochemistry and functional analysis in stably transfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent, the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology. Cells overexpressing S399 mutant Omi/HtrA2 were more susceptible to stress-induced cell death than wild-type. On the basis of functional genomics, our results provide a novel link between mitochondrial dysfunction and neurodegeneration in PD.     

Phase I study using desferrioxamine and iron sorbitol citrate in an attempt to modulate the iron status of tumor cells to enhance doxorubicin activity

Summary a novel approach to enhance the activity of doxorubicin is to increase the availability of cellular chelatable iron to participate in doxorubicin-mediated free-radical generation. To achieve this, we designed a regimen consisting of desferrioxamine (DFO, 50 mg/kg daily given as an i. v. infusion over 72 h) to increase cellular iron uptake. Thereafter, the combination of iron sorbitol citrate (ISC) and doxorubicin (as a single agent or as part of the CHOP regimen) was given. In a phase I study we investigated the toxicity of this regimen in nine patients with refractory malignant disease. Severe but reversible ocular toxicity (i. e., acute maculopathy) was observed in two patients. As these patients were the only ones who were pretreated with cisplatin, we caution against the use of DFO in cisplatin-pretreated patients. Severe phlebitis was encountered in five of nine patients. A partial remission was observed in two of four patients with refractory Non-Hodgkin's lymphoma who were treated with DFO, ISC, and doxorubicin as part of the CHOP regimen. We conclude that pretreatment with DFO and iron sorbitol citrate may be of benefit in the treatment of malignancies with doxorubicin-containing regimens, but ocular toxicity and severe phlebitis limits the use of DFO in this approach. The attachment of DFO to biocompatible polymers may be a method of overcoming the observed toxicity and warrants further study.Abbreviations PR partial remission - PD progressive disease - OT ocular toxicity - Phl phlebitis of WHO grade>III - Dox doxorubicin dose given (whereas CHOP contains 50 mg/m² doxorubicin) - AC adenocarcinoma - NHL Non-Hodgkin's lymphoma - SCLC small-cell lung cancer - CHOP cyclophosphamide/doxorubicin/vincristine/prednisone - COP cyclophosphamide/vincristine/prednisone - VP16/MTX/Cycl etoposide/methotrexate/cyclophosphamide - ProMACE-MOPP prednisone/methotrexate/Adriamycin/cyclophosphamide/etoposide/nitrogen mustard/vincristine/procarbazine/prednisone - FAM(TX) 5-fluorouracil/doxorubicin/mitomycin/methotrexate(TX) - CP cyclophosphamide/cisplatin - CDDP cisplatin - Mitox mitoxantrone - CDE cyclophosphamide/doxorubicin/etoposide - Chl chlorambucil - E/MTX/C etoposide/methotrexate/cyclophosphamide     

Current autologous transfusion practices. Implications for the future

A questionnaire was distributed to 509 AABB institutional members to evaluate current autologous transfusion practices. Results were returned from 47 blood centers, 108 transfusion services and 64 hospital blood banks (response rate 43%). Results indicate that not all eligible patients are allowed to donate due to unnecessarily strict eligibility criteria. Thirty percent of autologous units are not tested for infectious disease markers. Of those units tested and found positive for anti-HIV or HBsAg, 53 and 72% respectively, of the institutions provide the units to the intended recipient. Forty-seven percent of institutions perform an AHG crossmatch for autologous recipients. Sixty five percent of institutions permit "crossing-over" of autologous units for homologous use. Implications of these findings for the development of standards for autologous transfusion programs are discussed.     

Hepatosplenic candidiasis: wheels within wheels

Eight immunocompromised cancer patients with tissue-proved candidiasis underwent serial abdominal ultrasound (US) and computed tomography (CT). At US, four patterns of hepatic and splenic candidiasis were recognized, one of which the authors call a "wheels-within-wheels" pattern. In addition, periportal linear areas of increased attenuation, possibly calcified, were identified at follow-up, nonenhanced CT. Some abscesses were better seen on nonenhanced CT scans, while others became visible only with enhancement. Although lesions not seen at US were often seen at CT, the opposite was also true. In two cases, pathologic proof of candidiasis was established even when all imaging studies were normal. For maximum imaging sensitivity, patients should be studied with US and nonenhanced and enhanced CT. Even when both US and CT scans are negative, if there is a strong clinical suggestion of candidiasis, open biopsy is recommended.     

Potential hazards of hypoglycaemia in the parturient

Hypoglycaemia can cause serious problems in anaesthetized patients, due to blockade by anaesthesia of the usual compensatory mechanisms. Gravid women develop hypoglycaemia more readily than non-pregnant patients because they live in a state of "accelerated starvation." Three cases are described of healthy parturients undergoing elective Caesarean section under lumbar epidural analgesia whose post-blockade hypotension was difficult to reverse until their low blood glucose concentrations had been normalized. Further investigations of the role played by blood glucose concentrations in the maintenance of cardiovascular homeostasis in pregnant women are indicated. In the meantime, a preanaesthetic blood glucose determination will facilitate measures to ensure a normal blood glucose level before induction of anaesthesia for Caesarean section.     

Electrophysiological evidence that early glaucoma affects foveal vision

The pattern electroretinogram (PERG) and visual evoked potential (PVEP) were recorded simultaneously using a 1.1 cpd pattern which was counterphase modulated at 1 Hz. The responses of ocular hypertensive (OHT) eyes (with normal visual fields) and eyes with early glaucoma (with early visual field defects and/or early cupping of the optic nervehead) were compared to age-matched normal observers. All patients (26 eyes) and normal observers (14 eyes) had normal transient flash electroretinograms. Delays were seen in mean PERG latency in both OHT and early glaucoma eyes, while mean PERG amplitude was significantly reduced only in the early glaucoma eyes. The PVEP responses were unmeasurable in 11/26 patient eyes because the waveforms were grossly abnormal in shape, making it impossible to identify the N- and P-components. The data were categorized in this manner: a patient response was considered abnormal if latency or amplitude exceeded normal limits (PERG or PVEP) or if the waveform was unmeasurable due to its shape (PVEP only). Of the 26 patient eyes, we found that 8 eyes had normal PERG and PVEP, 11 eyes had abnormal PERG and PVEP, one eye had an abnormal PERG and a normal PVEP, and 6 eyes (3 patients) had a normal PERG and an abnormal PVEP. These data support the proposition that foveal vision (as assessed by the PVEP) may be affected by early glaucomatous damage. The relationship between the PERG and PVEP also was evaluated using a new measurement which we call the latency window. Using this measurement, 15/26 patient eyes were abnormal - 9 of these had unmeasurable PVEPs. This measurement could be useful in classifying W-shaped PVEPs as normal or abnormal.This study was supported in part by Grants EY01708 and EY01867 from the National Eye Institute, Bethesda, MD, by Fight For Sight Grant-in-Aid G-274, and by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY.