Lack of mutations in the epsilon-sarcoglycan gene in patients with different subtypes of primary dystonias.

Primary dystonias represent a clinically and genetically heterogeneous group of movement disorders. Mutations in the epsilon-sarcoglycan (SGCE) gene have been found recently to cause myoclonus-dystonia (MD). Considerable clinical variation of SGCE mutation carriers leads to the hypothesis that mutations in the SGCE gene might also be relevant for other subtypes of dystonias. To determine the contribution of mutations in the SGCE gene in patients with different subtypes of dystonias, we analyzed the coding sequence of the SGCE gene in a group of 296 patients with a clinical phenotype of primary dystonia and in 2 patients with a clinical phenotype of myoclonus-dystonia. Patients with mutations in the DYT1 gene were excluded. We could not detect a mutation in the SGCE gene in any of the 298 patients. Our results suggest that mutations in the SGCE gene cannot be held responsible for other subtypes of primary dystonia.     

Early pregnancy complications: endovaginal sonographic findings correlated with human chorionic gonadotropin levels

Endovaginal sonography results were compared with quantitatively determined human chorionic gonadotropin (hCG) levels in 84 women referred for early pregnancy complications. Of the 27 with normal intrauterine pregnancies, an intrauterine gestational sac was prospectively identified in one of five cases (20%) in which hCG levels were below 500 IU/L (Second International Standard), four of five (80%) with hCG levels of 500-1,000 IU/L, and all 17 with hCG levels above 1,000 IU/L. In comparison, 17 of the 26 women with ectopic pregnancies (65%) had hCG levels greater than 1,000 IU/L, and none of the 26 had an intrauterine gestational sac. Endovaginal sonography demonstrated an adnexal mass and/or a gestational sac-like structure in 16 of the 17 cases (94%) in which hCG levels were above 1,000 IU/L, compared with only three of the nine (33%) with lower hCG levels (P less than .01). These findings indicate that an intrauterine gestational sac should be normally visualized with endovaginal sonography when the hCG level exceeds 1,000 IU/L, and that visualization of an extrauterine gestational sac and/or adnexal mass is significantly more likely in ectopic pregnancies when the hCG level exceeds 1,000 IU/L.     

马兜铃酸的倍半萜的酯类化合物VI.绵毛马兜铃中马兜铃酸萜酯I的结构鉴定

从绵毛马兜铃(Aristolocha mannisima Hance)中分得一个马兜铃酸倍半萜的酯类化合物,经红外、紫外、高分辩质谱和多种一维和二维核磁共振谱鉴定,确定了其骨架结构及顺反构型,命名为马兜铃酸萜酯I。     

Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds

OBJECTIVE—Spinocerebellar ataxia type 6 (SCA6) isan autosomal dominant cerebellar ataxia (ADCA) of which the mutationcausing the disease has recently been characterised as an expanded CAGtrinucleotide repeat in the gene coding for theα_1A-subunit of the voltage dependent calcium channel. Theaim was to further characterise the SCA6 phenotype
METHODS—The SCA6 mutation was investigated in 69 German families with ADCA and 61 patients with idiopathic sporadiccerebellar ataxia and the CAG repeat length of the expanded allele wascorrelated with the disease phenotype.
RESULTS—Expanded alleles were found in nine of 69 families as well as in four patients with sporadic disease. Diseaseonset ranged from 30 to 71 years of age and was significantlylater than in other forms of ADCA. Age at onset correlated inverselywith repeat length. The SCA6 phenotype comprises predominantlycerebellar signs in concordance with isolated cerebellar atrophy onMRI. Non-cerebellar systems were only mildly affected with external ophthalmoplegia, spasticity, peripheral neuropathy, and parkinsonism. Neither these clinical signs nor progression rate correlated with CAGrepeat length.
CONCLUSIONS—This study provides the first detailedcharacterisation of the SCA6 phenotype. Clinical features apart fromcerebellar signs were highly variable in patients with SCA6. Bycomparison with SCA1, SCA2, and SCA3 no clinical orelectrophysiological finding was specific for SCA6. Therefore, themolecular defect cannot be predicted from clinical investigations. InGermany, SCA6 accounts for about 13% of families with ADCA. However,up to 30% of SCA6 kindreds may be misdiagnosed clinically as sporadicdisease due to late manifestation in apparently healthy parents.Genetic testing is therefore recommended for the SCA6 mutation also inpatients with putative sporadic ataxia.

     

Modification of blood coagulation by the anti-arrhythmia drug prajmalium bitartrate in vivo

We studied the effects of prajmaliumbitartrate (PBT, Neo-Gilurytmal, Giulini Pharma, Hannover, FRG), an antiarrhythmic drug on some parameters of blood coagulation in patients. PBT, 20 mg given three times a day, significantly prolonged template bleeding time and ex vivo thrombus formation time in a modified Chandler's loop. Ex vivo platelet aggregation using different agonists and tests of the plasmatic coagulation system remained unchanged.     

Improved mitochondrial bioenergetics by anesthetic preconditioning during and after 2 hours of 27 degrees C ischemia in isolated hearts

We examined if sevoflurane given before cold ischemia of intact hearts (anesthetic preconditioning, APC) affords additional protection by further improving mitochondrial energy balance and if this is abolished by a mitochondrial KATP blocker. NADH and FAD fluorescence was measured within the left ventricular wall of 5 groups of isolated guinea pig hearts: (1) hypothermia alone; (2) hypothermia+ischemia; (3) APC (4.1% sevoflurane)+cold ischemia; (4) 5-HD+cold ischemia, and (5) APC+5-HD+cold ischemia. Hearts were exposed to sevoflurane for 15 minutes followed by 15 minutes of washout at 37 degrees C before cooling, 2 hours of 27 degrees C ischemia, and 2 hours of 37 degrees C reperfusion. The KATP channel inhibitor 5-HD was perfused before and after sevoflurane. Ischemia caused a rapid increase in NADH and a decrease in FAD that waned over 2 hours. Warm reperfusion led to a decrease in NADH and an increase in FAD. APC attenuated the changes in NADH and FAD and further improved postischemic function and reduced infarct size. 5-HD blocked the cardioprotective effects of APC but not APC-induced alterations of NADH and FAD. Thus, APC improves redox balance and has additive cardioprotective effects with mild hypothermic ischemia. 5-HD blocks APC-induced cardioprotective effects but not improvements in mitochondrial bioenergetics. This suggests that mediation of protection by KATP channel opening during cold ischemia and reperfusion is downstream from the APC-induced improvement in redox state or that these changes in redox state are not attenuated by KATP channel antagonism.     

Anticoagulation management and cardiac surgery in patients with heparin-induced thrombocytopenia

Unfractionated heparin (UFH) is the gold standard for anticoagulation during cardiopulmonary bypass (CPB). Of patients undergoing CPB operations, 25% to 50% develop heparin-dependent antibodies during the postoperative period, typically between day 5 and 10, if UFH is continued during the postoperative course. In 1% to 3% of all patients undergoing CPB operation with UFH anticoagulation, these antibodies activate platelets causing a prothrombotic disorder, known as heparin-induced thrombocytopenia (HIT), which can lead to life-threatening thromboembolic complications. If urgent cardiac operation with the use of CPB in patients with positive antibody titer is required, different anticoagulatory approaches are available, such as lepirudin, bivalirudin, and danaparoid or UFH in combination with platelet antagonists, such as epoprostenol or tirofiban. In patients with previous HIT but no detectable antibodies, UFH alone can be used only during CPB, but alternative anticoagulation has to be used pre- and postoperatively.     

Über den Stoffwechsel von Sulfaphenazol (Orisul®)

Zusammenfassung Der Stoffwechsel von¹⁴C-Sulfaphenazol (1-Phenyl-5-sulfanilamido-pyrazol, Oris ul®) wurde am Menschen untersucht. Nach oraler Gabe werden ca. 70% der Dosis mit dem Harn und der Rest mit den Faeces ausgeschieden. Im Serum wurde neben geringen Mengen N⁴-acetylderivat nur unverändertes Sulfaphenazol gefunden. Hydrolysenprodukte des Sulfaphenazols ließen sich weder im Serum noch im Harn nachweisen. Auch bei Inkubationsversuchen mit Menschenserum unter Verwendung von³⁵S- sowie¹⁴C-signiertem Material konnte keine hydrolytische Aufspaltung des Sulfaphenazol beobachtet werden. ca.99% der im Harn eliminierten Substanzen liegen als stark polare, extrem gut wasserlösliche Glucuronide vor. Der Hauptmetabolit wurde isoliert und konnte als das am N-2 des Pyrazolringes mit Glucuronsäure kondensierte Sulfaphenazol identifiziert werden.

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Summary The metabolism of¹⁴C-labelled Sulfaphenazole (1-phenyl-5-sulfanilamido-pyrazole, Orisul®) in the human organism was investigated. After oral administration, 70% of the dose were eliminated in the urine, the rest of the dose in the faeces.Aside from small amounts of N⁴-acetylderivative, only unaltered Sulfaphenazole was found in the serum. No products of hydrolysis of Sulfaphenazole were detectable in the serum and in the urine. Also in vitro, no hydrolytic cleavage of Sulfaphenazole was detectable after incubation of the¹⁴C- as well as the³⁵S-labelled compound in human serum.About 99% of the renally excreted radioactive material proved to be strongly polar, extremely well watersoluble glucuronides.The main metabolite was isolated and identified as a substituted Sulfaphenazole, carrying the glucuronic acid attached to the N-2 of the pyrazole ring.

     

MRI after magnetic drug targeting in patients with advanced solid malignant tumors

The purpose of this study was to evaluate the ability of MRI to detect magnetic particle uptake into advanced solid malignant tumors and to document the extension of these tumors, carried out in the context of magnetic drug targeting. In a prospective phase I trial, 11 patients were examined with MRI before and after magnetic drug targeting. The sequence protocol included T1-WI and T2-WI in several planes, followed by quantitative and qualitative evaluation of the signal intensities and tumor extensions. In nine patients, a signal decrease was observed in the early follow-up (2–7 days after therapy) on the T2-weighted images; two patients did not show a signal change. The signal changes in T1-WI were less distinct. In late follow-up (4–6 weeks after therapy), signal within nine tumors reached their initially normal level on both T1-WI and T2-WI; two tumors showed a slight signal decrease on T2-WI and a slight signal increase on T1-WI. Within the surveillance period, tumor remission in 3 out of 11 patients was observed, and in 5 patients tumor growth had stopped. The remaining three patients showed significant tumor growth. There was no statistically significant correlation between signal change and response. MRI is a suitable method to detect magnetite particles, deposited at the tumor site via magnetic drug targeting. MRI is therefore eligible to control the success of MDT and to assess the tumor size after the end of therapy.The used data are part of the thesis of M.-I. Senfft von Pilsach.