Neurofilament heavy-chain NfH(SMI35) in cerebrospinal fluid supports the differential diagnosis of Parkinsonian syndromes.

We aimed to evaluate the potential of the cerebrospinal fluid (CSF) axonal damage biomarker NfH(SMI35) in the laboratory-supported differential diagnosis of parkinsonian syndromes. Patients with idiopathic Parkinson's disease (PD; n = 22), multiple-system atrophy (MSA; n = 21), progressive supranuclear palsy (PSP; n = 21), corticobasal degeneration (CBD; n = 6), and age-matched controls (n = 45) were included. CSF levels of NfH(SMI35) were measured using ELISA. Levels of CSF NfH(SMI35) were elevated in PSP compared to PD and controls (P < 0.05 each). They were also significantly higher in MSA than in PD and controls (P < 0.05 each). NfH(SMI35) differentiated PD from PSP with a sensitivity of 76.5% and a specificity of 94.4%. Axonal damage as measured by CSF NfH(SMI35) is most prominent in the more rapidly progressive syndromes PSP and MSA as compared to PD or CBD. CSF NfH(SMI35) may therefore be of some value for the laboratory-supported differential diagnosis of atypical parkinsonian syndromes.     

Serious intraoperative problems — a five-year review of 83,844 anesthetics

PURPOSE: The low incidence of mortality and major morbidity in anesthesia makes it difficult to study the pattern of potential accidents and to develop preventive strategies. Anesthetic 'near-misses', however, occur more frequently. Using data from a simple routine-based system of problem reporting, we have analyzed the pattern and causes of serious non-fatal problems, in order to improve preventive strategies. METHODS: We prospectively recorded anesthesia-related information from all anesthetics for five years. The data included intraoperative problems, which were graded into four levels, according to severity. We analyzed only the serious nonfatal problems, which were sorted according to clinical presentation, and also according to which factor was most important in the development of the problem. We assessed any untoward consequences for the patient, and whether the problems could have been prevented. RESULTS: Serious problems were recorded in 315 cases out of 83,844 (0.4%). Anesthesia was considered the major contributing factor in 111 cases. Difficult intubation, difficult emergence from general anesthesia, allergic reactions, arrhythmia and hypotension were the dominating problems. Twenty-six anesthesia related problems resulted in changes in level of postoperative care, and one patient later died in the intensive care unit after anaphylactic shock. Eighty-two problems could have been prevented by simple strategies. CONCLUSION: Analysis of serious nonfatal problems during anesthesia may contribute to improved preventive strategies. Data from a routine-based system are suitable for this type of analysis. Intubation, emergence, arrhythmia, hypotension and anaphylaxis cause most serious problems, and should be the object of preventive strategies.     

Bilateral carcinomas of the breast with local recurrence: analysis of genetic relationship of the tumors.

Local recurrence of bilateral breast carcinomas is rare, but of biological interest, since it is unclear as to which tumor the local recurrence is related to, the ipsilateral or the contralateral, or whether it is an independent neoplasm. The aim of this study was to investigate the genetic relationship of bilateral breast carcinomas to each other and to their local recurrences. Eight cases of bilateral breast carcinomas, five with and three without local recurrence were analyzed using a microsatellite assay for 13 microsatellite loci. The presence of loss of heterozygosity and microsatellite instability in the various tumors was used for clonal analysis. All eight bilateral breast carcinomas showed divergent alterations in at least two microsatellite loci, which ruled out a genetic relationship. Four of five local recurrences were genetically related to the ipsilateral tumor and unrelated to the contralateral tumor. Only one local recurrence that occurred 11.8 years after the surgery of an infiltrative lobular carcinoma simultaneously with distant metastases was genetically related to the contralateral breast carcinoma. Although the number of cases in our study is limited, there is evidence that local recurrence of bilateral breast carcinoma frequently arises from the ipsilateral tumor.     

Microsatellite analysis of breast carcinoma and corresponding local recurrences

Local recurrence is a serious complication of breast carcinoma that reduces quality of life and influences prognosis. The aim of this study was to determine whether local recurrences of breast carcinoma are genetically related to the primary tumours. Forty cases of locally recurrent breast carcinomas (median onset: 3.6 years after primary surgery) were analysed: 22 patients had undergone breast-conserving therapy and 18 mastectomy. Eighteen microsatellites on chromosomes 2p, 3p, 5q, 10q, 11p, 11q, 13q, 17q, 17p, 18p were amplified by PCR using fluorescent-labelled primers, automatically detected after polyacrylamide gel electrophoresis and analysed for loss of heterozygosity (LOH) or microsatellite instability (MSI). Follow-up data were available for 39 cases with a median value of 89 months. All LOH and MSI found in the primary tumours were also present in the corresponding recurrences, indicating that they are genetically related to the primary tumours and not secondary malignancies in the same breast. MSI was found in three cases, of which one harboured MSI at more than two loci. The median value of LOH per case was significantly higher in the recurrent (four per case) compared to the primary tumours (two per case; p < 0.001, Mann-Whitney test), reflecting the genotype of tumour progression. Early local recurrence was associated with specific LOH for TP53.15 (p = 0.018, log-rank test) in the primary tumours. LOH on D13S1699 or D17S855 was associated with lymph node metastases (p = 0.024 and p = 0.019, respectively; chi-square test). In addition, tumour grade, lack of oestrogen or progesterone receptor expression, young patient age and early appearance of local recurrence significantly correlated with poor survival. The development of local recurrence despite clear resection margins may result from residual DCIS distant from the invasive carcinoma, homing of circulating tumour cells, or genetically altered, histologically normal breast tissue not immediately adjacent to the invasive carcinoma.     

Contractile activity and reperfusion-induced calcium gain after ischemia in the isolated rat heart

Reperfusion of cardiac muscle after an ischemic episode results in the cells becoming overloaded with Ca2+. Gross ultrastructural changes, including the formation of contraction bands, also occur. The present study investigates the relationship, if any, between contractile activity during reperfusion and Ca2+ gain. Contractile activity was inhibited with 2,3-butanedione monoxime (BDM). Isolated perfused rat hearts were subjected to 30 minutes ischemia before reperfusion in the presence or absence of BDM. BDM (10 MIN) significantly reduced the Ca2+ gained during reperfusion. It also enhanced the ATP and creatine phosphate supplies. Ultrastructural examination of cells from hearts reperfused in the presence of BDM for 30 minutes revealed cells with relaxed myofibrils, some glycogen and intact sarcolemmal membranes, compared with cells from hearts reperfused in the absence of BDM which showed contraction bands, sarcolemmal discontinuities and swollen mitochondria. The 'protection' afforded by BDM did not result in a restoration of the cells to their normal state. Removal of BDM and continued reperfusion with Krebs-Henseleit buffer resulted in a gain in Ca2+ and ultrastructural damage, including contraction band formation. These findings suggest a role for contractile activity in the Ca2+ gain. However, preventing the damage which occurs as a result of contractile activity is not sufficient to restore the cells to their preischemic state. This suggests that the damage caused as a result of contractile activity is secondary to some other primary deleterious event.     

Stage-associated risk of transmission of the lyme disease spirochete by EuropeanIxodes ticks

To more closely define the risk of infection by the agent of Lyme disease in Europe, we determined whether spirochetal prevalence increases throughout the development of theIxodes ricinus vector tick. Of all ticks that could be flagged from vegetation,I. ricinus were by far the most abundant. Spirochetal infection rates in the adult stage of this tick (15%) are no higher than those in nymphs (18%) but greatly exceed those in larvae (0.7%). This tick therefore appears to attain infection mainly from the host of its larval stage, generally feeds on hosts that are noncompetent as reservoirs in its nymphal stage, and rarely inherits infection. Risk of human infection mainly derives from contact with the nymphal stage of the vector tick because the larva is rarely infected and the adult is large enough to be noticed and promptly removed.This work was supported in part by grant AI 19693 from the National Institute of Allergy and Infectious Disease and by grants from the city of Berlin     

Effects of iodoproxyfan,a potent and selective histamine H3 receptor antagonist,onα 2 and 5-HT3 receptors

We determined the affinity and/or potency of the novel H₃ receptor antagonist iodoproxyfan at ₂ and 5-HT₃ receptors. Iodoproxyfan and rauwolscine (a reference ₂ ligand) (i) monophasically displaced³H-rauwolscine binding to rat brain cortex membranes (pK_i 6.79 and 8.59); (ii) facilitated the electrically evoked tritium overflow from superfused mouse brain cortex slices preincubated with³H-noradrenaline (pEC₅₀ 6.46 and 7.91) and (iii) produced rightward shifts of the concentration-response curve (CRC) of (unlabelled) noradrenaline for its inhibitory effect on the evoked overflow (pA₂ 6.65 and 7.88). In the guinea-pig ileum, iodoproxyfan 6.3µmol/l failed to evoke a contraction by itself but depressed the maximum of the CRC of 5-hydroxytryptamine (pD₂ 5.24). Tropisetron (a reference 5-HT₃ antagonist) produced rightward shifts of the CRC of 5-hydroxytryptamine (pA₂ 7.84). In conclusion, the affinity/potency of iodoproxyfan at H₃ receptors (range 8.3-9.7 [1]) exceeds that at ₂ receptors by at least 1.5 log units and that at 5-HT₃ receptors by at least 3 log units.     

Effects of the novel H1 agonists 2-(3-trifluoromethylphenyl)- and 2-(3-bromophenyl)histamine and of 2-(2-thiazolyl)ethylamine on cardiovascular paramenters in the pithed rat

The effect of the newly synthetized H₁ agonists 2-(3-trifluoromethylphenyl)histamine (2-TFMPH) and 2-(3-bromophenyl)histamine (2-BPH) and of the reference compound 2-(2-thiazolyl)ethylamine (2-TEA) on diastolic blood pressure and heart rate was studied in pithed and vagotomized rats. 2-TFMPH and 2-BPH were at least equipotent with 2-TEA in producinga dimethindene-sensitive, short-lasting vasodepressor response. At the highest dose, 2-TFMPH and 2-BPH produced an additional small vasopressor response, which was followed by a long-lasting vasodepressor effect not counteracted by dimethindene and ranitidine 2-TEA, at the highest dose, induced an additional vasopressor response abolished by prazosin plus rauwolscine. Basal heart rate was increased by 2-TEA (in a desipramine-sensitive manner) but not affected by 2-TFMPH or 2-BPH. In conclusion, 2-TFMPH and 2-BPH are potent H₁ agonists, devoid of an indirect sympathomimetic effect; at high doses, they produce a vasodepressor response not mediated via histamine receptors.Recipient of a fellowship provided by the Alexander von Humboldt-Stiftung (Bonn, Germany)