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Inhibitors of nuclear PARP enzymes (e.g., PARP-1) have improved clinical outcomes in ovarian cancer, especially in patients with BRCA1/2 gene mutations or additional homologous recombination (HR) DNA repair pathway deficiencies. These defects serve as biomarkers for response to PARP inhibitors (PARPi). We sought to identify an additional biomarker that could predict responses to both conventional chemotherapy and PARPi in ovarian cancers. We focused on cellular ADP-ribosylation (ADPRylation), which is catalyzed by PARP enzymes and detected by detection reagents we developed previously. We determined molecular phenotypes of 34 high-grade serous ovarian cancers and associated them with clinical outcomes. We used the levels and patterns of ADPRylation and PARP-1 to distribute ovarian cancers into distinct molecular phenotypes, which exhibit dramatically different gene expression profiles. In addition, the levels and patterns of ADPRylation, PARP-1 protein, and gene expression correlated with clinical outcomes in response to platinum-based chemotherapy, with cancers exhibiting the highest levels of ADPRylation having the best outcomes independent of BRCA1/2 status. Finally, in cell culture-based assays using patient-derived ovarian cancer cell lines, ADPRylation levels correlated with sensitivity to the PARPi, Olaparib, with cell lines exhibiting high levels of ADPRylation having greater sensitivity to Olaparib. Collectively, our study demonstrates that ovarian cancers exhibit a wide range of ADPRylation levels, which correlate with therapeutic responses and clinical outcomes. These results suggest ADPRylation may be a useful biomarker for PARPi sensitivity in ovarian cancers, independent of BRCA1/2 or homologous recombination deficiency status.

Dose-dense (dd) regimens are one of the preferred options for the adjuvant treatment of breast cancer patients with intermediate to high risk. The German Adjuvant Intergroup Node-positive trial aimed at optimizing intense dd (idd) strategies by evaluating drug combinations and the addition of capecitabine.Women (aged 18 years and biologically 65 years) with histologically involved axillary lymph nodes were randomly assigned to receive three courses each of epirubicin (E) 150 mg/m2, paclitaxel (P) 225 mg/m2 and cyclophosphamide (C) 2500 mg/m2 (reduced to 2000 mg/m2 after recruitment of 1200 patients) q2w intravenously (i.v.) (iddEPC-regimen) or ddEC (E 112.5 mg/m2 + C 600 mg/m2, i.v. q2w for 4 cycles) followed by paclitaxel weekly (Pw 67.5 mg/m2 i.v. q8d for 10 weeks) plus capecitabine (X 2000 mg/m2 p.o. days 1-14, q22 for 4 cycles) (ddEC-PwX-regimen). Further randomization assigned patients to ibandronate for 2 years versus observation and to pegfilgrastim day 2 versus 4.From June 2004 to August 2008, 2994 patients were randomized to either iddEPC (N = 1498), or ddEC-PwX (N = 1496) and started treatment. Median age was 50 years; pN1 (37.8%), pN2 (35.3%); pN3 (26.9%); 46.4% were G3 tumors; 76.9% hormone receptor-positive and 22% HER2-positive. After a median follow-up of 74 months, 645 events and 383 deaths were recorded. Hematological adverse events grades 3-4 were more common with iddEPC (P 0.001), nonhematological with ddEC-PwX (P = 0.04), even if the toxicity profile of the two regimens was different. At 5 years, estimated disease-free survival rates for ddEC-PwX and iddEPC were 81.7% [95% confidence interval (CI) 79.5-83.6] versus 80.2% (95% CI 78.0-82.2). Hazard ratio (HR)=0.95 (95% CI 0.81-1.11, log-rank P = 0.49). Five-year overall survival rates were 89.4% for ddEC-PwX (95% CI 87.7-91.0) and 89.0% for iddEPC (95% CI 87.2-90.6), HR = 0.85 (95% CI 0.69-1.04, log-rank P = 0.10).Adding capecitabine to ddEC-Pw did not improve outcome in comparison to iddEPC but increased toxicity and should not be recommended for further use.

Purpose Bisphosphonates prevent skeletal-related events in patients with metastatic breast cancer. Their effect in early breast cancer is controversial. Ibandronate is an orally and intravenously available amino-bisphosphonate with a favorable toxicity profile. It therefore qualifies as potential agent for adjuvant use. Patients and Methods The GAIN (German Adjuvant Intergroup Node-Positive) study was an open-label, randomized, controlled phase III trial with a 2 × 2 factorial design. Patients with node-positive early breast cancer were randomly assigned 1:1 to two different dose-dense chemotherapy regimens and 2:1 to ibandronate 50 mg per day orally for 2 years or observation. In all, 2,640 patients and 728 events were estimated to be required to demonstrate an increase in disease-free survival (DFS) by ibandronate from 75% to 79.5% by using a two-sided α = .05 and 1-β of 80%. We report here the efficacy analysis for ibandronate, which was released by the independent data monitoring committee because the futility boundary was not crossed after 50% of the required DFS events were observed. Results Between June 2004 and August 2008, 2,015 patients were randomly assigned to ibandronate and 1,008 to observation. Patients randomly assigned to ibandronate showed no superior DFS or overall survival (OS) compared with patients randomly assigned to observation (DFS: hazard ratio, 0.945; 95% CI, 0.768 to 1.161; P = .589; OS: HR, 1.040; 95% CI, 0.763 to 1.419; P = .803). DFS was numerically longer if ibandronate was used in patients younger than 40 years or older than 60 years compared with patients age 40 to 59 years (test for interaction P = .093). Conclusion Adjuvant treatment with oral ibandronate did not improve outcome of patients with high-risk early breast cancer who received dose-dense chemotherapy.

ObjectivesTo evaluate the current patterns of use of minimally invasive surgical procedures, including traditional, robotic-assisted, and single-port laparoscopy, by Society of Gynecologic Oncology (SGO) members and to compare the results to those of our 2004 and 2007 surveys.MethodsThe Society of Gynecologic Oncology members were surveyed through an online or mailed-paper survey. Data were analyzed and compared with results of our prior surveys.ResultsFour hundred six (32%) of 1279 SGO members responded. Eighty-three percent of respondents (n = 337) performed traditional laparoscopic surgery (compared with 84% in 2004 and 91% in 2007). Ninety-seven percent of respondents performed robotic surgery (compared with 27% in 2007). When respondents were asked to indicate procedures that they performed with the robot but not with traditional laparoscopy, 75% indicated radical hysterectomy and pelvic lymphadenectomy for cervical cancer. Overall, 70% of respondents indicated that hysterectomy and staging for uterine cancer was the procedure they most commonly performed with a minimally invasive approach. Only 17% of respondents who performed minimally invasive surgery performed single-port laparoscopy, and only 5% of respondents indicated that single-port laparoscopy has an important or very important role in the field.ConclusionsSince our prior surveys, we found a significant increase in the overall use and indications for robotic surgery. Radical hysterectomy or trachelectomy and pelvic lymphadenectomy for cervical cancer and total hysterectomy and staging for endometrial cancer were procedures found to be significantly more appropriate for the robotic platform in comparison to traditional laparoscopy. The indications for laparoscopy have expanded beyond endometrial cancer staging to include surgical management of early-stage cervical and ovarian cancers, but the use of single-port laparoscopy remains limited.

Objective: To develop a short instrument to examine quality of life (QoL) which specifically addresses patients with movement disorders treated by deep brain stimulation (DBS). Design: The instrument was developed within an existing concept of a modular questionnaire (questions on life satisfaction: “general life satisfaction” QLS M -A, and “satisfaction with health” QLS M -G), in which each item is weighted according to its relative importance to the individual. Methods: Items were generated by interviews with 20 DBS patients, followed by item reduction and scale generation, factor analysis to determine relevant and final questionnaire items, estimation of reliability, and validation based on the medical outcome study 36 item short form health survey (SF-36) and the EuroQol (EQ-5D) (data from 152 patients with Parkinson’s disease, essential tremor, or idiopathic torsion dystonia, including 75 patients with DBS). Results: Initial questionnaires were reduced to 12 items for a “movement disorder module” (QLS M -MD), and five items for a “deep brain stimulation module” (QLS M -DBS). Psychometric analysis revealed Cronbach’s α values of of 0.87 and 0.73, and satisfactory correlation coefficients for convergent validity with SF-36 and EQ-5D. Conclusions: QLS M -MD and QLS M -DBS can evaluate quality of life aspects of DBS in movement disorders. Psychometric evaluation showed the questionnaires to be reliable, valid, and well accepted by the patients.

Background The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline–taxane–based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses. Patients and methods Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (α = 0.05, β = 0.8) 379 events had to be observed in the bevacizumab arms. Results With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1–3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups. Conclusions Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline–taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients. Clinical trial number NCT 00567554, www.clinicaltrials.gov .

The SELEDO (from selegiline plus levodopa) study was carried out as a randomized, prospective, placebo-controlled, double- blind, multicenter long-term, 5-year trial to evaluate the possible advantages of combining selegiline and levodopa in the early treatment of Parkinson's disease. One-hundred-and-sixteen patients were randomized either to selegiline or placebo. Before starting the study medication, the levodopa dose was titrated to the individual requirements of each patient. The primary study end point (time when levodopa had to be increased by >50% of the titrated dose) was reached in 23 of 59 patients in the selegiline group and 26 of 48 patients in the placebo group. At the end of the 5 years' treatment period the rates derived from a life-table analysis were 50.4% in the selegiline group and 74.1% in the placebo group (P = 0.027, log-rank test). The median time to reach the primary end point was 4.9 years in the selegiline group and 2.6 years in the placebo group. In patients treated with selegiline, the mean levodopa dose changed only slightly over the 5 years of treatment compared to the initially titrated dose, but rose markedly in the placebo group, where the dose of levodopa had to be adjusted earlier than in the selegiline group. At the same time, the lower levodopa dosage in the selegiline group was accompanied by at least equal therapeutic efficacy (which is necessary for an unambiguous interpretation). Subgroup analyses showed greater benefit for selegiline treated) patients in the earlier stages. Long-term side effects appeared later in the selegiline group, although the difference was not significant. The early combination of selegiline and levodopa proved to be clearly superior to levodopa monotherapy.

Introduction - In about 20% of MS patients an increased CSF/serum albumin quotient (Q Alb ) has been observed. The reason for this blood-CSF barrier dysfunction is yet unclear. Subjects and methods - Q Alb values from 48 MS patients in relapse were correlated with parameters of active CNS lesions as measured by gadolinium-DTPA MRIs. Q Alb values from 20 MS patients without relapse served as controls. Results - Mean Q Alb values (x10 3 ) of a group with spinal cord lesions (7.6±3.6; n=16) differed significantly from those of a control group (4.6±1.5; n=20; p

A 39 year old patient with cerebellar signs, juvenile cataracts, and dull normal intelligence had cerebrotendinous xanthomatosis without tendon xanthomas, diagnosed previously as Marinesco-Sjoegren syndrome. Cerebrotendinous xanthomatosis was proved by a greatly increased excretion of bile alcohols in the patient's urine. Cerebrotendinous xanthomatosis is a sterol storage disorder due to an autosomal recessive inherited defect of sterol 27-hydroxylase characterised by high cholestanol concentration in multiple tissues. If tendon xanthomas are not present, a diagnosis of cerebrotendinous xanthomatosis will often not be made, unless biochemical tests are performed. The clinical features of cerebrotendinous xanthomas strongly resembles Marinesco-Sjoegren syndrome. Marinesco-Sjoegren syndrome is a autosomal recessive disorder characterised by the triad cerebellar ataxia, congenital cataract, and mental retardation. Although a late onset after the first decade of life favours cerebrotendinous xanthomatosis as the underlying disease, a definite distinction between cerebrotendinous xanthomatosis without tendon xanthomas and Marinesco-Sjoegren syndrome based on clinical presentation may be difficult. It is considered that some patients with Marinesco-Sjoegren syndrome reported in the medical literature had cerebrotendinous xanthomatosis without tendon xanthomas. This is of crucial clinical relevance, because, by contrast with Marinesco-Sjoegren syndrome, treatment for cerebrotendinous xanthomatosis is already available.

OBJECTIVES:To pilot-test a visual aid developed to help counsel pregnant women.METHODS:After agreeing to participate, pregnant women at >28 weeks of gestation were assigned randomly to counseling with or without a visual aid. The visual aid contained pictures, graphics, and short messages about delivery room resuscitation, chances of survival, anticipated neonatal course, and long-term neurodevelopmental disabilities. A neonatal fellow performed counseling with a standardized script for an anticipated delivery at 23 weeks of gestation. In precounseling and postcounseling sessions, women were given a structured interview to assess their knowledge of chances of survival and disability and attitudes toward resuscitation.RESULTS:Of the 89 women who participated, 76% were black and 59% read below a 9th-grade level. Compared with the no–visual aid group, women in the visual aid group recalled more disabilities and predicted longer neonatal stays (P = .01). For both groups, mothers' perceptions of the chances of survival were lower after counseling; the decrease was greater in the visual aid group (P = .03). The majority of women in each group opted for resuscitation, which was not affected by counseling. In multivariate analyses, use of the visual aid was a significant independent factor in explaining before/after differences in survival chances and recall of a long NICU stay and number of disabilities; higher literacy levels also were significant for recalling the number of disabilities.CONCLUSIONS:Use of a visual aid improved mothers' knowledge and showed promise as a decision aid for counseling at the threshold of viability.

Preliminary data suggest that pegfilgrastim given on day 4 (P4) might be superior to pegfilgrastim on day 2 (P2) in reducing grade 4 leucopenia. Patients with node-positive primary breast cancer receiving epirubicin–paclitaxel–cyclophosphamide chemotherapy were randomized to receive P2 versus P4. Primary endpoint was leucopenia grade 4, assuming a risk reduction of 50% with P4 from 50% in P2 to 25% with P4. Three-hundred fifty-one patients were randomized to P2 (n = 174) versus P4 (n = 177). The rate of leucopenia (grade 4) was 47.1% with P2 and 42.0% with P4 (p = 0.387), neutropenia (grade 3 + 4) was 47.9% versus 40.8% (p = 0.337), FN was 4.7% versus 8.0% (p = 0.271), and infections was 29.9% versus 25.4% (p = 0.404), respectively. This study failed to demonstrate that pegfilgrastim on day 4 was more efficacious than on day 2 with respect to grade 4 leucopenia (the primary endpoint), febrile neutropenia, or infections.

The latencies and amplitudes of responses evoked by magnetic brain stimulation (magnetic evoked potentials, MEP) in the first dorsal interosseus and the anterior tibial (TA) muscles were investigated in 15 patients with psychogenic limb weakness and in 50 patients with limb weakness due to established organic central nervous system disease. Of the patients with psychogenic limb weakness, 3 presented with upper limb monopareses, 2 with lower limb monoparesis, 4 with hemipareses, 4 with parapareses and 2 with paraparesis. All patients with psychogenic weakness had MEP in arm and leg muscles with latencies within the normal range. MEP amplitudes were also normal except for 1 patient in whom the response amplitude in the TA of the plegic limb was reduced. In patients with limb weakness due to established organic disease, MEP were frequently but not invariably abnormal. In patients with plegic (i.e. completely paretic, MRC grade 0) muscles due to organic disease, MEP always were clearly abnormal. Normal MEP were sometimes elicited from paretic muscles, more commonly in association with cerebral hemisphere lesions than with spinal lesions. We conclude that psychogenic limb weakness is associated with normal MEP. However, normal MEP in mildly paretic muscles do not definitely exclude organic pathology.

GABG-IV B-93 is a prospective, randomised study comparing goserelin (n=384) with no further treatment (n=392) in hormone receptor (HR)-negative breast cancer patients (n=465) after 3 cycles cyclophosphamide, methotrexate, 5-fluorouracil (CMF) for patients with 0-3 positive lymph nodes (LN) or 4 cycles epirubicin, cyclophosphamide (EC) followed by 3 cycles CMF for patients with 4-9 positive LN. After completion of the ZEBRA trial the study was amended to enrol also HR-positive patients with 1-9+LN (n=311). After a median follow-up of 4.7 years neither HR-negative nor HR-positive patients showed a benefit for goserelin. The adjusted estimated hazard ratio for event-free survival in HR-negative patients was 1.01 (goserelin versus control, 95% confidence interval [CI] 0.72-1.42, P=0.97) and 0.77 in HR-positive patients (95% CI 0.47-1.24, P=0.27). These results do not support the general use of goserelin after adjuvant chemotherapy in this group of premenopausal patients.

Gonadotrophin-releasing hormone analogues were investigated as adjuvant treatment for patients with node-negative, hormone-sensitive, premenopausal breast cancer. Patients were randomised to either three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy (n=378) or goserelin every 28 d for 2 years (n=393). During a median follow-up of 4.9 years, 123 events were observed. The first-failure event of CMF versus goserelin, respectively, was ipsilateral locoregional recurrence (18 versus 20), contralateral breast cancer (7 versus 6), distant failure (35 versus 24) and death without recurrence (2 versus 2). Forty-two (23 versus 19) deaths of any cause occurred. The estimated adjusted hazard ratio for goserelin versus CMF (intention-to-treat analysis) was 0.79 (95% CI=0.54-1.14; P=0.19). It is concluded that medical ovarian ablation with goserelin represents a valid option for premenopausal patients with node-negative breast cancer.

Significant improvements of cerebral vasomotor reactivity during statin treatment were found in patients with cerebral small-vessel disease. The authors analyzed the cerebrovascular CO(2) reactivity before and after statin administration in healthy adults using a case-control study design.The mean cerebral blood flow velocity (CBFV) of both middle cerebral arteries and the vasomotor reserve capacity (VMRC) were measured by repeated and simultaneous bilateral transcranial Doppler sonography in 25 healthy adults (7 men, mean age 28.8 years [95% confidence interval (CI): 25.7; 31.9]) before, during (days 1, 3, 7, and 14), and after administration of 40 mg pravastatin for 14 days as compared to 10 healthy control persons (4 men, mean age 30.6 years [95% CI: 22.9; 38.3]). The VMRC was calculated off-line as the percentage change of CBFV per 1% increase in end-tidal CO2 by a blinded investigator.In the statin group, 5 persons were excluded from further analysis. In the remaining 20 volunteers, the authors observed a highly significant effect of statin administration on VMRC (P = .002). The VMRC was significantly increased after statin administration on day 7 as compared to the initial value (3.03 [95% CI: 2.67; 3.38] vs 2.64 [95% CI: 2.41; 2.86]; P = .04). The effect was most pronounced in patients with lower initial VMRC values. In the control group, the VMRC did not differ significantly from baseline at different time intervals.The findings indicate an improvement of cerebral vasoreactivity even after short-term statin administration in healthy adults. However, this effect was related to baseline vasoreactivity.

The existence of dissociative fugue is doubted by many psychiatrists. We describe a 22-year-old patient who traveled about 600 km to Munich during a dissociative fugue and then exhibited an irreversible amnesia for a period of 24 h. There was a severe, clearly understandable conflict in the sense of a subjective stalemate situation which has been described as typical for dissociative fugue. The patient had a labile personality structure with insufficient coping strategies. It was possible to rule out other psychiatric or neurological disorders with sufficient certainty, and simulation was very unlikely. The conflict could not be satisfactorily solved, and the patient committed suicide 5 months later by jumping off a bridge.

Motor imagery is a state of mental rehearsal of single movements or movement patterns and has been shown to recruit motor networks overlapping with those activated during movement execution. We wished to examine whether the brain areas subserving control of sequential processes could be delineated by pure mental imagery, their activation levels reflecting the processing demands of a sequential task. We studied six right-handed volunteers (39.0 +/- 14 years) with H(2)(15)O positron emission tomography (PET) while they continuously mentally pursued with their right hand one of five sequences differing in complexity (i.e., increases in sequence length, single-finger repetitions, and reversals). Conditions were repeated twice, alternating with two rest scans. Each imagined single motor element was paced at a frequency of 1 Hz. Significant activation increases (P0.05, corrected) associated with imagination of right finger movement sequences (conditions I to V combined)--compared to the rest condition--were observed in left sensorimotor cortex (M1/S1) and the adjacent inferior parietal cortex. Further activation increases (P0.001, uncorrected) occurred in bilateral dorsal premotor (PMd) cortex, left caudal supplementary motor area, bilateral ventral premotor cortex, right M1, left superior parietal cortex, left putamen, and right cerebellum. Activation decreases occurred in bilateral prefrontal and right temporo-occipital cortex. Activation increases that correlated with sequence complexity were observed only in specific areas of the activated network, notably in left PMd, right superior parietal cortex, and right cerebellar vermis (P0.05, corrected). In conclusion, our study, by varying the sequence structure of imagined finger movements, identified task-related activity changes in parietopremotor-cerebellar structures, reflecting their role in mediating sequence control.

The present study examined the cerebral control of velocity during handwriting. We employed H215O positron emission tomography (PET) to measure the regional cerebral blood flow (rCBF) in 10 healthy subjects. Participants were required to write the German verb 'bellen' ('to bark') either at their normal speed (i.e. fast open-loop handwriting) or to write at approximately half of their normal speed without visual feedback. The second task required a continuous modification of the motor output according to the kinaesthetic feedback from the hand (i.e. slow closed-loop handwriting). Pencil movements were recorded during PET scanning and analysed off-line using a stroke-based analysing program. The mean number of inversions in velocity (NIV) per stroke was used to quantify the mode of motor control during each PET scan. A NIV of 1 indicates fast open-loop processing, whereas an increase in NIV reflects a shift towards slow closed-loop processing of handwriting. Foci in the left primary sensorimotor cortex, the right lateral premotor cortex, the left anterior parietal cortex, the left anterior putamen, the left rostral supplementary motor area and the right precuneus showed a graded increase in functional activation with the mean NIV per stroke, suggesting that this set of brain regions is particularly involved in the processing of slow closed-loop writing movements. No area showed a negative relationship between rCBF and the mean NIV per stroke, suggesting that fast open-loop handwriting is achieved by an optimized cooperation of the manual sensorimotor network rather than by a selective activation of a distinct network component.

There is conjoining experimental and clinical evidence supporting a fundamental role of the basal ganglia as a sensory analyser engaged in central somatosensory control. This study was aimed at investigating the functional anatomy of sensory processing in two clinical conditions characterized by basal ganglia dysfunction, i.e. Parkinson's and Huntington's disease. Based on previously recorded data of somatosensory evoked potentials, we expected deficient sensory-evoked activation in cortical areas that receive modulatory somatosensory input via the basal ganglia. Eight Parkinson's disease patients, eight Huntington's disease patients and eight healthy controls underwent repetitive H(2)(15)O-PET activation scans during two experimental conditions in random order: (i) continuous unilateral high-frequency vibratory stimulation applied to the immobilized metacarpal joint of the index finger and (ii) rest (no vibratory stimulus). In the control cohort, the activation pattern was lateralized to the side opposite to stimulus presentation, including cortical [primary sensory cortex (S1); secondary sensory cortex (S2)] and subcortical (globus pallidus, ventrolateral thalamus) regional cerebral blood flow (rCBF) increases (P0.001). Between-group comparisons (P0.01) of vibration-induced rCBF changes between patients and controls revealed differences in central sensory processing: (i) in Parkinson's disease, decreased activation of contralateral sensorimotor (S1/M1) and lateral premotor cortex, contralateral S2, contralateral posterior cingulate, bilateral prefrontal cortex (Brodmann area 10) and contralateral basal ganglia; (ii) in Huntington's disease, decreased activation of contralateral S2, parietal areas 39 and 40, and lingual gyrus, bilateral prefrontal cortex (Brodmann areas 8, 9, 10 and 44), S1 (trend only) and contralateral basal ganglia; (iii) in both clinical conditions relative enhanced activation of ipsilateral sensory cortical areas, notably caudal S1, S2 and insular cortex. Our data show that Parkinson's disease and Huntington's disease, beyond well-established deficits in central motor control, are characterized by abnormal cortical and subcortical activation on passive sensory stimulation. Furthermore, the finding that activation increases in ipsilateral sensory cortical areas may be interpreted as an indication of either altered central focusing and gating of sensory impulses, or enhanced compensatory recruitment of associative sensory areas in the presence of basal ganglia dysfunction. Altered sensory processing is thought to contribute to pertinent motor deficits in both conditions.

In 13 of 14 patients with Guillain-Barré syndrome (GBS), we observed multiple A waves in at least one limb nerve on routine electroneurographic studies within 7 days after onset of symptoms. The patient without A waves had a severe axonal type of GBS with tetraplegia and almost complete loss of M responses following electrical stimulation of limb nerves. In the remaining 13 patients, on average 8 +/- 2 (mean +/- SD) A waves were present in each tibial nerve (n = 24) and 4 +/- 1 A waves in each peroneal nerve (n = 26). About half of the A waves were below 50 microV in amplitude, whereas amplitudes were higher than 120 microV in only 22 of 299 A waves. Of these A waves, 68 were not constantly elicitable. There was a significant correlation between the number of A waves up to 50 ms poststimulus and the reduction in amplitude of the compound muscle action potential when elicited with proximal compared to distal stimulation in the peroneal (n = 26, P0.0005; Kendall's tau) and tibial nerves (n = 24, P0.002). Therefore, in GBS both conduction block and A waves are presumably signs of inflammatory nerve lesions. The existence of multiple A waves soon after onset of symptoms seems to be a sensitive sign of GBS.

Repeated PET cerebral blood flow measurements using H2(15)O were performed in 13 patients with confirmed Huntington's disease and nine age-matched controls. The activation paradigm consisted of an externally triggered finger opposition task (1.5 Hz) with the dominant hand, the control condition being the auditory input. In the patients with Huntington's disease, impaired activity of the striatum and its frontal motor projection areas (rostral supplementary motor area, anterior cingulate and premotor cortex) could be demonstrated along with enhanced activity mainly in parietal areas during movement. The results suggest that the pathology of Huntington's disease causes impairment of the output part of the basal ganglia-thalamo-cortical motor circuit and may induce a compensatory recruitment of additional accessory motor pathways involving the parietal cortex.

OBJECTIVE--To investigate whether the dose of intrathecal baclofen necessary for a sufficient reduction of muscle tone and spasms changes during treatment of severe spasticity. METHODS--A group of 27 patients received intrathecal baclofen for 61 (SD 18) months. RESULTS--Spasticity remained absent or strongly reduced after stopping the intrathecal baclofen infusion in seven patients. The dose of baclofen could be reduced to 40% of that dose which was originally necessary in 10 patients. The dose remained the same or increased slightly in 10 patients. Possible reasons for the continuing reduction of spasticity after terminating long term intrathecal baclofen infusion in some patients could be: lasting morphological changes in spinal cord neurons by second messenger controlled modulation of gene expression, a toxic effect of baclofen on spinal neurons, muscular atrophy, inflammation due to the catheter, or progression of multiple sclerosis. CONCLUSIONS--A higher initial daily dose of intrathecal baclofen might lead to a faster, lasting suppression of spasticity and the development of spastic symptoms might even be prevented by pre-emptive treatment with baclofen in patients with newly acquired lesions of the spinal cord.

Islet transplantation represents an alternative to whole pancreas transplantation for the treatment of patients suffering from diabetes type I. The transplantation of a sufficient number of islets is an essential condition for successful allograft. Islet cryopreservation allows the storage of islet preparations for subsequent pooling, at the time of transplantation, of cryopreserved islets with a fresh preparation in order to increase the mass of transplanted pancreatic endocrine tissue. From May 1994 to April 1995, islets were isolated from 22 human pancreases using a modified automated method, and 19 preparations were cryopreserved. The function of cryopreserved islets was tested in vitro (static incubation and perifusion). The results of static incubation experiments confirmed that the insulin secretion of cryopreserved human islets in response to glucose stimulation was comparable to the response of islets that have not been frozen. In static incubation experiments, the mean (+/- SEM) insulin secretion of islets, prior to cryopreservation, was 239.3 (+/- 58.9) and 479.5 (+/- 59.5) pg/islet/15 min at 2.8 mM glucose and 16.7 mM glucose respectively. The mean (+/- SEM) insulin secretion of cryopreserved islets was 274 (+/- 103.2) and 468.5 (+/- 191.9) pg/islet/15 min at 2.8 mM and 16.7 mM glucose respectively. The perifusion experiments also demonstrated a significant increase of insulin secretion from cryopreserved islets perifused with a stimulating glucose concentration. Our experiments allow us to envisage the use of cryopreserved islet preparations for allotransplantation in diabetic patients.

The association between cerebrovascular complications and detection of antiphospholipid antibodies (aPA) has been under clinical and immunological investigation during the last ten years. The occurrence of aPA in coincidence with recurrent thrombosis, miscarriages and thrombocytopenia is termed "primary antiphospholipid syndrome". The most important neurological symptoms are recurrent cerebral arterial and venous ischemias. Especially in the case of young patients with a history of recurrent infarcts, migraine-like headaches and the absence of classical risk factors should lead to a determination of these antibodies. Although the pathogenetic importance of these antibodies is still unclear, patients positive for them seem to carry a higher cerebrovascular risk and should be observed more cautiously. More studies are necessary to define the origin of these antibodies and their role in thrombogenesis. To develop standards for therapeutic management a multicenter study is desirable.

The purpose of this study was to examine what aspects of the mother-child relationship are measured by the Nursing Child Assessment Teaching Scale (NCATS). A racially heterogeneous sample of 128 mothers completed questionnaires measuring maternal depression, parenting self-efficacy, knowledge of developmental and parenting principles, and perceived difficult toddler temperament. Mothers and children were also videotaped during home visits while completing two teaching tasks that were later scored using NCATS. NCATS Parent subscale scores were significantly related to maternal knowledge and education but unrelated to depression and self-efficacy. Child subscale scores were unrelated to all of the study variables, including perceived difficult temperament. Significant differences were noted among African-American, Hispanic, and white mothers. The findings suggest that the NCATS taps cognitive factors more reliably than affective factors underlying the mother-child relationship and the cognitive factors may be culturally biased.

Magnetically and electrically elicited blink reflexes were studied in 11 normal subjects and in 5 patients with partial peripheral facial nerve palsy. Both methods were able to elicit a reproducible blink reflex. In both groups the latencies of the magnetically elicited reflexes were equal to those that followed electrical stimulation. The magnetic stimulation technique offered 2 advantages over the electrical stimulation: (1) it was less painful and therefore better tolerated and (2) the coil position in the middle of the forehead was sufficient to elicit a bilateral blink reflex because the windings of the stimulation coil excited both supraorbital nerves simultaneously. This bilateral response enables one to reduce the number of stimuli and can be used in the examination of patients that have peripheral facial nerve palsies without the concomitant impairment of the reflex pathway in the brainstem. The magnetic technique can also elicit a blink reflex at stimulation points distant from the supraorbital notch. This finding offers an alternative explanation of the late responses of facial muscles following transcranial magnetic stimulation of the motor cortex.

F-wave responses of the posterior tibial nerve have been studied in 22 patients with spasticity and in 18 normal control subjects with surface EMG. Mean amplitude and mean duration of the F-waves were significantly (p less than 0.001) longer in patients with spasticity than in healthy controls. These findings could be the result of an enhanced spinal excitability in spasticity. Based on the present results F-wave recording may be used as a simple and practical technique for detection and documentation of spasticity.

✓ The present study evaluates the interdependence of clinical stage, cerebral vasospasm, intracranial pressure (ICP), and transcranial Doppler ultrasonographic parameters. The mean flow velocity of blood in the middle cerebral artery and the index of cerebral circulatory resistance as a measure of the peripheral vascular flow resistance were determined in 76 patients with spontaneous subarachnoid hemorrhage. The ICP was measured using an epidural transducer in 41 patients. There was no case in which both high ICP and a high mean flow velocity were observed simultaneously. The investigations led to the following conclusions. 1) In patients with a resistance index of less than 0.5, changes in the mean flow velocity seem to reflect sufficiently the actual severity and time course of vasospasm. 2) During the time course of vasospasm, an increase in the resistance index above values of 0.6 with a simultaneously decreased mean flow velocity indicates a rise in ICP rather than a reduction in vasospasm. 3) With a pronounced increase in ICP, evaluation of the severity and time course of vasospasm by transcranial Doppler ultrasonography based solely upon the mean flow velocity can lead to false-negative results.

10 patients suffering from a widespread continuous fasciculation of the lower extremities without any other neurological signs and symptoms are presented. A follow up study of 6 of these patients could be done. The fasciculation potentials were polyphasic with changing shape from discharge to discharge and appeared irregularly in most of the muscles of the legs. In 5 patients no change of clinical and neurophysiological signs could be detected over the period of observation, whereas in one patient a sensory polyneuropathy was evident in course of time. The findings illustrate that a state of widespread continuous fasciculations without other signs and symptoms is not predicative for the development of a amyotrophic lateral sclerosis.

This investigation deals with the temporal aspects of air volume changes during speech. Speech respiration differs fundamentally from resting respiration. In resting respiration the duration and velocity of inspiration (air flow or lung volume change) are in a range similar to that of expiration. In speech respiration the duration of inspiration decreases and its velocity increases; conversely, the duration of expiration increases and the volume of air flow decreases dramatically. The following questions arise: are these two respiration types different entities, or do they represent the end points of a continuum from resting to speech respiration? How does articulation without the generation of speech sound affect breathing? Does (verbalized?) thinking without articulation or speech modify the breathing pattern? The main test battery included four tasks (spontaneous speech, reading, serial speech, arithmetic) performed under three conditions (speaking aloud, articulating subvocally, quiet performance by tryping to exclusively 'think' the tasks). Respiratory movements were measured with a chest pneumograph and evaluated in comparison with a phonogram and the identified spoken text. For quiet performance the resulting respiratory time ratio (relation of duration of inspiration versus expiration) showed a gradual shift in the direction of speech respiration--the least for reading, the most for arithmetic. This change was even more apparent for the subvocal tasks. It is concluded that (a) there is a gradual automatic change from resting to speech respiration and (b) the degree of internal verbalization (activation of motor speech areas) defines the degree of activation of the speech respiratory pattern.

The visual evoked potential (VEP) to pattern reversal was recorded in 79 patients with neurosyphilis. Sixteen patients (20%) had abnormal VEP latencies with a predominance of pathological VEP values in the group of tabes dorsalis (50%) as compared to general paresis (18%) or meningovascular forms (13%). A comparison of the frequency of abnormal VEPs with that of other ophthalmological tests (visual acuity, visual field, central campimetry, pupillary reactions, dark adaptation, optic fundus) yielded no diagnostic superiority of VEP.

How memorized visuo-spatial information influences motor control and whether this information is able to replace the feedback processing in cases of visual deprivation was studied using an unrestrained finger- and hand-movement paradigm. Nineteen right-handed subjects were asked to grasp and lift a small block with the index finger and thumb of the right hand, as quickly as possible. The efficiency of motor performance was analysed by measuring the grasping time derived from tangential velocity profiles of the fingertips. The data revealed significantly shorter grasping times under continuous visual guidance than during blind grasping. Grasping times increased under conditions with stepwise prolongation of visual deprivation time prior to the movement onset. The results support the general concept that within the first seconds of visual deprivation, stored visuo-spatial information can partly compensate for the lack of continuous visual feedback.

The extent to which estimations of intracranial pressure can be derived from intracranial flow patterns was studied. The blood flow velocity in the middle cerebral artery was recorded with the EME TC 2-64 transcranial Doppler (TCD) device in 26 patients suffering from various severe cerebral diseases. Simultaneously the mean intracranial pressure (ICP) was measured by means of an epidural device. Arterial carbon-dioxide tensions were monitored by blood gas analysis. In all patients it was observed that the middle cerebral artery flow patterns changed distinctly when the ICP increased; these changes were distinguished by a decrease of the mean flow velocity and an increase of the Pourcelot index. A good correlation between the ICP and the flow parameters (especially the product mean systemic arterial pressure x Pourcelot index/mean flow velocity) was found in a select group of 13 patients, in whom comparable initial conditions existed and in whom additional parameters influencing the TCD recordings could be kept constant (r = 0.873; P less than 0.001).

The aim of the present study was to answer the question whether electrophysiological examination of the m. flexor carpi ulnaris, especially of the distal latency (stimulation point 2 cm above the sulcus ulnaris) to this muscle, represents a valid procedure for the localisation of an ulnar nerve lesion at the elbow. In 64 patients, a total of 68 ulnar nerve lesions at the elbow were subjected to conventional clinical and electrophysiological examinations. A pathologically prolonged distal latency to m. flexor carpi ulnaris (>4.0 ms) was found in 82.4% of the patients. In terms of their value in the topo-diagnosis of an ulnar lesion, measurement of the distal latency to m. flexor carpi ulnaris and conventional analysis of trans-sulcal motor conduction velocity of the fibres to the hypothenar muscles yield equivalent information. However, evaluation of the distal latency to m. flexor carpi ulnaris is not only subject to fewer sources of error but is also techniqually much easier to perform. In the localisation of a clinically suspected ulnar nerve lesion at the elbow, we therefore suggest that the electrophysiological investigation should commence with an examination of the distal latency to m. flexor carpi ulnaris.

A new genetic syndrome of the combined occurrence of hypogonadotropic hypogonadism, anosmia (Kallmann syndrome) and congenital mirror movements in four brothers is presented. Mirror movements were manifest only within the distal parts of the upper extremities and resembled congenital mirror movements described for isolated or familial cases or those occurring in combination with other genetic defects. The hypothesis is supported, that a midline fusion disorder with preponderance of uncrossed pyramidal tract fibers is a major pathogenetic factor for the occurrence of congenital mirror movements.

Interval analyses of denervation potentials (fibrillation-potentials and positive sharp waves) in human skeletal muscles were performed using a DEC PDP-12 computer. Extremely small differences between consecutive intervals (usually less than 1%) and slow up and down drifts in the spontaneous discharge frequency were found to be characteristic of repetitive denervation potentials. These two findings are safe criteria for the clinical diagnosis of denervation and they may be superior to the more commonly used criteria based upon the shapes, amplitudes, and durations of the potentials. Physiological data from the literature as well as hypotheses relating to spontaneous activity are reviewed. Generator potentials across the muscle fibre membrane, lowered firing threshold, and constant-sized after-potentials are considered the basic factors relevant to spontaneous and rhythmical firing and to the slow drift observed in the firing frequency.

In two normal subjects and in a patient with an old poliomyelitis and a normocalcaemic tetany, repetitive fasciculation potentials in the triceps and in the adductor pollicis respectively showed a pause after contraction of the relevant muscle. The duration of the pause increased in proportion to the duration of the preceding muscle contraction. Results were obtained which suggest that the pause originated proximal to the motor nerve endings. In one of the subjects, radial nerve anaesthesia abolished the fasciculation in the triceps. This fasciculation was also evoked by electrical stimulation of the radial nerve. Afferent conduction of the stimulus-induced volley was shown to be involved in originating the evoked fasciculation, which was, however, not an H reflex and not an antidromic recurrent discharge. The fasciculation could not have originated distal to the axilla in the motor fibres which conducted the efferent command for the fasciculation. It probably originated in the spinal cord or very near to it.

Pattern reversal visual evoked potentials (VEPs) were studied in 80 chronic alcoholics and in 43 normal subjects. In the patient group, P2 latencies and inter-eye differences were found above the 98% confidence limit in 30%, and above the 99.9% confidence limit in 10%. An abnormal waveform was observed in 12.5% and 7.5% of the patients. VEP abnormalities showed some statistical correlation with the gamma-type of alcoholism of Jellinek, but almost no correlation was observed with a variety of clinical and laboratory data. This suggest that VEP abnormalities are unrelated to other toxic effects of alcohol on the peripheral and central nervous systems or on metabolism.

The aim of the present investigation was to establish the value of gluteal muscles (m.gluteus medius, GME; m.gluteus maximus, GMX) as segmental reference muscles in the topical diagnosis of lumbar root compression syndromes. The methodological rationale consisted in determining the frequency with which denervation potentials could be recorded in the GME and GMX of patients with clinically and electromyographically well-defined monosegmental or bisegmental lumbar root compression syndromes. Of the L5-syndromes (N=36), 81% revealed denervation potentials in GME, but only 6% in GMX. Of the S1 syndromes (N=26), 63% exhibited denervation potentials in GMX and 32% in GME. L5 syndromes showed a better correlation of positive findings to GME than S1 syndromes to GMX. As far as the differential diagnosis is concerned, the advantages of recording EMG from GME and GMX are two-fold: (a) the immediate certainty of excluding a peripheral nerve lesion and (b) a reduction in the incidence of false negative findings.

Treatment results of randomized clinical trials on primary breast cancer are given by tables including surgical treatment and adjuvant modalities like chemo-, hormone-, and immunotherapy.

The flexor reflex evoked in the tibialis anterior muscle by stimulation of the medial plantar nerve was investigated in 54 normal subjects. Three main reflex components were identified (excitation--inhibition-- excitation), the early excitation being composed of two subcomponents. Occasionally, a fourth (excitatory) reflex component was seen breaking through EMG inhibition. The individual reflex components were differentially susceptible to facilitatory influences which suggested transmission via a central multichannel system. Methodological experiments showed that the amplitudes and to some degree also the latencies of the individual reflex components were modified by both the parameters of the stimulus as well as by the degree of pre-innervation. However, the patterning of the reflex response was basically independent from methodological permutations.

The decay and recovery of stapedial reflex amplitude was investigated in 19 patients with myasthenia gravis and 30 control subjects. In 9 untreated patients the amplitude was reduced to less than 10% of the initial amplitude following continuous stimulation for 120 s, whereas the maximum decay in the control subjects was only 50%. In the group of treated patients the reflex decay showed individual variations. The rate of recovery after prolonged stimulation (5 min) was slower in the patient group, especially within the first 30 s of recovery. With increasing age, the rate of decay rose in the patient group as well as in the control group. The technical parameters necessary for obtaining information of clear diagnostic value are indicated, with which it was shown that the continuous prolonged stimulation of the stapedial muscle is a practical and valid method for the evaluation of patients with myasthenia gravis.

The organization and coordination of cutaneo-muscular reflexes of human finger and arm muscles to electrical stimulation of the digital nerves were investigated in 14 healthy volunteers. Thumb and finger muscles, although antagonists, showed homonymous reflex effects whereas the wrist and elbow muscles exhibited an reciprocally alternating reflex pattern in pairs of antagonists (Fig. 1). The mechanographical correlate of the homonymous reflex activity in distal muscles was a short release (Fig. 6). The receptive field for evoking such reflex effects covered both the palmar and dorsal surfaces of the fingers (Fig. 2). However, with stimulation of the thumb, the muscles of the fingers and of the wrist showed reflex reversal (Figs 3, 5). If the stimulus was moved from the second to the fifth fingers, a successive attenuation of the transcortical reflex component was seen (Fig. 4). It is concluded that the reflexes investigated are complex flexor reflexes comprising both a distal release and a proximal flexion synergy. According to opposition of the thumb in grasping, the receptive field terminates between thumb and index finger. These reflexes are supposed to have no assisting function during corticalized manipulatory movements--in contrast to the long-loop reflexes evoked by epicritic sensibility. The transcortical servo is blocked if the eliciting stimulus is contaminated by nociceptive signals; its receptive field is confined to those fingers used in the precision grip.

Somatosensory evoked potentials (SSEP) from the scalp of the sensori-motor cortex were recorded together with long latency reflexes in the EMG of the contralateral biceps muscle in 17 human subjects, who were instructed to compensate a sudden biceps stretch. In this ‘compensate’ condition the earliest deviation from the shape of the SSEP obtained in a ‘let go’ situation (exhibiting only short latency reflexes) occurred as early as 35–40 ms. The results indicate that SSEP changes associated with the occurrence of long latency reflexes might be compatible with a transcortically mediated reflex activity.

In rapid goal-directed elbow flexion movements the influence of both movement amplitude and inertial load on the three-burst pattern and the consequences on movement time were studied. Subjects performed visually guided, self-paced movements as rapidly and as accurately as possible. An increase of both the movement amplitude and the inertial load were found to be interacting factors for the modulation of the three-burst-pattern and movement time. The first biceps burst progressively increased in duration and amplitude for larger movements, resulting in prolonged movement times. Surplus inertial loads further prolonged the agonist burst for large, but not for small movement amplitudes. The activity of the antagonist burst, in contrast, was largest in small movements and successively decreased at increasing movement amplitudes. Its duration, however, remained fairly constant. As was similarly observed for the agonist burst, surplus inertial loads lead to a prolongation of antagonist burst duration and an increase of the activity integral for large, but not for small movement amplitudes. It is suggested that in elbow flexion movements the programming of fastest goal-directed movements must take into account neural constraints and biomechanical characteristics of the agonist muscle and the antagonist muscle. Due to neural constraints of the biceps muscle, in contrast to finger movements, the concept of movement time invariance does not hold for elbow movements. Furthermore, neural constraints of the antagonist muscle lead to a limited force production of the agonist muscle at small movement amplitudes in order to avoid an overload of the braking process. The complexity of the relationship between neural and mechanical factors indicate that the size and timing of the three-burst-pattern has to be subtly adjusted to the precise nature of the task and its biomechanical characteristics.