Christoph J. G. Lang

A blood based 12-miRNA signature of Alzheimer disease patients.

BackgroundAlzheimer disease (AD) is the most common form of dementia but the identification of reliable, early and non-invasive biomarkers remains a major challenge. We present a novel miRNA-based signature for detecting AD from blood samples.ResultsWe apply next-generation sequencing to miRNAs from blood samples of 48 AD patients and 22 unaffected controls, yielding a total of 140 unique mature miRNAs with significantly changed expression levels. Of these, 82 have higher and 58 have lower abundance in AD patient samples. We selected a panel of 12 miRNAs for an RT-qPCR analysis on a larger cohort of 202 samples, comprising not only AD patients and healthy controls but also patients with other CNS illnesses. These included mild cognitive impairment, which is assumed to represent a transitional period before the development of AD, as well as multiple sclerosis, Parkinson disease, major depression, bipolar disorder and schizophrenia. miRNA target enrichment analysis of the selected 12 miRNAs indicates an involvement of miRNAs in nervous system development, neuron projection, neuron projection development and neuron projection morphogenesis. Using this 12-miRNA signature, we differentiate between AD and controls with an accuracy of 93%, a specificity of 95% and a sensitivity of 92%. The differentiation of AD from other neurological diseases is possible with accuracies between 74% and 78%. The differentiation of the other CNS disorders from controls yields even higher accuracies.ConclusionsThe data indicate that deregulated miRNAs in blood might be used as biomarkers in the diagnosis of AD or other neurological diseases.

Neurologic manifestations of cerebral air embolism as a complication of central venous catheterization.

Objective, Patients, and Methods: A severe case of cerebral air embolism after unintentional central venous catheter disconnection was the impetus for a systematic literature review (1975‐1998) of the clinical features of 26 patients (including our patient) with cerebral air embolism resulting from central venous catheter complications. Results: The jugular vein had been punctured in eight patients and the subclavian vein, in 12 patients. Embolism occurred in four patients during insertion, in 14 patients during unintentional disconnection, and in eight patients after removal and other procedures. The total mortality rate was 23%. Two types of neurologic manifestations may be distinguished: group A (n = 14) presented with encephalopathic features leading to a high mortality rate (36%); and group B (n = 12) presented with focal cerebral lesions resulting in hemiparesis or hemianopia affecting mostly the right hemisphere, with a mortality rate as high as 8%. In 75% of patients, an early computed tomography indicated air bubbles, proving cerebral air embolism. Hyperbaric oxygen therapy was performed in only three patients (12%). A cardiac defect, such as a patent foramen ovale was considered the route of right to left shunting in 6 of 15 patients (40%). More often, a pulmonary shunt was assumed (9 of 15 patients; 60%). For the remainder, data were not available. Conclusion: When caring for critically ill patients needing central venous catheterization, nursing staff and physicians should be aware of this potentially lethal complication.

Creutzfeldt–Jakob disease via dural and corneal transplants

A review of all published cases of iatrogenic Creutzfeldt-Jakob disease (CJD) via dural (N=71) and corneal (N=4) transplants is given. All but three of the dural cases were obviously due to a commercial product recalled in 1996. Two of the corneal grafts were taken from patients who had died of sporadic CJD. These cases differed from CJD due to human growth hormone injections and the new variant. Instead. they were akin to sporadic cases, but memory loss, disorders of higher cerebral functions and extrapyramidal signs were fewer, while cerebellar abnormalities were more frequent. Progressive dysarthria and gait disorder/gait ataxia were prominent signs during the early stages, myocloni the most salient feature later. A nonperiodic EEG did not contradict the diagnosis. Using current diagnostic criteria the disease was underdiagnosed ante mortem. Utmost care is needed in selecting, harvesting and handling dural and corneal grafts to avoid inadvertent transmission of CJD.

Herniated cervical intervertebral discs with radiculopathy : An outcome study of conservatively or surgically treated patients

To study the functional outcomes of patients with cervical herniated intervertebral discs with radiculopathy but without signs of cervical myelopathy using a retrospective cohort study design. The patients were retrospectively identified by chart reviews. Inclusion criteria were (a) cervical radiculopathy with defined neurological disturbances (sensory disorder, reflex abnormalities, and motor weakness); (b) a spinal computed tomograph scan or magnetic resonance image demonstrating neuroradiologic abnormalities (soft or hard disc); and (c) completion of conservative physical and pharmacological treatment. Of 119 consecutive patients who were treated at the Departments of Neurology and Neurosurgery, University of Erlangen-Nuremberg, between January 1, 1985, and December 31, 1995, 60 patients met the inclusion criteria and were prospectively assessed, with an average follow-up time of 5.5 years. The patients were interviewed with regard to their daily activities, ability to work, and the surgical treatment they had undergone. A complete neurological examination also was performed. In 88.3%, the onset of disease was acute and in 11.7% subacute or chronic. The most common signs and symptoms were brachialgia (98.3%), neck pain (93.3%), sensory disorders (88.3%), reflex abnormalities (61.7%), and motor weakness (51.7%). The neuroimaging procedures demonstrated a disc prolapse (soft disc) in approximately 90% and spondylotic osteophytes (hard disc) in approximately 10%. During an average follow-up time of 5.5 years (range, 4.6 months-10.6 years) 39 (65%) patients had been treated using only conservative methods (COG = conservatively treated group), and 21 (35%) patients had undergone surgery (ventral discectomy) (SUG = surgically treated group). Brachialgia was completely or essentially improved in 100% of the COG and 95.1% of the SUG. Sensory disorders remitted completely or markedly in 97% of the COG and 75% of the SUG. The reflex abnormalities normalized or improved in 59.2% of the COG and in 53.3% of the SUG. Motor weakness improved in 94.1% of the COG and in 50% of the SUG. Neck pain was difficult to treat. It improved in only 36.1% of the COG and in 20% of the SUG. Occupational capacity was lost in 10% of the COG and in 38.9% of the SUG. In a self-rating scale, 89.7% of patients in the COG did not feel disabled in their everyday activities, compared with 66.7% of the patients in the SUG. Patients with a herniated cervical intervertebral disc with radiculopathy can be treated conservatively with good results, although a residual intermittent neck pain syndrome often persists. The patients in the SUG, who initially showed more severe and long-lasting neurological disturbances, were improved at the time of examination, although with more marked residual disorders. Surgery is indicated only when appropriate conservative treatment for a reasonable time has failed.

Taste disorders in acute stroke : A prospective observational study on taste disorders in 102 stroke patients

Background and Purpose— The aim of the study was to assess whether and how frequently patients with acute first-ever stroke exhibit gustatory dysfunction. Methods— We performed a 1-year prospective observational study. Gustatory function was assessed using the standardized “taste strips” test. In addition, we assessed olfactory function, swallowing, stroke location, comorbidities, and the patients’ medication. Results— A total of 102 consecutive patients were enrolled (45 female, 57 male; mean age, 63 years); 31 of them (30%) exhibited gustatory loss and 7 (6%) had lateralized impairment of taste function. Predictors of impaired taste function were male gender (P=0.003), high National Institutes of Health Stroke Scale (NIHSS) score at admission (P=0.009), coexisting swallowing dysfunction (P=0.026), and a stroke of partial anterior circulation subtype (PACS) (P=0.008). In particular, in hypogeusic patients the lesion was most frequently localized in the frontal lobe (P=0.009). Follow-up examinations in 14 patients indicated improvement of taste sensitivity. Conclusion— Taste disorders after stroke are frequent. A significant association was found for male gender, high NIHSS score, swallowing disorder, and PACS, particularly in the frontal lobe. Generally, taste disorders after stroke seem to have a good prognosis.

Evaluation of the Unified Wilson's Disease Rating Scale (UWDRS) in German patients with treated Wilson's disease

Wilsons disease (WD) is an inherited autosomal‐recessive disorder of copper metabolism characterized by a wide variety of neurological, hepatic, and psychiatric symptoms. The aim of the present study was the development and evaluation of a clinical rating scale, termed Unified Wilsons Disease Rating Scale (UWDRS), to assess the whole spectrum of clinical symptoms in WD. Altogether 107 patients (mean age 37.6 ± 11.9 years; 46 male, 61 female) with treated WD participated in the study. Cronbachs alpha as a measure of the internal consistency for the entire scale was 0.92, whereas the intraclass correlation coefficient (ICC) was 0.98 (confidence interval (CI95%) 0.97–0.99), indicating an excellent interrater reliability as determined in 32 patients. Besides the total score was significantly correlated with the earning capacity of the patients as indicated by an estimated Spearmans ρ ≈ 0.54 (CI95% 0.40–0.69, P < 0.001). In summary, the UWDRS appears to be a promising tool to assess the disease severity in WD. Its usefulness in clinical research and drug trials should be further addressed.

Frequency Analysis Unveils Cardiac Autonomic Dysfunction after Mild Traumatic Brain Injury

Long-term mortality is increased after mild traumatic brain injury (mTBI). Central cardiovascular-autonomic dysregulation resulting from subtle, trauma-induced brain lesions might contribute to cardiovascular events and fatalities. We investigated whether there is cardiovascular-autonomic dysregulation after mTBI. In 20 mTBI patients (37±13 years, 5-43 months post-injury) and 20 healthy persons (26±9 years), we monitored respiration, RR intervals (RRI), blood pressures (BP), while supine and upon standing. We calculated the root mean square successive RRI differences (RMSSD) reflecting cardiovagal modulation, the ratio of maximal and minimal RRIs around the 30th and 15th RRI upon standing (30:15 ratio) reflecting baroreflex sensitivity (BRS), spectral powers of parasympathetic high-frequency (HF: 0.15-0.5 Hz) RRI oscillations, of mainly sympathetic low-frequency (LF: 0.04-0.15 Hz) RRI oscillations, of sympathetic LF-BP oscillations, RRI-LF/HF-ratios reflecting sympathovagal balance, and the gain between BP and RRI oscillations as additional BRS index (BRS(gain)). We compared supine and standing parameters of patients and controls (repeated measures analysis of variance; significance: p<0.05). While supine, patients had lower RRIs (874.2±157.8 vs. 1024.3±165.4 ms), RMSSDs (30.1±23.6 vs. 56.3±31.4 ms), RRI-HF powers (298.1±309.8 vs. 1507.2±1591.4 ms(2)), and BRS(gain) (8.1±4.4 vs. 12.5±8.1 ms·mmHg(-1)), but higher RRI-LF/HF-ratios (3.0±1.9 vs. 1.2±0.7) than controls. Upon standing, RMSSDs and RRI-HF-powers decreased significantly in controls, but not in patients; patients had lower RRI-30:15-ratios (1.3±0.3 vs. 1.6±0.3) and RRI-LF-powers (2450.0±2110.3 vs. 4805.9±3453.5 ms(2)) than controls. While supine, mTBI patients had reduced cardiovagal modulation and BRS. Upon standing, their BRS was still reduced, and patients did not withdraw parasympathetic or augment sympathetic modulation adequately. Impaired autonomic modulation probably contributes to cardiovascular irregularities post-mTBI.

Neuropsychological findings in treated Wilson's disease.

Seventeen patients, treated for Wilsons disease (WD), underwent a set of neuropsychological tests and were compared with a closely matched control group. There were clear differences between the groups (χ2‐test, p < 0.0001). Wilson patients with only hepatic involvement, however, did not at all differ from their controls. Wilson patients with neuropsychiatric signs differed from controls on a reasoning test (p = 0.0016), and the entire WD group differed on a perceptual speed task (p = 0.0025). Compared to normal test values, however, the patients’group means were all within plus or minus one standard deviation from the normal mean. Special testing procedures and construction of the test battery excluded a factor of motor deficits as a major cause for the differences. The neuropsychological findings are viewed in relation to other findings in patients with motor disorders and predominantly subcortical lesion sites. Wilsons disease may be a dementing condition, but not when treated adequately.

Influence of repetitive magnetic stimuli on verbal comprehension.

The influence of repetitive magnetic transcranial stimulation over the temporo-parietal cortex on verbal comprehension was investigated in 44 healthy subjects. In right-handed subjects, trains of 50 Hz magnetic stimuli over the left hemisphere produced more errors than stimulation over the right hemisphere. The result is not very clearcut, however; thus the test cannot be used for diagnostic investigation of language dominance.

Rise in German Wholesale Electricity Prices: Fundamental Factors, Exercise of Market Power, or Both?

It is the objective of this paper to quantify the significance of fundamental factors (like rising fuel costs) and of the increasing exercise of market power on rising prices in the German wholesale electricity market. A successive MIP/LP approach was used for this. The calculations show that, if the whole period from 2000 to 2005 is considered, fundamental factors explain most of the price movement. The increasing exercise of market power is less important for rising wholesale market electricity prices. Further analysis clarifies that the price-cost margin widened substantially already in 2003. In this year, the price-cost-margin was most extensive with almost 30%. The increasing exercise of market power was the single cause for the rising price in 2003. The price-cost-margin eroded in the following two years to 14 and 16% respectively. That means that only fundamental factors were responsible for the sharp price rise in 2005. Over the whole year, the price-cost-margin in 2005 was more or less the same as in 2004. But in contrast to 2004, the monthly values were very unstable. There are months when the price-cost-margin is more or less zero or even negative and there are months when the price-cost-margin is very large. As discussed in detail, one possible reason for this surprising result might be that the German power producers were in a strategic dilemma in 2005 because of the discussion that 2005 would probably be the new base year for the CO2 allowance allocation of trading period 2. The quite stable level of mark-ups for 18 hours in 2004 and, at least if fly-ups are not considered, the quite stable level of mark-ups in 2003 for 18 hours and in 2005 for 14 hours is surprising and conflicts with the typical expectation that mark-ups are larger if the demand is higher and the market tighter. As clarified, one possible explanation might be that for political reasons suppliers do not exercise all market power they possess but decide to have more or less stable margins on their bids during the hours when they possess market power.