[Irreversible brain death-Part 2. Spinalization phenomena]. / Irreversibler Hirnfunktionsausfall ­ Teil 2. Spinalisationsphänomene.

Spinal automatisms and reflexes, peripheral neurogenic and myogenic reactions are common in patients with irreversible brain death. They are therefore compatible and are even understood by experienced investigators as confirmation of irreversible brain death. This article provides an overview of the phenomenology of irreversible brain death and discusses it from a neuropathological perspective. Furthermore, irreversible brain death is described in order to distinguish it from pathological movements and motor reactions in comatose patients or patients with disturbed consciousness due to severe brain disorders.

[Irreversible loss of brain function-Part 1: pitfalls in clinical diagnosis]. / Irreversibler Hirnfunktionsausfall ­ Teil 1: Fallstricke der klinischen Diagnostik.

A significant change in the fourth update of the German guidelines on determining brain death is that it includes an explicit profile of requirements on physicians involved in ILBF diagnosis. These requisite qualification criteria have also been formulated due to the fact that, in many hospitals, ILBF diagnosis is only rarely carried out and, as a result, uncertainty frequently arises. Typical difficulties emerge at all stages of ILBF diagnosis, and numerous relevant pitfalls arise that need to be taken into consideration and which might also be relevant in the selection of the method(s) to detect irreversibility. The approaches presented here are suited to achieving a valid result in the evaluation of equivocal ILBF.

[Off-label therapy: current problems from the perspective of the Pharmaceutical Commission of the German Medical Profession]. / Off-Label-Therapie: aktuelle Probleme aus Sicht der Arzneimittelkommission der deutschen Ärzteschaft.

The off-label use of approved pharmaceuticals outside the authorized status is implemented in pharmacotherapy of many diseases, especially for rare diseases and in cases of therapy resistance. The German regulations are presented and analyzed and the relative literature is discussed.

[Long-term treatment of refractory myasthenia gravis with immunoadsorption]. / Langzeitbehandlung der therapierefraktären Myasthenia gravis mittels Immunadsorption.

BACKGROUND AND OBJECTIVE: Myasthenia gravis in the majority of patients is a well treatable neurological autoimmune disorder with a prevalence of 60-150 per million. For the treatment of myasthenic crisis in the intensive care unit the use of therapeutic apheresis, e. g. immunoadsorption or plasma exchange, is well established due to its rapid therapeutic effect, whereas the necessity in long term treatment is still questioned. Aim of this retrospective cohort-study was the assessment of patients with refractory myasthenia gravis in Germany treated by regular immunoadsorption, the characterization of previous therapies and the efficacy of long-term treatment. PATIENT AND METHODS: In total 14 patients (9 women, 5 men, mean age: 40.5 years) were identified in Germany using regular therapeutic apheresis. 13 were treated with different modes of immunoadsorption (10 yen l-tryptophan-adsorption, 2 yen epitope-specific adsorption, 1 yen polyclonal sheep antibody on sepharose) and 1 with plasma exchange. Mean duration of standard treatment of myasthenia gravis before initiation of regular apheresis was 7.8 years. RESULTS: Average duration of analyzed apheresis treatment was 6.4 years, with a mean treatment-interval of 1.1 per week. Mean reduction rate of autoantibodies against acetylcholine-receptor-protein was 50-60 % per session. After initiation of immunoadsorption the mean time of hospitalisation decreased significantly by app. 60 %. In particular the number of myasthenic crises could be reduced by 89 % per year. Tolerability of immunoadsorption was very good, no severe adverse events occurred. CONCLUSION: In conclusion, for the treatment of the subgroup of myasthenia gravis patients becoming refractory to standard treatment immunoadsorption should be regarded as integral part of the therapeutic armamentarium to stabilize and optimize the state of neurologic rehabilitation. This evaluation should be also carefully considered by carriers of health care cost as currently best available evidence to decide on appropriate treatment regimens for these rare patients.

Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Predictors of in-hospital mortality and attributable risks of death after ischemic stroke: the German Stroke Registers Study Group.

BACKGROUND: There is a lack of information about factors associated with in-hospital death and the impact of neurological complications on early outcome for patients with stroke treated in community settings. We investigated predictors for in-hospital mortality and attributable risks of death after ischemic stroke in a pooled analysis of large German stroke registers. METHODS: Stroke patients admitted to hospitals cooperating within the German Stroke Registers Study Group (ADSR) between January 1, 2000, and December 31, 2000, were analyzed. The ADSR is a network of regional stroke registers, combining data from 104 academic and community hospitals throughout Germany. The impact of patients' demographic and clinical characteristics, their comorbid conditions, and the treating hospital expertise in stroke care on in-hospital mortality was analyzed using Cox regression analysis. Attributable risks of death for medical and neurological complications were calculated. RESULTS: A total of 13 440 ischemic stroke patients were included. Overall in-hospital mortality was 4.9%. In women, higher age (P<.001), severity of stroke defined by number of neurological deficits (P<.001), and atrial fibrillation (hazard ratio [HR], 1.3; 95% confidence interval [CI], 1.0-1.6) were independent predictors for in-hospital death. In men, diabetes (HR, 1.3; 95% CI, 1.0-1.8) and previous stroke (HR 1.4; 95% CI, 1.0-1.9) had a significant negative impact on early outcome in addition to the factors identified for women. The complication with the highest attributable risk proportion was increased intracranial pressure, accounting for 94% (95% CI, 93.9%-94.1%) of deaths among patients with this complication. Pneumonia was the complication with the highest attributable proportion of death in the entire stroke population, accounting for 31.2% (95% CI, 30.9%-31.5%) of all deaths. More than 50% of all in-hospital deaths were caused by serious medical or neurological complications (54.4%; 95% CI, 54.3%-54.5%). CONCLUSIONS: Substantial differences were found in the impact of comorbid conditions on early outcome for men and women. Programs aiming at an improvement in short-term outcome after stroke should focus especially on a reduction of pneumonia and an early treatment of increased intracranial pressure.

Mini-infarct encephalopathy associated with uncommon microvessel convolute formation presenting with presenile dementia.

A female patient started to suffer from transient ischemic attacks when she was 47 years of age, followed by increasing predominantly left-side spastic tetraparesis, generalized seizures and progressive dementia over a period of 11 years. She died when she was 58 years of age. On gross examination the brain showed enlarged ventricles and arteriosclerotic changes of large extracerebral vessels of the circulus arteriosus. Microscopic examination of the atrophic brain showed innumerable incomplete microinfarcts in the white and gray matter throughout all parts of the brain. In the white matter these lesions were characterized by small foci of demyelination and loss of oligodendrocytes while occasionally some scavenger cells were seen. Axons seemed to be unaffected or displayed irregular axonal regeneratory growth. Any inflammatory reaction failed. In the cerebral cortex and subcortical nuclei the lesions showed loss of neurons and decrease in synaptophysin expression. Intracerebral arteries showed fibrosis or fibrohyalinosis of the entire intracerebral small-vessel network. In addition, numerous uncommon clusters of angioma-like telangiectatic vessels were observed. Medium-sized ischemic infarcts were found in the right putamen and adjacent internal capsule region, left-side dorsolateral brain stem and cerebellar hemisphere as well as a left-side pyramidal tract degeneration. Contralateral pseudohypertrophy of the inferior olivary nucleus was seen. The clinical and the neuropathologic observations made in this patient are compatible with small vessel disease characterized by a multicentric special and not yet described type of incomplete mini-infarcts in cerebral cortex and white matter accompanied by some larger ischemic infarcts of the common type in brain stem and cerebellum.

Harm reduction theories and strategies for control of human immunodeficiency virus: a review of the literature.

AIM: To provide a comprehensive review of the literature on harm reduction theories and strategies related primarily to licit and illicit drug use. BACKGROUND: Although human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) disease transmission is well understood, it continues to spread, particularly among injection drug users (IDUs). Despite early indications that HIV would be contained within the IDU community, it is spreading to non-IDU sexual partners and to children of IDUs, threatening a more widespread epidemic. METHODS: An examination of research studies and theoretical writings including reviews and policy papers published in English between 1990 and 2000. RESULTS: Harm reduction does not seek to eliminate drug use; it focuses on minimizing the personal and social harms and costs associated with drug use and spread of HIV. It seeks to ameliorate conditions surrounding drug use responsible for the spread of HIV in the IDU community: unequal access to health services; sharing of infected needles; racial and social discrimination; poverty; exposure to street violence; inadequate housing; lack of employment; poor general or mental health and other demographic and social determinants. Some controversial harm reduction strategies are described: methadone maintenance programmes, illegal drugs dispensing under controlled conditions, needle exchanges, HIV testing, vein maintenance, safe-sex and would-care programmes. CONCLUSION: The main challenge is to get IDUs to protect themselves against HIV when suffering physical and social privations and addiction needs. Diverse perspectives on harm reduction are problematic with consequences for success of drug use initiatives. Practical, ethical and theoretical complexities exist but further research is needed to build support for a harm-reduction orientation in practice and policy formulation.

[Carotid stenting--stratification of the acute phase, indications in secondary prevention from the neurological viewpoint]]. / Carotisstenting--Stratifizierung in der Akutphase, Indikation in der Sekundärprävention aus neurologischer Sicht.

The progress in the technical procedures of stenting in the ICA and the growing expertise in this field need primary multidisciplinary efforts for improving both, indication and periinvasive management of stroke patients. From a neurological point of view in the acute stroke there is an indication on the single case basis, only, e.g. in crescendo-TIA and given TEA-indication but without operability given in the patient. Later on, the stenting should be taken into account only after complex neurovascular workup, incl. CMRT with DWI and PWI, interdisciplinary definitive indication and qualified periinvasive management, i.e., apparative monitoring and neurological examination, e.g., on a stroke unit. Some indications emerge from the present expertise: re-stenosis after TEA, radiogenic stenosis, given indication for TEA, but no operability for technical reasons, e.g. distal ICA-stenosis, or class III or IV risk patients. The contraindications remain to be clarified.

Acute pseudohepatitis in a chronic substance abuser secondary to occult seat belt injury.

Causes of a massive elevation in serum aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) in the substance-abusing patient include viral hepatitis and drug hepatotoxicity. A patient chronically addicted to injection heroin and cocaine presented to the emergency room in a confused state and was admitted to a medical ward with an AST of 4120 U/L, ALT 3820 U/L and right upper quadrant discomfort. Investigations for viral and hepatotoxic causes for the liver dysfunction revealed only hepatitis C seropositivity. A computed tomogram of the abdomen, however, revealed a significant contusion to the right lobe of the liver consistent with traumatic injury. A motor vehicle accident, in which the patient was wearing a seat belt, and which had occurred a few days before admission and had been thought to be minor, was the cause of the liver dysfunction. Significant blunt abdominal traumatic injuries are usually managed exclusively by surgical trauma units. This case underlines the need for medical specialists to be aware of hepatic contusion injuries and to have a high index of suspicion when investigating unexplained hepatocellular dysfunction in chronic substance abusers who have been in motor vehicle accidents.

Hashimoto's encephalitis as a differential diagnosis of Creutzfeldt-Jakob disease.

OBJECTIVES: During an epidemiological study of Creutzfeldt-Jakob disease in Germany, Hashimoto's encephalitis was encountered as a differential diagnosis, which has not yet been described in this context. METHODS: The symptoms and findings of seven patients who fulfilled the criteria for "possible" Creutzfeldt-Jakob disease are presented. RESULTS: A Hashimoto's thyroiditis with antibodies against thyroglobulin or thyroid peroxidase, or both and a hypoechoic thyroid ultrasonogram were found in all cases. Analysis of CSF disclosed an increased leucocyte count in three patients, and a raised CSF:serum concentration ratio of albumin (QA1b) in four patients. The 14-3-3 protein, typical of Creutzfeldt-Jakob disease, could not be detected in any of our patients. No periodic sharp wave complexes, which are typical of Creutzfeldt-Jakob disease, were detected on EEG in any of the cases. By contrast with Creutzfeldt-Jakob disease, which leads to death within a few months, the patients with Hashimoto's encephalitis often recover quickly when treated adequately. All the patients improved after administration of corticosteroids. CONCLUSION: The clinical symptomatology of both diseases may be very similar: dementia, myoclonus, ataxia, and personality change or psychotic phenomena are characteristic symptoms.

Endothelin-1 and thromboxane A2 increase pulmonary vascular resistance in granulocyte-mediated lung injury.

OBJECTIVE: To examine the pathophysiologic role of vasoactive eicosanoids and endothelin-1 in granulocyte-mediated effects in the pulmonary vasculature. DESIGN: Prospective experimental study in rabbits. SETTING: Experimental laboratory in a university teaching hospital. SUBJECTS: Thirty adult rabbits. INTERVENTIONS: The experiments were performed on 30 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution. MEASUREMENTS AND MAIN RESULTS: The pulmonary arterial pressure and the lung weight gain were continuously registered. Intermittently perfused samples were taken to determine endothelin-1 and thromboxane A2 concentrations. Six experiments without intervention served as the sham group. The granulocytes in the pulmonary circulation were stimulated with N-formyl-L-leucin-methionyl-L-phenylalanine (FMLP; 10(-6) M; control, n = 6). To investigate whether activated granulocytes influence the pulmonary vasculature via endothelin-1, the endothelin-A receptor antagonist LU135252 (10(-6) M) was added to the perfusate before FMLP injection (n = 6). The potential involvement of thromboxane A2 in granulocyte-endothelial interaction was investigated by pretreatment with the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6). Activation of granulocytes resulted in an acute increase in pulmonary arterial pressure (>9 mm Hg), which was followed by a second delayed pressure increase after 60 mins (>14 mm Hg) and was paralleled by a massive generation of thromboxane A2 (>250 pg/ mL). Fifteen minutes after FMLP-injection, endothelin-1 was detectable in the perfusate. Pretreatment with the selective endothelin-A antagonist LU135252 significantly (p< .01) reduced the initial pressure response after FMLP stimulation, while diclofenac significantly reduced (p < .05) the delayed pressure increase. Using diclofenac (10 microg/mL) in conjunction with LU135252 (10(-6) M; n = 6) before FMLP injection significantly reduced the early and the delayed pressure increase. CONCLUSIONS: Activated granulocytes seem to enhance pulmonary vascular resistance via endothelin-1 and thromboxane A2. The endothelin-1 effects are probably mediated via endothelin-A receptors since the endothelin-A receptor antagonist LU135252 was able to suppress the early pressure reaction after FMLP injection, whereas the cyclooxygenase inhibitor diclofenac was able to reduce the second pressure increase.

[The effect of endothelin on granulocyte-endothelium interaction]. / Bedeutung von Endothelin bei der Granulozyten-Endothel-Interaktion.

PURPOSE: The interaction of activated granulocytes and endothelial cells influences not only capillary permeability but also increases pulmonary vascular resistance. The aim of this study was to evaluate the role of endothelin-1 (ET-1) during the granulocyte-mediated increase in pulmonary pressure. METHODS: The experiments were performed on isolated and ventilated rabbit lungs perfused with a blood-free buffer solution. Isolated, washed human granulocytes were injected into the pulmonary artery and stimulated by 10(-6) M N-formyl-L-leucin-methionyl-L-phenylalanine (FMLP). Pulmonary arterial pressure (PAP) was continuously registered, and perfusate samples were taken to determine ET-1 and eicosanoid levels. To analyse the role of ET-1, six lung preparations were pretreated with the ETA receptor antagonist BQ123 (10(-6) M) prior to FMLP injection. To analyse the role of thromboxane A2, six additional lung preparations were pretreated with the cyclooxygenase inhibitor diclofenac (10 micrograms/ml). Additionally, granulocytes were stimulated in vitro with FMLP for 15 min, and ET-1 concentration was measured in the supernatant. RESULTS: Immediately after FMLP injection, PAP increased to 18.5 +/- 1.6 mmHg, descending to values 4.8 +/- 0.8 mmHg above the baseline after 15 min. At this time, ET-1 could be detected in the perfusate. The concentrations of the cyclooxygenase products thromboxane A2 and prostacyclin remained nearly unchanged during the observation period. Pretreatment with the ETA receptor antagonist BQ123 significantly reduced the pressure response after FMLP injection (p < 0.01 at 5 and 10 min; p < 0.05 at 15 and 30 min). Pretreatment with the cycloocygenase inhibitor diclofenac failed to inhibit the pressure reaction evoked by activated granulocytes. In contrast to this, ET-1 was not detected after in vitro stimulation of granulocytes. CONCLUSION: ET-1 is involved as a mediator of pulmonary vasoconstriction due to granulocyte activation. Since in vitro FMLP-stimulation of human granulocytes did not induce ET-1 production, it seems likely that isolated activated granulocytes would not produce ET-1, but provoke the endothelial cells to release ET-1 in the pulmonary circulation.

Obscure gastrointestinal bleeding from an ampullary tumour in a patient with a remote history of renal cell carcinoma: a diagnostic conundrum.

Metastasis of renal cell carcinoma to the ampulla of Vater is a rare occurrence. The outlined case, which presented as an upper gastrointestinal bleed, is only the eighth such reported case in the English-language literature. This case is the longest reported time interval between surgical nephrectomy to presentation with ampullary metastasis at 17.5 years. The ampullary source of bleeding in this case was initially obscure and missed by conventional gastroscopy. Diagnosis was made with a side-viewing endoscope, emphasizing the usefulness of this instrument in the investigation of active bleeding from a small bowel source.

Site and extent of mineral absorption in lactating cows fed whole-crop cereal grain silage of alfalfa silage.

The site of apparent absorption of Na, K, Ca, P, Mg, and S in lactating dairy cows fed whole-crop barley, oats, triticale, or alfalfa silages was studied. Eight ruminally and duodenally cannulated Holstein cows with ad libitum access to a total mixed diet were assigned to one of four treatments as a replicated 4 x 4 Latin square design. All diets contained the same concentrate (50%, DM basis) plus one experimental silage. The concentrations of Na, K, Ca, P, Mg, and S in the concentrate were .84, .71, .85, .78, .27, and 38%, respectively. Dry matter intake was higher (P < .05) for cows fed alfalfa and barely silages than for cows fed oats and triticale silages (19.6, 18.6, 16.7, and 17.2 kg/d, respectively). Alfalfa silage contained a higher concentration of all minerals studied than the cereal silages, except Na. Sodium flow at the duodenum was substantially greater than dietary intake and apparent total tract digestibilities ranged between 74.5 and 85.2%. Secretion of P in the forestomach ranged from 34 to 61 g/d and the major site of absorption was in the intestine. The correlation between P intake and fecal excretion of P was significant (P < .001, r/ = .39) and linear. Potassium absorption occurred before the duodenum and in the intestine. Apparent digestibilities of K were lower for cereal silages (range 74.0 to 82.9%) than for alfalfa silage (88,7%). Apparent total tract digestibilities of Ca (28 to 32%), P(27 to 34%), and MG (17 to 24%) were similar for all diets so that Ca, P, and Mg absorption (g/d) reflected dietary Ca, P, and Mg levels. Data indicate that forage source can influence the site and extent of absorption, fecal output, and apparent digestibilities of macrominerals.

[Long-term treatment with 7S immunoglobulins in myasthenia gravis. Preliminary clinical results]. / Zur Langzeitbehandlung mit 7S-Immunglobulinen bei Myasthenia gravis. Vorläufige klinische Ergebnisse.

After initial high-dose intravenous 7S immunoglobulin therapy, six patients with seropositive myasthenia gravis received intermittent low-dose 7S immunoglobulins for at least 4-12 months. This treatment was started in five cases following an acute exacerbation of myasthenic symptoms (Oosterhuis class 3-4) and in one case because of marked clinical fluctuations (Oosterhuis class 3). In five of the six patients, there was a clinical response to the immunoglobulin therapy within 2 weeks, followed by marked long-standing improvement and stability of the clinical outcome. In four cases a decrease in the titer of acetylcholine receptor antibodies was noted in parallel. Our observations suggest an additional positive therapeutic effect of long-term, low-dose intravenous immunoglobulin therapy following the acute management of myasthenic exacerbations.