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In the actual version of the WHO diagnostic guidelines, the ICD-10, subtypes of bipolar disorder are not specified, in contrast to the American DSM-IV, where bipolar disorder has already been differentiated in bipolar I (severe manic and depressive episodes) and bipolar II disorder (depressive and hypomanic episodes). Furthermore, aspects of the longitudinal course of the illness, like rapid cycling (RC), are reflected as well. Rapid cycling is defined as four or more affective episodes within one year of the illness. It has been postulated that rapid cycling is related with a poor response to lithium, to the same extent as mixed episodes or an atypical onset (depressive episode first) of the disease. Here, the current status of alternative pharmacological and supportive therapy of rapid cycling is presented and discussed. Furthermore, the article also displays biological parameters associated with rapid cycling like higher prevalence in women, hypothyreoidism, subtype of bipolar disorder, COMT-allele, influence of sleep or risk of antidepressant induced cycling.

Unlabelled: Myelinolysis may occur as a severe complication of eating disorders, especially anorexia nervosa (AN). One of the most important reasons can be a rapid correction of hyponatremia caused by tubulopathy, water intoxication (WI), or abuse of diuretics in individuals with AN. METHOD AND RESULTS We report on a 24-year-old female patient with an 8-year history of AN. A rapid correction of severe hyponatremia and hypokalemia induced by WI led to central pontine myelinolysis, which was confirmed by magnetic resonance imaging (MRI) examination. Besides affective lability, incoherence, and an acute confusional state, surprisingly, no severe neurological symptoms emerged., Conclusion: Thus, physicians should be aware of the risk of pontine myelinolysis with new psychiatric symptoms emerging in the absence of obvious neurological deficits., (Copyright 2001 by John Wiley & Sons, Inc.)

Background: A series of open studies suggests that topiramate has efficacy in bipolar disorder. To further investigate the potential value of topiramate as an antimanic agent, we conducted an open trial in 11 manic patients., Method: Eleven patients with bipolar I disorder with an acute manic episode (DSM-IV) were treated with a mood stabilizer and/or antipsychotics in sufficient and fixed doses. All had a Young Mania Rating Scale (YMRS) score of at least 24 (mean +/- SD = 33.5+/-8.1). Topiramate was added after stable plasma levels of concomitant mood stabilizers had been reached and was titrated within 1 week to a final dose in the range of 25 to 200 mg/day, depending on clinical efficacy and tolerability. Topiramate was discontinued after 10 days, while concomitant medication remained unchanged. After 5 days, topiramate was reintroduced at similar or increased dosages for another 7 days. Patients were assessed with the YMRS; the Clinical Global Impressions scale version for bipolar patients; and the 21-item Hamilton Rating Scale for Depression., Results: Seven of the 11 patients initially showed a good antimanic response with > 50% reduction in YMRS score. One patient showed psychotic features following rapid increase in topiramate dosage and dropped out on day 10. After discontinuation of topiramate, 7 of the remaining 10 patients worsened (increase of > or = 25% in YMRS score), 2 remained stable, and 1 discontinued follow-up after good recovery. After reintroducing topiramate, all patients improved again within a week, with 8 of 9 meeting the responder criterion of > or = 50% YMRS score reduction when comparing baseline values with those of day 22. With the exception of the patient who developed psychosis, topiramate was well tolerated. Concomitant medication did not interfere with plasma levels of drug, except for carbamazepine level in 1 patient., Conclusion: The antimanic response among patients in this study appears reproducibly linked to the addition of topiramate.

Pharmacotherapeutic intervention in psychiatric patients often bears the risk of drug abuse for suicide attempts. Especially intoxication with tricyclic antidepressants, e.g., amitriptyline, may cause severe complications such as cardiac arrhythmia. Even under intensive care conditions, 2-3% of intoxicated patients still die. Here, we report on a depressed female patient who, thanks to timely and intense intervention, survived a suicide attempt with amitriptyline despite highly toxic plasma levels.

Unlabelled: Valproate has recently emerged as a drug of first choice in treating acute mania because of its efficacy and relative safety. It can be administered as an intravenous, oral non-sustained release or oral sustained release loading therapy. A new sustained release formulation of valproate consists of "mini-tablets" with the possible advantage of a less problematic and more reliable administration of the drug. We report on eleven patients with an acute manic exacerbation who were investigated for sufficient control of manic symptoms and the duration of building up and maintaining sufficient blood levels of valproate in once/d versus twice/d administration of valproate delayed release mini-tablets (VPA mrt.). Acute and prophylactic effectiveness in mania were rated with the Young-Mania Rating Scale (YMRS), respectively the Global Clinical Impression Scale for Bipolar Disorder (CGI-BP)., Results: Within a short period of time sufficient blood levels in both groups (once/d versus twice/d administration) were built up. Seven of eleven patients were responders according to a reduction of 50% of the YMRS. In respect of prophylactic treatment all of the ten patients showed satisfactory results and no re-exacerbation of manic symptoms or depression.

Background: Diabetic foot syndrome (DFS) is a frequent complication of long-standing diabetes mellitus, occurring in 10 to 30 percent of all diabetics with a vital risk for the affected limb and high mortality rates. Macroangiopathy, diabetic polyneuropathy and infections are trigger factors for DFS. Recent results imply a pathogenic role of functional and structural microcirculatory changes. The exact role of microangiopathy and the value of microcirculatory diagnostic methods in DFS have not yet been defined., Patients and Methods: 78 patients with DFS (28 type I, 50 type II diabetics, mean age 63 years) were evaluated with video capillary microscopy, transcutaneous partial oxygen tension (tcpO2) measurement and laser Doppler fluxmetry (LDF) at the forefoot of the affected leg at admission and after revascularisation. Mean hospital stay was 28 +/- 11.7 days. Patients were stratified according to the etiology of DFS in patients with neuropathic lesions, macroangiopathic ulcers and mixed neuropathic-angiopathic lesions., Results: All groups had impaired microcirculation, and significant differences between groups were found in respect to capillary density. Reactive hyperemia, LDF pattern and tcpO2 did not differ significantly. Microcirculatory examinations did not yield additional information to clinical and Doppler sonographic results., Conclusion: In clinical practice, the role of microcirculation evaluation techniques for diabetic foot syndrome is limited.

Neurodegenerative disorders often exhibit "classical" psychiatric symptoms as an initial presentation of the disease. Here we present four patients with different psychopathological abnormalities who were later diagnosed as having Huntington's disease. The range of symptoms covered affective and psychotic symptoms, antisocial behavior, cognitive problems reminiscent of dementia and suicidal idealisation. The pattern of progress of neuronal degeneration may be helpful in explaining the antecedent manifestation of psychiatric symptoms.

Background: Because a GABAergic hypofunction has been implied in the pathophysiology of mania, we have tested the antimanic properties of the GABA transporter 1 inhibitor tiagabine., Method: An open trial was conducted in 8 acutely manic inpatients with DSM-IV bipolar I disorder, 2 of them with tiagabine monotherapy and 6 with tiagabine as an add-on to previously insufficient mood-stabilizing medication. The study duration was 14 days. Changes in psychopathology were assessed by the Bech-Rafaelsen Mania Rating Scale., Results: None of the patients showed clear-cut relief from manic symptoms during the 2-week observation period. In 2 patients, we saw pronounced side effects (nausea and vomiting in one and a generalized tonic-clonic seizure in the other)., Conclusion: The results from this open trial suggest that tiagabine seems to have no pronounced antimanic efficacy compared with standard treatments such as valproate, lithium, or neuroleptics. It also appears that rapid dosage increases for antimanic treatment can cause potentially severe side effects.

Recently, valproate has emerged as a drug of primary choice for the treatment of acute mania, especially mixed mania and, partially, rapid cycling. Because of its relative safety, it can be administered in high doses as an oral loading therapy, with approximately 60% to 70% of patients showing a favorable response. Here we report on seven bipolar I patients, two of which have euphoric mania, three have a mixed manic state (including one patient with ultra-rapid cycling and one with very prominent depressed features), and two have solely depressed mood. All but one of the manic patients showed a rapid and favorable response to intravenous valproate loading, which built up sufficient blood levels that were maintained by subsequent oral treatment. Of the two patients with solely depressed mood, however, one experienced only minor benefits and the other showed no change in the depressive symptomatology. Intravenous valproate was tolerated without problems and also led to a drastic reduction in and eventual withdrawal of benzodiazepine treatment in two cases. All of the patients showed a drastic remission of mania with valproate blood levels at or only slightly above 50 microg/mL (blood drawn 12 hours after last application). It is interesting to note that one patient who was previously nonresponsive to oral valproate loading responded well to intravenous valproate. Besides the obvious efficacy and safety of this treatment regimen, these findings may also imply that a difference in pharmacokinetics with intravenous loading may result in a quick saturation of plasma-binding proteins, and hence, peak concentrations of valproate may be reached rapidly, which could contribute to the beneficial action, even in patients previously nonresponsive to oral valproate.

Despite newly developed pharmacological possibilities, treatment of acute mania may still be a problem in single patients. Independent of the first choice of medication, i.e. neuroleptics, lithium, carbamazepine or valproate, the average response rate is only approximately 50-70%. Therefore, treating mania often implies a number of monotherapeutic and polypharmaceutic attempts for several months, until a sufficient mood stabilization has been reached. The aim of this case report is to remind that electroconvulsive therapy (ECT) is still in use for treating mania, which has been widely neglected in Germany despite its high success rate, mainly reported from Anglo-Saxon countries. As demonstrated in this report, ECT may be a useful tool for a fast antimanic response in patients which may be either refractory to standard treatment or are medically severely ill, and should, in our opinion, therefore be considered already at an earlier stage of treatment in this group. However, persistence of improvement can usually only be achieved with the overlapping start of drug treatment unless the option of maintenance ECT is given.

We present the case of a 60-year old bipolar-I-patient showing a rapid antimanic response to gabapentin after having been non-responsive to lithium and perazine. This case encouraged us to further evaluate the antimanic potency of gabapentin in an open label trial. 20 patients with acute mania were treated for up to 21 days with gabapentin in a dose range from 1200 to 4800 mg/day. Ten patients were treated with gabapentin as add-on medication and ten patients were treated with a high dose of gabapentin alone. The BRMAS score declined significantly in patients with moderate mania, whereas gabapentin alone was not efficacious in patients with very severe mania. Keeping in mind the limitations of an open study, it can still be said that gabapentin as add-on medication with other effective mood stabilizers appears to be safe and efficacious in the treatment of moderate mania.

Akathisia is characterized by subjective discomfort and motor restlessness. The motor hyperactivity can express itself by frequent changes of posture, constant limb shaking or restless pacing. If symptoms of akathisia are severe, treatment becomes extremely complicated and patients may even become suicidal as seen in the case described here. In the literature, different forms of akathisia are distinguished (Barnes and Braude, 1985): the acute form of neuroleptic-induced akathisia (recent onset, related to an increase in antipsychotic drug dose), pseudoakathisia (motor signs but no subjective symptoms), and chronic or tardive akathisia. The acute form of akathisia is well known and described (Zubenko et al., 1984a,b). In a retrospective analysis of clinical features and therapeutic trials for tardive akathisia, Burke et al. (1989) showed that almost all of the 52 cases developed this chronic form after an average of 4.5 yr following neuroleptic drug initiation, 34% even within 1 yr. Twenty-six of the patients who were able to stop taking dopamine antagonists still had symptoms of akathisia persisting for 0.3-7 yr (mean = 2.7 yr).

Although much progress has been made in successfully treating bipolar disorder, there is increasing awareness of the limitations of traditional treatment regimens such as lithium and neuroleptics. The large family of anticonvulsant drugs, however, appears to be capable of providing new treatment options, not only as medication of second choice in patients refractory to treatment, but often as a treatment standard with high efficacy and low incidence of side effects. Besides established mood stabilizers such as carbamazepine and valproate, new antiepileptic drugs are entering the field with promising initial results in the treatment of bipolar patients. Furthermore, bringing to light the mechanisms of action of anticonvulsants and the similarities between anticonvulsants effective in bipolar disorder may also deepen our understanding of the pathophysiological basis of the disorder.

Background: Several studies proved the co-existence of peripheral arterial occlusive disease (PAOD) and hypercoagulability. However, in practice coagulation parameters are mainly determined from venous blood samples. In this study several coagulation parameters in arterial and venous blood were examined for differences and the validity of coagulation parameters determined in venous blood was investigated., Patients and Methods: In 22 patients with peripheral artery disease venous and arterial blood samples from vessels of the diseased leg were examined for the concentration of thrombine-antithrombine III-complex (TAT), prothrombin fragments (F1 and F2) and D-dimers, and results were compared., Results: Mean concentrations of TATs and prothrombin fragments F1 and F2 were significantly higher in arterial than in venous blood. TAT-complex was the most sensitive parameter for quantification of thrombin generation. D-dimer levels did not differ in arterial and venous blood. TAT and F1 and F2 concentrations in arterial and venous blood did not correlate in individual patients whereas D-dimer concentration did., Conclusion: The determination of TAT and F1 + F2 in venous blood does not adequately reflect the degree of the local coagulation activation in the arterial system. As indicators for hypercoagulability, D-Dimer values are less sensitive than F1 + 2, but venous D-dimer concentrations mirror arterial levels.

A 60-year old female patient was referred to our University hospital with the diagnosis of severe treatment-resistant major depression to perform electroconvulsive therapy (ECT). For almost two years the patient had been treated with several antidepressants and, temporarily, neuroleptics. After showing no favourable response to ECT, the diagnosis of idiopathic Parkinson's disease was made and the patient was treated with L-dopa plus benserazide and pergolide in combination with the monoamine oxidase inhibitor moclobemide. Both depressed mood and motor symptoms showed dramatic improvement under this therapy.

The new anticonvulsant, lamotrigine, is becoming an important tool in the treatment of bipolar disorder, including bipolar depression. Its efficacy in bipolar depression might be linked to its inhibition of serotonin uptake. We present the case of a female schizoaffective patient successfully treated with 400 mg of lamotrigine developing considerable genital disorder, a side effect well known from the treatment with selective serotonin reuptake inhibitors (SSRIs). We suggest that female genital disorder induced by high doses of lamotrigine is a serotoninergic side effect.

Objective: To determine if the chemokine monocyte chemo-attractant protein-1 (MCP-1) is produced locally in patients with bladder cancer and to analyse a possible correlation between tumour stage, grade and metastatic spread, and the urinary and systemic levels of MCP-1. PATIENTS SUBJECTS AND METHODS: Urine and serum samples were obtained from 60 patients with bladder cancer and 20 control subjects. Tumour stage, grade, metastasis and nodal status were assessed. MCP-1 levels in serum and urine were determined using a sandwich enzyme-linked immunosorbent assay. Two transitional cell cancer cell lines (grade I and grade III) were analysed for MCP-1 production under normal and nutritive-stress cell culture., Results: The correlation of urinary MCP-1 levels with tumour stage, grade and distant metastasis was highly significant. Patients with stage T2-T4 bladder cancer had three to fourfold higher mean MCP-1 concentrations (pg/mL) in their urine than those with T1 stage tumours or than the controls (controls 260; T1 359; T2 967; T3 917; T4 1829; P < 0.005). A tumour grade of > GI and the existence of distant metastasis (M1) also correlated significantly with higher urinary MCP-1 levels (GI 373; GII 661; GIII 1111; M0 644; M1 1379; P < 0.05). No differences in circulating serum MCP-1 level were detected between controls and patients. The low-grade (GI) RT4 bladder cancer cell line produced only traces of MCP-1, which did not change under nutritional stress; in contrast, the highly malignant T24 bladder cancer cell line (GIII) spontaneously secreted large amounts of MCP-1 (approximately 7000 pg/mL) which increased under nutritive stress to 13,000 pg/mL., Conclusion: MCP-1, as a potent monocyte chemo-attractant to tumour sites, is probably produced by bladder cancer cells; MCP-1 levels in the vicinity of the tumour (i.e. urine) correlate significantly with TNM stage and grade. As has already been shown in other neoplasms, the resulting monocyte/macrophage infiltrate possibly facilitates tumour neovascularization and tissue invasion. Therefore, MCP-1 levels in the urine of patients with bladder cancer may be a prognostic marker for the natural course of the disease, and modulation of this chemokine might be a future therapeutic approach for adjuvant treatment of bladder cancer.

Nup475 is a nuclear zinc-binding protein of unknown function that is induced in mammalian cells by growth factor mitogens. Nup475 contains two tandemly repeated sequences YKTELCX8CX5CX3H (Cys3His repeats) that are thought to be zinc-bindin domains. Similar sequences have been found in a number of proteins from various species of eukaryotes. To determine the metal binding properties and secondary structure of the putative zinc-binding domains of Nup475, we have used synthetic or recombinant peptides that contain one or two domain sequences. The peptide with a single domain bound 1.0 +/- 0.1 equivalents of Co2+, and the peptide with two domains bound 1.7 +/- 0.4 equivalents of Co2+. Both peptides bound Co2+ and Zn2+ with affinities similar to those of classical zinc finger peptides. In each case, the Co2+ complex exhibited strong d-d transitions characteristic of tetrahedral coordination. For structural studies by nuclear magnetic resonance spectroscopy, we used a more soluble two-domain peptide that had a single amino acid substitution in a nonconserved amino acid residue in the second Cys3His repeat. The mutant peptide unexpectedly showed loss of one of its metal binding sites and displayed ordered structure for only the first Cys3His sequence. On the basis of the nuclear magnetic resonance data, we propose a structure for the Nup475 metal-binding domain in which the zinc ion is coordinated by the conserved cysteines and histidine, and the conserved YKTEL motif forms a parallel sheet-like structure with the C terminus of this domain. This structure is unlike that of any previously described class of metal binding domain.

Although most T cells express the alpha/beta TCR, the gamma/delta TCR is expressed only on a small percentage of peripheral lymphocytes and CD3+ intestinal T cells. The most striking feature is a wide variation in the proportion of gamma/delta+ T cells in freshly isolated peripheral blood cells from normal individuals and patients with IBD. The augmentation of the gamma/delta+ T cell subpopulation derived from human intestinal biopsies after repeated stimulation with MT, even in the absence of filler cells, suggests that gamma/delta+ cells from human gut mucosa may play a role in generating a primary immune response to MT.

The frequency of occurrence of Helicobacter pylori in the antral mucosa was investigated prospectively in a group of 66 patients (17 men, 49 women, mean age 58 +/- 8.4 years) who had been treated with nonsteroidal anti-rheumatic drugs and 33 controls (14 men, 19 women, mean age 60.7 +/- 6.6 years) who had not received these drugs. In the first group the indication for gastroscopy was ingestion of nonsteroidal antirheumatic drugs for at least 8 weeks, irrespective of dyspeptic symptoms (present in 25 patients), while in the second group the reason for endoscopy was either clinical symptoms (n = 18) or the presence of blood in the faeces. Helicobacter pylori was demonstrated by culture in 36 out of the 66 patients who had received nonsteroidal antirheumatics (54.5%); these comprised 24 out of 46 patients (52.2%) with chronic inactive gastritis and 12 out of 15 patients (80%) with chronic active gastritis. In the control group H. pylori was detected by culture in 22 out of 33 patients (66.7%); these included 11 out of 19 patients (57.9%) with chronic inactive gastritis and 11 out of 12 patients (91.7%) with chronic active gastritis. H. pylori was not demonstrated in any of the seven patients who had histologically normal gastric mucosa. In both groups there was significant correlation between demonstration of the microorganism and severity of inflammation. There is hence no evidence that nonsteroidal antirheumatic drugs have any influence on the colonisation of the antral mucosa by Helicobacter pylori.

Sugar uptake through the basolateral membrane into epithelial cells was investigated in lamb colon stripped of serosa and muscle layers. Only the antiluminal surface of the mucosa was exposed to the incubtion medium. 2-Deoxy-D-glucose (2-DG) and 2-O-methyl-D-glucose (3-MG) were used as model substrates. Both sugars were taken up by a saturable process. Transport apparently occurred by facilitated diffusion. 2-DG uptake was inhibited by D-glucose and 3-MG, but not by D-galactose and alpha-methyl-D-glucoside and 3-MG uptake was inhibited by 2-DG and D-glucose but not by alpha-methyl-D-glucoside. Thus 2-DG, 2-MG and glucose appear to compete for a common transport mechanism. Carrier-mediated uptake of glucose through the basolateral membranes is probably important for the energy supply of colon epithelium.

The kinetics of [3H]hypoxanthine entry into lamb mid-jejunum were measured using 2-min mucosal exposures. Mucosal hypoxanthine uptake occurred by a Na+- and energy-dependent saturable mechanism indicating that a carrier-mediated active transport process is involved. Inhibitory measurements indicate that hypoxanthine, adenosine, uracil and thymine complete for a common entry mechanism. Adenine, uric acid, allantoin and thymidine produced no significant inhibition of hypoxanthine entry. In additional experiments hypoxanthine was transported against a high concentration gradient from the mucosal to the serosal side of everted sacs of mid-jejunum. Therefore hypoxanthine appears to be absorbed by active transport from the lamb jejunum.