North Atlantic climate far more predictable than models imply.

Quantifying signals and uncertainties in climate models is essential for the detection, attribution, prediction and projection of climate change1-3. Although inter-model agreement is high for large-scale temperature signals, dynamical changes in atmospheric circulation are very uncertain4. This leads to low confidence in regional projections, especially for precipitation, over the coming decades5,6. The chaotic nature of the climate system7-9 may also mean that signal uncertainties are largely irreducible. However, climate projections are difficult to verify until further observations become available. Here we assess retrospective climate model predictions of the past six decades and show that decadal variations in North Atlantic winter climate are highly predictable, despite a lack of agreement between individual model simulations and the poor predictive ability of raw model outputs. Crucially, current models underestimate the predictable signal (the predictable fraction of the total variability) of the North Atlantic Oscillation (the leading mode of variability in North Atlantic atmospheric circulation) by an order of magnitude. Consequently, compared to perfect models, 100 times as many ensemble members are needed in current models to extract this signal, and its effects on the climate are underestimated relative to other factors. To address these limitations, we implement a two-stage post-processing technique. We first adjust the variance of the ensemble-mean North Atlantic Oscillation forecast to match the observed variance of the predictable signal. We then select and use only the ensemble members with a North Atlantic Oscillation sufficiently close to the variance-adjusted ensemble-mean forecast North Atlantic Oscillation. This approach greatly improves decadal predictions of winter climate for Europe and eastern North America. Predictions of Atlantic multidecadal variability are also improved, suggesting that the North Atlantic Oscillation is not driven solely by Atlantic multidecadal variability. Our results highlight the need to understand why the signal-to-noise ratio is too small in current climate models10, and the extent to which correcting this model error would reduce uncertainties in regional climate change projections on timescales beyond a decade.

Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results.

In a 6-month, placebo-controlled trial, oral fingolimod (FTY720) 1.25 or 5.0 mg, once daily, significantly reduced MRI inflammatory activity and annualized relapse rate compared with placebo in patients with relapsing multiple sclerosis (MS). The objectives were to monitor the 36-month, interim efficacy and safety results of the ongoing extension of this study. In the extension (months 7-36), placebo-treated patients were re-randomized to either dose of fingolimod; fingolimod-treated patients continued at the same dose. During months 15-24, all patients receiving fingolimod 5.0 mg switched to 1.25 mg. Of the 250 patients who entered the extension study, 173 (69%) continued to month 36. Most patients were free from gadolinium-enhanced lesions (88-89%) or new T2 lesions (70-78%) at month 36. Patients receiving continuous fingolimod treatment had sustained low annualized relapse rates of 0.20-0.21, and 68-73% remained relapse-free at month 36. Over 36 months, nasopharyngitis (34%), headache (30%), fatigue (19%) and influenza (18%) were the most commonly reported adverse events. Pulmonary function remained stable and blood pressure was stable after an initial increase (3-5 mmHg) during the first 6 months of fingolimod treatment; serious adverse events included infections and skin cancer. The low MRI and clinical disease activity at 6 months were maintained at 36 months with fingolimod, which was generally well tolerated by most patients. The efficacy and safety of oral fingolimod are being further evaluated in a large phase III MS study programme.

Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study.

OBJECTIVE: To report the results of a 24-month extension of a phase II trial assessing the efficacy, safety, and tolerability of the once-daily oral sphingosine-1-phosphate receptor modulator, fingolimod (FTY720), in relapsing multiple sclerosis (MS). METHODS: In the randomized, double-blind, placebo-controlled core study, 281 patients received placebo or FTY720, 1.25 or 5.0 mg/day, for 6 months. During the subsequent dose-blinded extension, patients assigned to placebo were re-randomized to either dose of FTY720; those originally assigned to FTY720 continued at the same dose. Patients receiving FTY720 5.0 mg were switched to 1.25 mg during the month 15 to month 24 study visits. RESULTS: Of 281 patients randomized in the core study, 250 (89%) entered the extension phase, and 189 (75.6%) received treatment for 24 months. During the core study, FTY720 significantly reduced gadolinium-enhanced (Gd(+)) lesions and annualized relapse rate (ARR) compared with placebo, with no differences between doses. During the extension phase, patients who switched from placebo to FTY720 showed clear reductions in ARR and lesion counts compared with the placebo phase; ARR and lesion counts remained low in patients who continued FTY720 treatment. After 24 months, 79 to 91% of patients were free from Gd(+) lesions and up to 77% of patients remained relapse free. FTY720 was well tolerated; no new safety concerns emerged during months 7 to 24 compared with the 6-month core study. CONCLUSIONS: Once-daily oral treatment with FTY720, 1.25 or 5.0 mg, for up to 2 years, was well tolerated and was associated with low relapse rates and lesion activity.

Phase II/III randomized trial of TCH346 in patients with ALS.

BACKGROUND: TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS. METHODS: Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patient's rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT). RESULTS: Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT). CONCLUSION: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.

Advanced head and neck cancer: long-term results of chemo-radiotherapy, complications and induction of second malignancies.

BACKGROUND: Chemo-radiotherapy is superior to radiotherapy alone in the treatment of advanced, inoperable head and neck cancer. The long-term treatment results, the induction of second malignant tumors, and other long-term toxicities are not well defined. PATIENTS AND METHODS: 100 consecutive patients with advanced head and neck cancer who were treated at our center were studied. Treatment results, survival, the occurrence of late complications, and second malignant tumors (SMT) were investigated. 78 patients were treated with a protocol combining cisplatinum, 5-fluorouracil, folinic acid and hyperfractionated irradiation. 22 patients were treated with other chemo-radiotherapy protocols. The relative risk of developing an SMT was compared with that within the normal population. RESULTS: The cumulative total probability of survival was 51.1% at 2 years and 38.7% at 4 years. The probability of relapse-free survival was 39.9% at 2 years and 36.7% at 4 years. A total of 7 patients developed SMT (4 cases of lung cancer, 2 colon cancers, 1 skin cancer). After 6 years, a cumulative risk of SMT of 8.7% was observed. The relative risk of developing an SMT was significantly increased (4.45-fold in males) compared with a normal population. 13 of 38 evaluable patients (34.2%) had severe late complications like fibrosis of soft tissues, nerve lesions, or were dependent on tracheal cannulas. CONCLUSIONS: The treatment results and long-term prognoses in our population of unselected high-risk patients are unsatisfactory, but comparable to those from multicenter studies. About 35% of patients become long-term (> 4 years) survivors. SMT generally occur early, have a poor prognosis and, most likely, are not treatment-related. Approximately 30% of long-term survivors have severe, often incapacitating late effects. The treatment and - if possible - prevention of these late effects is important for the quality of life of patients who survived advanced head and neck cancer.

Spontaneous Bleeding in a Patient with Malignant Lymphoma: A Case of Acquired Hemophilia.

BACKGROUND: Acquired hemophilia is a rare condition which can be associated with lymphoproliferative disease. CASE REPORT: Eleven years after the diagnosis of immunocytoma had been made, a 72-year-old man developed a high-titer factor VIII inhibitor. At this time, the lymphoma was without significant progress and there was no paraprotein in the serum. Partial thromboplastin time (PTT) was 83s, factor-VIII clotting activity was <1%, and inhibitor level was 50.4 Bethesda units. The patient presented with spontaneous hematomas in the skin and musculature of the extremities. Following combination chemotherapy with cyclophosphamide, vincristine and prednisolone (COP), there was a prompt disappearance of the inhibitor and normalization of coagulation; however, the patient developed serious infectious complications. When the inhibitor recurred he was treated with low-dose cyclophosphamide and prednisolone. This time there was a more delayed response, but the inhibitor disappeared again completely. Two months after cessation of therapy, there was again relapse. CONCLUSION: Causal relationship between lymphoma and acquired hemophilia remains speculative. At least in some cases of factor VIII inhibitors associated with malignant disease, immunosuppressive therapy may be sufficient to suppress the inhibitor. Copyright 2000 S. Karger GmbH, Freiburg

A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in adults with previously untreated epilepsy.

In the last 5 years oxcarbazepine (OXC) has been registered in many countries for use as first-line and add-on treatment for partial seizures with or without secondarily generalized seizures (PS) and generalized tonic-clonic seizures without partial onset (GTCS). Its use as monotherapy in adults with newly diagnosed epilepsy was investigated in this double-blind, randomized, parallel-group comparison with phenytoin (PHT). A total of 287 adult patients, with either PS or GTCS, were randomized. After retrospective baseline assessment, patients were randomized to OXC or PHT in a 1:1 ratio. The double-blind treatment phase was divided into two periods: a flexible titration period of 8 weeks, followed by 48 weeks of maintenance treatment. In the efficacy analyses, no statistically significant differences were found between the treatment groups. Seventy patients (59.3%) in the OXC group and 69 (58.0%) in the PHT group were seizure-free during the maintenance period. A total of 56 of the patients in the OXC group discontinued treatment prematurely (five because of tolerability reasons) compared to 61 in the PHT group (16 for tolerability reasons). The number of premature discontinuations due to adverse experiences showed a statistically significant difference in favour of OXC. There was no statistically significant difference between the groups with respect to the total number of premature discontinuations. This trial provides further support for the efficacy and safety of OXC as first-line treatment in adults with PS and GTCS. In addition, the results show that OXC has significant advantages over PHT in terms of tolerability.

A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy.

In many countries oxcarbazepine (OXC) has been registered for use as first-line and add-on treatment for patients with partial seizures with or without secondarily generalized seizures (PS) and generalized tonic-clonic seizures without partial onset (GTCS). Its use as monotherapy in children and adolescents with newly diagnosed epilepsy was investigated in this double-blind, randomized, parallel-group comparison with phenytoin (PHT). A total of 193 patients aged 5-18 years with either PS or GTCS were enrolled. After a retrospective baseline assessment, patients were randomized to OXC or PHT in a 1:1 ratio. The double-blind treatment phase comprised two periods: an 8-week flexible titration period; followed by 48 weeks maintenance treatment. In the efficacy analyses, there were no statistically significant differences between OXC and PHT. Forty-nine (61%) patients in the OXC group and 46 (60%) in the PHT group were seizure-free during the maintenance period. In total, 24 patients in the OXC group discontinued treatment prematurely (two for tolerability reasons) compared with 34 in the PHT group (14 for tolerability reasons). The number of premature discontinuations due to adverse experiences was statistically significantly lower in the OXC group than in the PHT group. Moreover, the odds of an individual discontinuing prematurely (regardless of reason) were almost twice as high in the PHT group. This trial provides further support for the efficacy and safety of OXC as first-line treatment in children and adolescents with PS and GTCS. In addition, the results show that OXC in these patients has significant advantages over PHT in terms of tolerability and treatment retention.

A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy.

Oxcarbazepine (OXC) has been licensed as monotherapy and add-on treatment in epilepsy patients with partial seizures with or without secondarily generalized seizures (PS) and generalized tonic-clonic seizures without partial onset (GTCS). Its use as monotherapy in adults with newly diagnosed epilepsy was investigated in a double-blind, randomized, parallel-group comparison with sodium valproate (VPA). Two-hundred and forty-nine patients with either PS or generalized seizures aged 15-65 years were randomized. After a retrospective baseline, patients were randomized to VPA or OXC in a 1:1 ratio. The double-blind treatment phase was divided into two periods, flexible titration and maintenance. The titration period was 8 weeks followed by 48 weeks of individualized, maintenance treatment given three times a day. Three primary analyses were used to assess efficacy, tolerability, and the association between the two. In the efficacy analyses comprising 212 patients who had at least one seizure assessment during the maintenance period, no statistically significant difference at the 5% level was found between the treatment groups. Sixty patients (56.6%) in the OXC group and 57 patients (53.8%) in the VPA group were seizure free during maintenance treatment. Fifty-two patients in the OXC group discontinued treatment prematurely (15 because of tolerability reasons) compared to 41 patients in the VPA group (ten due to tolerability reasons). There was no statistically significant difference between the treatment groups with respect to the total number of premature discontinuations or those due to adverse experiences. This trial provides support for the efficacy and safety of OXC as first-line treatment in adults with PS and GTCS.

Prevalence of antibodies to hepatitis C virus (HCV) in haemophiliacs.

The prevalence of 1) hepatitis C virus (HCV), an agent likely to be responsible for parenterally transmitted hepatitis non-A, non-B, 2) hepatitis B virus (HBV) and 3) human immunodeficiency virus (HIV) infection was studied in 211 patients with clotting disorders (78% of the patients had residual factor activities of less than or equal to 2%). Of these patients 71% were positive for HBV markers and 44% for HIV markers. Using a new ELISA technique, 80% were anti-HCV-positive. The prevalence of anti-HCV was greater in patients with more severe clotting disorders and was related to the total amount of replacement therapy received; the prevalence was less in older patients. Seroconversion after a single exposure to dry heat-treated factor concentrates was documented in 3 patients 3-4 months after exposure.

[Distribution and extent of hemophilic arthropathy in adulthood in severe factor VIII deficiency]. / Verteilung und Ausmass der Hämophilie-Arthropathie im Erwachsenenalter bei schwerem Faktor-VIII-Mangel.

This study deals with the distribution and extent of hemophilic arthropathy in 52 adult patients suffering from severe hemophilia A. A clinical and radiological score-evaluation of knee, ankle and elbow joints was undertaken, 4.7 of 6 examined joints proved to be affected in the third life-decade in the average, the extent of destruction being most pronounced at the knee joints. A rather close correlation of clinical and radiological signs was found to exist only related to the knee joints.

Radiological evaluation of chronic hemophilic arthropathy by the Pettersson score: problems in correlation in adult patients.

This study deals with the distribution and extent of hemophilic arthropathy (HA) in 52 adult patients suffering from severe hemophilia A. A clinical and radiological evaluation was undertaken and the results were compared. The limitations of the currently used radiological scoring system are discussed.

[In vitro and in vivo photochemical reactivity of methaqualone-1-oxide]. / In-vitro- und in-vivo-Untersuchungen zur fotochemischen Reaktivität von Methaqualon-1-oxid.

Methaqualone-1-oxide (1) exhibits photochemical reactivity. By irradiation of 1 with solar light the oxaziridin 3 is formed at first, which reacts in vitro (human proteins) and in vivo (rats) with macromolecules. As result of the photochemical in vitro and in vivo reactions of 1 the photoproduct 2-acetamidobenzoic acid-2'-methylanilide (6), involved in oxidation of protic compounds, was detected and after hydrolysis of proteins it appears that the short-lived 3 was adding to proteins.

[In vitro and in vivo photochemical reactivity of quinine- and quinidine-N-oxide]. / In-vitro- und in-vivo-Untersuchungen zur fotochemischen Reaktivität der Chinin- und Chinidin-N-Oxide.

By irradiation with UV-light quinine- and quinidine-1,1'-dioxide in polar solvents are rearranged to 2'-oxo derivatives and in nonpolar solvents to formylindol derivatives. Rats being exposed to UV-light after oral administration of quinine- or quinidine-1,1'-dioxide showed in blood plasma the 2'-oxo derivates too. In accordance with the results of the different fotochemical reactivity of quinoline-1-oxide-, chlordiazepoxide, methaqualone-1-oxide and some pyrido-pyrimidine-8-oxides a first drafting is developed due to the supposed toxic effects of the exited imino-N-oxides.

[Photochemical reactivity of methaqualone-1-oxide]. / Fotochemische Reaktivität von Methaqualon-1-oxid.

The photoreactivity of methaqualone-1-oxide a main metabolite of the hypnotic methaqualone has been studied in polar and apolar solvents using UV- and daylight. Five photoproducts were isolated and identified by their analytical behaviour (TLC, UV, IR, high-resolution MS). The structure of the compounds 4, 6, 7, and 8 refer to unstable, reactive intermediates (oxaziridine, biradical) during the photolysis.