Energetic costs of mange in wolves estimated from infrared thermography.

Parasites, by definition, extract energy from their hosts and thus affect trophic and food web dynamics even when the parasite may have limited effects on host population size. We studied the energetic costs of mange (Sarcoptes scabiei) in wolves (Canis lupus) using thermal cameras to estimate heat losses associated with compromised insulation during the winter. We combined the field data of known, naturally infected wolves with a data set on captive wolves with shaved patches of fur as a positive control to simulate mange-induced hair loss. We predict that during the winter in Montana, more severe mange infection increases heat loss by around 5.2-12 MJ per night (1,240-2,850 kcal, or a 65-78% increase) for small and large wolves, respectively, accounting for wind effects. To maintain body temperature would require a significant proportion of a healthy wolf's total daily energy demands (18-22 MJ/day). We also predict how these thermal costs may increase in colder climates by comparing our predictions in Bozeman, Montana to those from a place with lower ambient temperatures (Fairbanks, Alaska). Contrary to our expectations, the 14°C differential between these regions was not as important as the potential differences in wind speed. These large increases in energetic demands can be mitigated by either increasing consumption rates or decreasing other energy demands. Data from GPS-collared wolves indicated that healthy wolves move, on average, 17 km per day, which was reduced by 1.5, 1.8, and 6.5 km for light, medium, and severe hair loss. In addition, the wolf with the most hair loss was less active at night and more active during the day, which is the converse of the movement patterns of healthy wolves. At the individual level, mange infections create significant energy demands and altered behavioral patterns, this may have cascading effects on prey consumption rates, food web dynamics, predator-prey interactions, and scavenger communities.

Short-term cognitive training improves mental efficiency and mood in patients with multiple sclerosis.

OBJECTIVES: The aim of this study was to evaluate a short-term non-specific home-based 6-week cognitive training for its effect on neuropsychological deficits and depression. SUBJECTS AND METHODS: Cognitive and affective abilities of patients with MS were compared with healthy controls using an identical neuropsychological test battery. Re-testing was performed after 6 weeks of cognitive home-based training. RESULTS: Patients already showed cognitive deficits at baseline. Cognitive training resulted in a significant improvement in several skills, in particular with respect to visuoconstructive and figural long-term memory. In addition, prior depressed mood and quality of life improved in MS patients during the training period and remained up to 6 months. CONCLUSIONS: Our study corroborated the early appearance of neuropsychological deficits in MS. Mental training, although unspecific, lead to improvements with respect to attention and memory functions in patients, and to some degree in control subjects, which may last for more than 6 months.

Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours.

BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor (VEGFR) inhibitor that targets tumour cell proliferation and tumour angiogenesis. This Phase I study was undertaken to determine the safety profile, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and tumour response profile of oral BAY 43-9006 in patients with advanced, refractory solid tumours. BAY 43-9006 was administered daily for repeated cycles of 21 days on/7 days off. A total of 44 patients were enrolled at doses from 50 to 800 mg b.i.d. Pharmacokinetic profiles of BAY 43-9006 in plasma were determined during the first treatment cycle. The most frequently reported adverse events over multiple cycles were gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain (64%), or hepatic (61%) related. A MTD of 400 mg b.i.d. BAY 43-9006 was defined. BAY 43-9006 was absorbed rapidly; steady-state conditions were reached within 7 days. BAY 43-9006 exposure increased nonproportionally with increasing dose. In all, 32 patients were evaluated for tumour response: 15 patients showed tumour progression, 16 patients experienced stable disease (>6 months in eight patients), and one patient with renal cell carcinoma achieved a partial response. BAY 43-9006 given for 21 days with 7 days off treatment was safe, well tolerated, and showed antitumour activity.

Cognitive, but not mood dysfunction develops in multiple sclerosis during 7 years of follow-up.

Long-term development of psychological deficits in disability-free early multiple sclerosis (MS) was evaluated in 27 female patients over a period of 7 years and compared with healthy controls. Physical and cognitive parameters deteriorated significantly but not depression scores. In particular, the self-assessed somatic complaints remained non-similar between patients and controls. This indicates that although depression is clinically relevant and frequent in MS, in contrast to cognition it is not related to physical disease progression.

A phase I clinical and pharmacokinetic study of the camptothecin glycoconjugate, BAY 38-3441, as a daily infusion in patients with advanced solid tumors.

BACKGROUND: The aim of this study was to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of the camptothecin glycoconjugate BAY 38-3441, administered as an infusion for 30 min on two separate schedules every 3 weeks. PATIENTS AND METHODS: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules. RESULTS: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses > or = 470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses > or = 320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear. CONCLUSIONS: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.

[Devics neuromyelitis optica. Disease or variants of multiple sclerosis?]. / Devics Neuromyelitis optica. Entität oder Variante der Multiplen Sklerose?

Neuromyelitis optica (NMO, or Devic's syndrome) is a rare syndrome characterized by the combination of acute or subacute optic neuritis and transverse myelitis. This strict confinement of lesions together with immunologic parameters such as frequent absence of oligoclonal banding despite increased signs of CSF inflammation suggest that NMO is distinct from multiple sclerosis (MS). Magnetic resonance imaging (MRI) data support NMO and MS as separate entities due to lesion distribution and signal characteristics. This is further supported by epidemiological and genetic evidence associating HLA-DRB1*1501 with disseminated "western" MS in contrast to NMO associated with DRB1*802, DPB1 501, and DPA1 202, the "Asian" type. Most findings suggest a heterogeneous pathogenesis of NMO and, in spite of the distinct localization, rather unspecific immune reactions seem to be involved. As to the frequent relapses of NMO, therapeutic options besides prednisolone are difficult to assess and favor long-term immune suppression or modulation.

Serum autoantibody responses to myelin oligodendrocyte glycoprotein and myelin basic protein in X-linked adrenoleukodystrophy and multiple sclerosis.

We analyzed the sera of 51 patients with various phenotypes of X-linked adrenoleukodystrophy (X-ALD), 20 patients with multiple sclerosis (MS) and 22 healthy volunteers for the presence of autoantibodies specific for the recombinant extracellular immunoglobulin-like domain of human myelin oligodendrocyte glycoprotein (rhMOG(Igd)) and myelin basic protein (MBP). Anti-rhMOG(Igd) autoantibodies were significantly more frequent in X-ALD and MS patients as opposed to healthy individuals (p<0.05). Anti-MBP autoantibodies were present in about one-fourth of X-ALD and MS patients but in less than 10% of healthy individuals. Anti-rhMOG(Igd) autoantibody responses were not accompanied by increased T cell reactivity against rhMOG(Igd). These findings may have important implications for the understanding of humoral anti-myelin immunoreactivity in demyelinating diseases of the central nervous system such as X-ALD and MS.

Detection of brain-specific autoantibodies to myelin oligodendrocyte glycoprotein, S100beta and myelin basic protein in patients with Devic's neuromyelitis optica.

Neuromyelitis optica (NMO) is a rare syndrome characterized by the combination of acute optic neuritis and transverse myelitis, usually not seen in Multiple Sclerosis (MS) and other demyelinating syndromes of the central nervous system (CNS). A high prevalence of various autoantibodies has been described in patients with NMO suggesting a polyclonal activation of the humoral immune system. We examined autoantibody responses to myelin (MBP, MOG with isotypes and epitopes) and astroglial (S100beta) antigens in four patients with NMO by ELISA and Immunoblot. All patients showed a positive anti-MOG response, with one showing reaction to the MOG epitope corresponding to amino acid sequence 63-87. MBP-autoantibodies were only detected in two and S100beta-autoantibodies in one patient. Despite the limited number of samples, these findings suggest a predominant anti-MOG rather than anti-MBP or anti-S100beta autoantibody response in NMO, though no NMO-specific antibody pattern was found, which is in keeping with a widespread acute immune activation, including a strong B-cell response.

No association between anti-myelin oligodendrocyte glycoprotein antibodies and serum/cerebrospinal fluid levels of the soluble interleukin-6 receptor complex in multiple sclerosis.

Myelin-oligodendrocyte glycoprotein (MOG) specific antibodies (abs) are involved in autoantibody-mediated demyelination possibly contributing to lesion development in multiple sclerosis (MS). Interleukin-6 (IL-6) has been reported to play a crucial role for the pathogenesis of a MOG-induced animal model of MS. To investigate the link between anti-MOG abs production and IL-6 up-regulation in MS we determined the presence of anti-MOG abs and measured concentrations of IL-6 and its soluble receptors (sIL-6RC) in paired serum and cerebrospinal fluid (CSF) samples of MS patients and serum samples of age-matched healthy controls (HC). Anti-MOG abs were detected in 75% of MS sera, 57% of MS CSF samples and 20% of HC sera. There was no difference in IL-6 and sIL-6RC levels between anti-MOG abs positive and negative samples. Thus, no association between the presence of anti-MOG abs and serum/CSF levels of IL-6/sIL-6RC was found.

The fine specificity of the myelin oligodendrocyte glycoprotein autoantibody response in patients with multiple sclerosis and normal healthy controls.

Antibodies directed against the extracellular immunoglobulin (Ig)-like domain of the myelin oligodendrocyte glycoprotein (MOG(Igd)) mediate demyelination in experimental autoimmune encephalomyelitis (EAE) and are implicated in the immunopathogenesis of multiple sclerosis (MS). In this study we investigated the epitope specificity of MOG(Igd)-specific autoantibodies immunopurified from MS patients (n=17) and normal healthy controls (HD; n=9). ELISA, using a panel of synthetic MOG(Igd) peptides, revealed that the epitope specificity of this response was heterogeneous in both groups. The most frequently recognised epitopes were located in amino acid sequences (a.a.) 1-26 (13/17) and 63-87 (15/17) in MS patients, and 14-39 (6/9) and 63-87 (6/9) in HDs, but there was no association between MS and any particular peptide specificity. We therefore investigated the ability of the immunopurified antibodies to recognise native MOG(Igd) expressed on at the membrane surface by FACS. Unexpectedly, antibodies fulfilling this essential criterion for a demyelinating antibody response were detected only in one of the MS samples. These results indicate that the epitope specificity of the human B cell response to MOG is not only heterogeneous, but may only mediate demyelination in a limited subset of MS patients.

Multiple sclerosis: B- and T-cell responses to the extracellular domain of the myelin oligodendrocyte glycoprotein.

We report a comparative study of the B- and T-cell responses to the extracellular immunoglobulin (Ig)-like domain of human myelin-oligodendrocyte glycoprotein (MOG(Igd)) in the blood of patients with multiple sclerosis and healthy controls using a bacterial recombinant human protein (rhMOG(Igd)). The frequency of anti-rhMOG(Igd)-seropositive samples, as determined by Western blotting, was significantly higher in the multiple sclerosis group (54%) than in normal random controls (excluding laboratory workers exposed to MOG) (22%; P = 0.02). In contrast, there was no difference in rhMOG(Igd)-induced proliferation indices of peripheral blood T cells between patients and controls. To characterize the rhMOG(Igd)-reactive T-cell repertoire, we isolated a panel of MOG-specific CD4(+) T-cell lines from multiple sclerosis patients and normal subjects, and these revealed a heterogeneous response with respect to epitope specificity, cytokine response, MHC (major histocompatibility complex) restriction and T-cell receptor Vbeta-chain usage. The majority of the T-cell lines recognized epitopes in the N-terminal region of MOG (amino acids 1-60). One epitope (represented by peptide 27-50) was exclusively recognized by T-cell lines from normal controls. Forty per cent of the MOG-specific T-cell lines analysed displayed a Th-2 or Th-0 cytokine profile and could therefore act as helper T cells in vivo.

Microemboli are not a prerequisite in retinal artery occlusive diseases.

PURPOSE: Retinal artery occlusion (RAO) is caused by arterio-arterial or cardiovascular emboli in about 50% of all cases, but the role of non-embolic causes remains unclear. SUBJECTS AND METHODS: We studied 27 patients with amaurosis fugax (AFX), branch retinal artery occlusion (BRAO), central retinal artery occlusion (CRAO) and anterior ischaemic optic neuropathy (AION). Patients underwent an evaluation of cerebrovascular and cardiovascular risk factors, measurement of haemorheological parameters, and Doppler/duplex sonography including ultrasound detection of cerebral microembolic signals and echocardiography. RESULTS: Forty-one per cent of the patients had internal carotid atherosclerosis but only one patient had microembolic signals, probably due to a cardiac thrombus. Vascular risk factors, especially hypertension, were present in 82% of the patients correlating with abnormal haemorheological parameters such as increased thrombocyte reactivity. CONCLUSIONS: Our results indicate that altered haemorheological parameters, especially increased thrombocyte reactivity and vascular risk factors such as arterial hypertension, are non-embolic causes of vascular disease in a significant number of patients with RAO. This should guide diagnostic and therapeutic considerations concerning RAO in cases without proven embolic sources.

Cerebral hemodynamics during electrically induced seizures.

Electroconvulsive therapy (ECT) is an appropriate clinical model to investigate blood flow during seizures. In this study cerebral blood flow velocity (CBFV) was measured during 40 ECTs in 10 patients by means of transcranial Doppler sonography. EEG was recorded continuously. Under general anesthesia, the pre-convulsive blood flow velocity (Vmean) decreased significantly. After ECT, we measured a dramatic increase in Vmean which was significantly greater in the left MCA than in the right MCA. After termination of seizures, flow velocities returned to baseline levels. The striking increase in cerebral blood flow velocity reflects excessive cerebral metabolism during convulsive neuronal activation. The left hemisphere seems to be more sensitive to electrical stimuli as was indicated by its predominant augmentation of CBFVs.

Transcranial Doppler ultrasonographic features during drug withdrawal from drug-induced headache. A transcranial Doppler follow-up study.

BACKGROUND: A vascular component in ergotamine-induced headache has been proposed. No study has been carried out to evaluate cerebral hemodynamic changes by means of transcranial Doppler during withdrawal from migraine medication; in particular, ergotamine-containing drugs. METHOD: We examined 21 patients suffering from drug-induced headache during their in-hospital withdrawal from ergotamine (n=8) and compared them with patients during withdrawal from analgesics (n=13) and with healthy controls (n=14). Cerebral blood flow velocities were measured with transcranial Doppler, and pulsatility indices were calculated. Blood pressure, heart rate, and end-tidal carbon dioxide were documented. A subjective analog headache rating scaling was used for day-to-day evaluation of headache severity. RESULTS: Mean cerebral blood flow velocities dropped significantly after discontinuation of ergotamine-containing drugs but not after stopping common analgesics. Pulsatility indices remained unchanged. Cerebral blood flow velocities were higher in drug-ingesting patients compared to the control group and showed significant changes in patients with headache using ergotamine and in those using analgesics. Carbon dioxide, heart rate, and blood pressure remained unchanged. The headache rating scale did not show a constant trend. COMMENTS: Our results indicate that ergotamine and, to a lesser extent, common analgesics including caffeine might influence cerebral blood flow velocities and pulsatility indices causing transient and reversible disturbance of cerebral autoregulation.