The occurrence of dystonia in upper-limb multiple sclerosis tremor.

BACKGROUND: The pathophysiology of multiple sclerosis (MS) tremor is uncertain with limited phenotypical studies available. OBJECTIVE: To investigate whether dystonia contributes to MS tremor and its severity. METHODS: MS patients (n = 54) with and without disabling uni- or bilateral upper limb tremor were recruited (39 limbs per group). We rated tremor severity, writing and Archimedes spiral drawing; cerebellar dysfunction (SARA score); the Global Dystonia Scale (GDS) for proximal and distal upper limbs, dystonic posturing, mirror movements, geste antagoniste, and writer's cramp. RESULTS: Geste antagoniste, mirror dystonia, and dystonic posturing were more frequent and severe (p < 0.001) and dystonia scores were correlated with tremor severity in tremor compared to non-tremor patients. A 1-unit increase in distal dystonia predicted a 0.52-Bain unit (95% confidence interval (CI) 0.08-0.97), p = 0.022) increase in tremor severity and a 1-unit (95% CI 0.48-1.6, p = 0.001) increase in drawing scores. A 1-unit increase in proximal dystonia predicted 0.93-Bain unit increase (95% CI 0.45-1.41, p < 0.001) in tremor severity and 1.5-units (95% CI 0.62-2.41, p = 0.002) increase in the drawing score. Cerebellar function in the tremor limb and tremor severity was correlated (p < 0.001). CONCLUSIONS: Upper limb dystonia is common in MS tremor suggesting that MS tremor pathophysiology involves cerebello-pallido-thalamo-cortical network dysfunction.

Optical switch probes and optical lock-in detection (OLID) imaging microscopy: high-contrast fluorescence imaging within living systems.

Few to single molecule imaging of fluorescent probe molecules can provide information on the distribution, dynamics, interactions and activity of specific fluorescently tagged proteins during cellular processes. Unfortunately, these imaging studies are made challenging in living cells because of fluorescence signals from endogenous cofactors. Moreover, related background signals within multi-cell systems and intact tissue are even higher and reduce signal contrast even for ensemble populations of probe molecules. High-contrast optical imaging within high-background environments will therefore require new ideas on the design of fluorescence probes, and the way their fluorescence signals are generated and analysed to form an image. To this end, in the present review we describe recent studies on a new family of fluorescent probe called optical switches, with descriptions of the mechanisms that underlie their ability to undergo rapid and reversible transitions between two distinct states. Optical manipulation of the fluorescent and non-fluorescent states of an optical switch probe generates a modulated fluorescence signal that can be isolated from a larger unmodulated background by using OLID (optical lock-in detection) techniques. The present review concludes with a discussion on select applications of synthetic and genetically encoded optical switch probes and OLID microscopy for high-contrast imaging of specific proteins and membrane structures within living systems.

HLA-DRB1 associations with disease susceptibility and clinical course in Australians with multiple sclerosis.

Human leucocyte antigen (HLA)-DRB1*1501 and other class II alleles influence susceptibility to multiple sclerosis (MS), but their contribution if any to the clinical course of MS remains uncertain. Here, we have investigated DRB1 alleles in a large sample of 1230 Australian MS cases, with some enrichment for subjects with primary progressive (PPMS) disease (n = 246) and 1210 healthy controls. Using logistic regression, we found that DRB1*1501 was strongly associated with risk (P = 7 x 10(-45)), as expected, and after adjusting for DRB1*1501, a predisposing effect was also observed for DRB1*03 (P = 5 x 10(-7)). Individuals homozygous for either DRB1*15 or DRB1*03 were considerably more at risk of MS than heterozygotes and non-carriers. Both the DRB1*04 and the DRB1*01/DRB1*15 genotype combination, respectively, protected against PPMS in comparison to subjects with relapsing disease. Together, these data provide further evidence of heterogeneity at the DRB1 locus and confirm the importance of HLA variants in the phenotypic expression of MS.

Monte Carlo electron-trajectory simulations in bright-field and dark-field STEM: implications for tomography of thick biological sections.

A Monte Carlo electron-trajectory calculation has been implemented to assess the optimal detector configuration for scanning transmission electron microscopy (STEM) tomography of thick biological sections. By modeling specimens containing 2 and 3 at% osmium in a carbon matrix, it was found that for 1-microm-thick samples the bright-field (BF) and annular dark-field (ADF) signals give similar contrast and signal-to-noise ratio provided the ADF inner angle and BF outer angle are chosen optimally. Spatial resolution in STEM imaging of thick sections is compromised by multiple elastic scattering which results in a spread of scattering angles and thus a spread in lateral distances of the electrons leaving the bottom surface. However, the simulations reveal that a large fraction of these multiply scattered electrons are excluded from the BF detector, which results in higher spatial resolution in BF than in high-angle ADF images for objects situated towards the bottom of the sample. The calculations imply that STEM electron tomography of thick sections should be performed using a BF rather than an ADF detector. This advantage was verified by recording simultaneous BF and high-angle ADF STEM tomographic tilt series from a stained 600-nm-thick section of C. elegans. It was found that loss of spatial resolution occurred markedly at the bottom surface of the specimen in the ADF STEM but significantly less in the BF STEM tomographic reconstruction. Our results indicate that it might be feasible to use BF STEM tomography to determine the 3D structure of whole eukaryotic microorganisms prepared by freeze-substitution, embedding, and sectioning.

Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians.

A recent genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC) identified a number of putative MS susceptibility genes. Here we have performed a replication study in 1134 Australian MS cases and 1265 controls for 17 risk-associated single nucleotide polymorphisms (SNPs) reported by the IMSGC. Of 16 SNPs that passed quality control filters, four, each corresponding to a different non-human leukocyte antigen (HLA) gene, were associated with disease susceptibility: KIAA0350 (rs6498169) P=0.001, IL2RA (rs2104286) P=0.033, RPL5 (rs6604026) P=0.041 and CD58 (rs12044852) P=0.042. There was no association (P=0.58) between rs6897932 in the IL7R gene and the risk of MS. No interactions were detected between the replicated IMSGC SNPs and HLA-DRB1*15, gender, disease course, disease progression or age-at-onset. We used a novel Bayesian approach to estimate the extent to which our data increased or decreased evidence for association with the six most-associated IMSGC loci. These analyses indicated that even modest P-values, such as those reported here, can contribute markedly to the posterior probability of 'true' association in replication studies. In conclusion, these data provide support for the involvement of four non-HLA genes in the pathogenesis of MS, and combined with previous data, increase to genome-wide significance (P=3 x 10(-8)) evidence of an association between KIAA0350 and risk of disease.

Determination of quantitative distributions of heavy-metal stain in biological specimens by annular dark-field STEM.

It is shown that dark-field images collected in the scanning transmission electron microscope (STEM) at two different camera lengths yield quantitative distributions of both the heavy and light atoms in a stained biological specimen. Quantitative analysis of the paired STEM images requires knowledge of the elastic scattering cross sections, which are calculated from the NIST elastic scattering cross section database. The results reveal quantitative information about the distribution of fixative and stain within the biological matrix, and provide a basis for assessing detection limits for heavy-metal clusters used to label intracellular proteins. In sectioned cells that have been stained only with osmium tetroxide, we find an average of 1.2+/-0.1 Os atom per nm(3), corresponding to an atomic ratio of Os:C atoms of approximately 0.02, which indicates that small heavy atom clusters of Undecagold and Nanogold can be detected in lightly stained specimens.

One-year outcome with antidepressant--treatment of bipolar depression.

OBJECTIVE: To examine the risk of relapse into mania or depression with varying duration of antidepressant treatment in a cohort of 59 patients with bipolar disorder. METHOD: An open naturalistic evaluation using life charting methods of patients with 1 year follow-up, who responded to antidepressant treatment and who then less or more than 6 months of antidepressant treatment. RESULTS: Patients who received more than 6 months of antidepressant treatment were less likely to relapse into depression at follow-up of 1 year. There was no difference in relapse rates for mania in the different antidepressant treatment duration groups. Gender and bipolar subtype did not significantly affect relapse rates for depression or mania. CONCLUSION: Our data, taken with other studies, suggest that the duration of optimal antidepressant treatment in bipolar disorder must be further evaluated.

Does a combination regimen of thyroxine (T4) and 3,5,3'-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial.

Some hypothyroid patients receiving levothyroxine replacement therapy complain of depressive symptoms despite normal TSH measurements. It is not known whether adding T(3) can reverse such symptoms. We randomized 40 individuals with depressive symptoms who were taking a stable dose of levothyroxine for treatment of hypothyroidism (excluding those who underwent thyroidectomy or radioactive iodine ablation of the thyroid) to receive T(4) plus placebo or the combination of T(4) plus T(3) in a double-blind manner for 15 wk. Participants receiving combination therapy had their prestudy dose of T(4) dropped by 50%, and T(3) was started at a dose of 12.5 micro g, twice daily. T(4) and T(3) doses were adjusted to keep goal TSH concentrations within the normal range. Compared with the group taking T(4) alone, the group taking both T(4) plus T(3) did not report any improvement in self-rated mood and well-being scores that included all subscales of the Symptom Check-List-90, the Comprehensive Epidemiological Screen for Depression, and the Multiple Outcome Study (P > 0.05 for all indexes). In conclusion, the current data do not support the routine use of combined T(3) and T(4) therapy in hypothyroid patients with depressive symptoms.

Induction of mania and cycle acceleration in bipolar disorder: effect of different classes of antidepressant.

OBJECTIVE: To assess the effect of different antidepressants on induction of mania and cycle acceleration, commonly accepted unwanted effects of antidepressant treatment for acute bipolar depression. There is, however, the suggestion that certain classes of antidepressants may be less likely than others to cause these unwanted effects. METHOD: We conducted a prospective, open, naturalistic, life charting study to assess the occurrence of onset of mania and cycle acceleration attributable to two antidepressant classes: selective serotonin reuptake inhibitors (SSRIs) and bupropion. RESULTS: No difference was found between the two drug classes for either antidepressant-induced mania or cycle acceleration. Antidepressant-induced mania was much more likely to occur in bipolar I rather than bipolar II patients. The overall occurrence of induction of mania and cycle acceleration was low across antidepressant classes. CONCLUSION: These findings suggest that there is probably no difference in the risk of antidepressant-induced mania or cycle acceleration across commonly used classes of antidepressants for the treatment of bipolar depression.

Group cognitive behavioral therapy for bipolar disorder: a feasibility and effectiveness study.

BACKGROUND: Bipolar disorder (BD) is a common disorder that results in significant psychosocial impairment, including diminished quality of life and functioning, despite aggressive pharmacotherapy. Psychosocial interventions that target functional factors could be beneficial for this population, and we hypothesized that the addition of group cognitive behavioral therapy (CBT) to maintenance pharmacotherapy would improve functioning and quality of life. METHODS: Patients diagnosed (by SCID) with bipolar disorder attending an outpatient clinic of a mood disorders program participated in the study. All patients were on maintenance mood stabilizers, and were required to have controlled symptoms before entering the study. Mood symptoms were assessed with the Hamilton Depression Rating scale and Young Mania scale at baseline and 14 weeks. Objective and subjective functioning was rated at the same interval using the Global Assessment of Functioning scale and the Medical Outcomes Survey SF-36. Treatment was provided via a specific manual based on CBT principles that could be applied to this population. RESULTS: Forty nine patients participated in this open trial, and 38 patients completed treatment. Objective and subjective indices of impairment showed improvement after 14 weeks. Both GAF and MOS scores increased significantly by the end of treatment. LIMITATIONS: This study was an open trial, and lack of control groups limits the interpretation of results. Because the study concerned effectiveness, the results do not clarify whether the improvement represents the normal course of illness or whether it is the result of the CBT intervention. CONCLUSIONS: The addition of group CBT to standard pharmacological treatment was acceptable to patients, and nearly 80% of patients complied with treatment. Despite the fact that mood symptoms were controlled at entry into the study, psychosocial functioning increased significantly at the end of treatment. Adjunctive CBT should be further investigated in this population.

Thyroid hormone levels and recurrence of major depression.

OBJECTIVE: The relationship between basal thyroid hormone levels and acute antidepressant response has been studied, but any relationship between basal thyroid hormone levels and long-term course of depressive illness has not been evaluated. METHOD: The authors used a Cox regression survival analysis to evaluate the relationship between life course of depressive illness and basal levels of thyroid hormones (triiodothyronine [T(3)], thyroxine [T(4)], and thyrotropin) in 75 outpatients with unipolar major depressive disorder. RESULTS: Time to recurrence of major depression was inversely related to T(3) levels but not to T(4) levels. CONCLUSIONS: These data may be of clinical interest in view of the fact that T(3) is used to augment antidepressant response.

Effect of number of episodes on wellbeing and functioning of patients with bipolar disorder.

OBJECTIVE: To examine the relationship between number of episodes and inter-episode functioning in bipolar disorder. METHOD: Sixty-four euthymic subjects with bipolar affective disorder completed the Medical Outcomes Questionnaire Short Form and the Global Assessment of Functioning Scale. Goodness-of-fit models were used to define the relation between episode number and level of function. RESULTS: Non-linear logarithmic and power relations best described the association between number of episodes and outcome. Number of past depressions was a stronger determinant of outcome than past manias. CONCLUSION: Strategies to minimize the number of episodes experienced by patients with bipolar illness must be pursued aggressively if function is to be maintained, with particular attention given to minimizing episodes of depression.

Double-blind comparison of addition of a second mood stabilizer versus an antidepressant to an initial mood stabilizer for treatment of patients with bipolar depression.

OBJECTIVE: This study's purpose was to clarify the appropriate treatment of bipolar depression by comparing the addition of an antidepressant versus a second mood stabilizer for inpatients being treated with lithium carbonate or divalproex sodium. METHOD: Twenty-seven patients were randomly assigned to groups that received double-blind treatment with paroxetine or a second mood stabilizer (lithium carbonate or divalproex sodium) for 6 weeks. RESULTS: Both groups showed significant improvement in depressive symptoms during the 6-week trial. There were significantly more noncompleters in the group being treated with the two mood stabilizers than in the group being treated with a mood stabilizer and paroxetine. CONCLUSIONS: Both treatments appeared to be effective; however, the addition of an antidepressant may have greater clinical utility in the treatment of bipolar depression.

Repair of cranial cruciate ligament rupture in an alpaca.

A mature male alpaca with acute lameness of the left handlimb was diagnosed as having a rupture of the cranial cruciate ligament. Repair was achieved using a combination of surgical techniques. A patellar ligament autograft was passed under the cranial meniscal ligament, through the joint and over the femoral condyle, and anchored using a screw and washer. Two nylon sutures were passed through a hole made in the tibial crest, and secured under the screw. The alpaca was confined in a stall for 3 months. Exercise was then increased progressively for 3 months. One year after surgery the alpaca is sound and has resumed breeding activity.

Gabapentin as an adjunctive treatment in bipolar disorder.

OBJECTIVE: To evaluate the efficacy of gabapentin as an adjunctive treatment for bipolar disorder in both depressed and manic phases. METHOD: Thirty seven patients with bipolar type I or II with or without a rapid cycling course were openly treated with gabapentin added to current treatment for up to six months. Mood symptoms were rated weekly for 12 weeks then monthly for 3 months utilizing the HamD and YMS. RESULTS: Participants experienced a significant reduction in both depressive and manic symptoms. CONCLUSIONS: These findings are consistent with others in establishing the efficacy of gabapentin in both phases of bipolar disorder. LIMITATIONS: Small sample size and the use of an open uncontrolled design limit interpretation of results.

Treatment of progressive ethmoidal haematoma using intralesional injections of formalin in three horses.

Three Thoroughbred horses with unilateral progressive ethmoid haematomas were treated using intralesional injections of 10% formalin (4% formaldehyde solution). Injections were performed in the standing sedated horse through the nasal passages under endoscopic guidance and, when the ethmoid haematoma involved the paranasal sinuses, through holes trephined into the affected sinus. Regression of the lesions occurred in all cases after repeated injections. This technique appears to be a safe and effective treatment for progressive ethmoid haematomas in the horse.