The national pharmacopoeias of the Baltic States.

After Estonia, Latvia and Lithuania proclaimed their independence in 1918 and began to create their national health care systems, one of their stated priorities was the formulation and publication of national pharmacopoeias. In order to accomplish this, working groups as well as commissions composed of pharmacists, medical specialists and even linguists had to be formed. The process was long and difficult. New terminology in native languages had to be created. Sources for the monographs had to be chosen, researched, analyzed and compared. There were organizational and financial problems. Nevertheless, by the late 1930s, all three Baltic States published their national pharmacopoeias. Officially, they were not able to use them for long because during World War II all three were occupied and annexed by the Soviet Union. Pharmacists in those countries were obliged to use the Soviet pharmacopoeias, although unofficially, they also made good use of their national ones. Currently, the European Pharmacopoeia is in use in Estonia, Latvia and Lithuania.

[A case of anti-NMDA-receptor encephalitis]. / Anti-NMDA-éntsefalit - klinicheskii sluchai

A clinical case of encephalitis caused by antibodies to NMDA-receptors is presented. This rare pathology is characterized by severe cognitive impairment and needs careful differential diagnosis.

Cognitive dysfunction during anti-NMDA-receptor encephalitis is present in early phase of the disease.

Anti-NMDA-receptor encephalitis is an autoimmune disorder with a well-defined set of clinical features including psychiatric changes (anxiety, agitation, bizarre behaviour, delusional or paranoid thoughts), epileptic seizures and cognitive disturbance followed by movement disorders including orofacial dyskinesias, alterations in the level of consciousness and dysautonomia. Although the cognitive changes are not always very clear at presentation, they can persist after recovery from the acute and often prolonged illness. However, there are few studies describing neuropsychiatric changes in depth, both in the early course of the disease and in long-term follow-up.

Health-related quality of life in patients with hereditary spastic paraplegia in Estonia.

STUDY DESIGN: Observational population-based cohort study. OBJECTIVES: The main aim of this study was to examine the relative effect of hereditary spastic paraplegia (HSP) on the health-related quality of life (HRQoL). METHODS: HRQoL was evaluated using a RAND 36-Item Health Survey 1.0 questionnaire. Fifty-eight patients received a questionnaire through mail and signed an informed consent. The results for the control group were obtained from the RAND-36 data collected in 2004 in the European Social Survey. R2.9.0 and Statistica 6.1 were used to analyze the RAND-36 data. SETTING: The study was performed in Estonia, a country with a population of 1.3 million. RESULTS: Completed questionnaires were received from 49 participants (response rate was 84.5%). The control group consisted of 549 individuals from the Estonian population. Patients with HSP had lower mean scores in all categories as compared with the control group. Six of the eight categories showed significant differences, with P<0.0001. For the vitality category, the P-value ranged from 0.000006 from 0.002, and the P-value for the mental health category ranged from 0.001 to 0.055. CONCLUSIONS: The HRQoL in patients with HSP was found to be significantly worse than that for the general population. The level of education might affect the HRQoL experienced by HSP patients.

The prevalence of depression in hereditary spastic paraplegia.

OBJECTIVE: To evaluate the prevalence of depression and sensitivity and specificity of the single-item interview 'Are you depressed?' for people with hereditary spastic paraplegia in Estonia. DESIGN: Single-item interview 'Are you depressed?' was used as a screening question for depression; all participants then completed the Beck Depression Inventory. SETTING: People with hereditary spastic paraplegia identified from the epidemiological database who agreed to participate in the study. MAIN MEASURES: Beck Depression Inventory, clinical interview. RESULTS: The epidemiological database consisted of 59 patients with clinically confirmed diagnosis of hereditary spastic paraplegia. Forty-eight of these consented to participate in the study. The Beck Depression Inventory score was higher than cut-off point in 58% (28/48) and lower in 42% (20/48). Of the study group, 44% (21/48) had mild, 13% (6/48) moderate and one person revealed severe depression. There was a statistically significant correlation between Beck Depression Inventory score and level of mobility; no other significant correlations with other measures were detected. Of the participants, 54% (26/48) had subjective complaints about depression and answered 'Yes' to the single-item interview 'Are you depressed?'. The sensitivity of the one-item interview in the hereditary spastic paraplegia group was 75% and specificity 75%. CONCLUSIONS: Our results show that mild depression is prevalent among people with hereditary spastic paraplegia. Although the single question may be helpful, it cannot be relied upon entirely when assessing a person for depression.

Clean intermittent self-catheterization in persons with multiple sclerosis: the influence of cognitive dysfunction.

BACKGROUND: Bladder problems are very common in persons with multiple sclerosis (PwMS). OBJECTIVE: The aim of this study was to investigate the ability of PwMS to learn clean intermittent self-catheterization (CISC). METHODS: The physical disability of 23 PwMS was evaluated with the Expanded Disability Status Scale (EDSS), and cognitive status was evaluated with the Brief Repeatable Battery of Neuropsychological Tests (BRB-N). CISC was taught by the same continence advisor who was blinded to the cognitive test results. The ability to learn CISC was evaluated immediately after sessions and 3 months later. Twenty-three consecutive PwMS participated in the study. RESULTS: In all, 87% (20/23) of the PwMS successfully finished CISC training. The number of lessons needed to acquire CISC skills differed significantly depending on the EDSS (Spearman r=0.682, P=0.0003), but the total cognitive decline subscore did not influence the ability to learn CISC. Only 13% (3/23) of the PwMS failed to learn CISC. The ability to learn CISC depended on the number of lessons needed to acquire CISC (r=-0.499, P=0.0313) and the EDSS score (r=-0.433, P=0.0390) but not on the course of the disease (r=0.125, P=0.5696) or on cognitive decline (r=-0.311, P=0.1480). After 3 months of follow-up, 30% (6/20) of the PwMS had ceased performing CISC. A follow-up indicated no statistically significant correlations among any of the subscores of the cognitive test battery, the EDSS score, the course of the disease, and the time required to learn CISC and effective bladder management. CONCLUSIONS: Our study thus confirmed that most (87%) PwMS were able to learn CISC in spite of cognitive dysfunction and therefore to improve their quality of life.

One question as a screening instrument for depression in people with multiple sclerosis.

OBJECTIVE: To evaluate how effectively one question 'Are you depressed?' works as a screening tool for depression in people with multiple sclerosis. DESIGN: The results from a single question were compared with formal clinical diagnosis and the classification from a standard questionnaire. SETTING: Estonian Multiple Sclerosis Centre, from October 2001 to April 2002. SUBJECTS: One hundred and thirty-four consecutive inpatients with multiple sclerosis. INTERVENTION: During two weeks of inpatient stay the mood disorder was analysed. On the basis of clinical interview and Beck Depression Inventory the diagnosis of depression was confirmed. MAIN MEASURES: Beck Depression Inventory and structured clinical interview. RESULTS: Fifty-seven per cent (77/134) of people with multiple sclerosis answered 'Yes' to the question 'Are you depressed?'. The diagnosis of depression was confirmed in 94% (72/77) of people with multiple sclerosis and not confirmed in 6% (5/77). Hence, the screening test sensitivity was 91%. Forty-three per cent (57/134) answered 'No'; 70% (40/57) did not have depression. In this case the sensitivity was 54%. In this group 30% (17/57) were actually depressed according to tests and clinical impression. The age, sex, duration of disease, cognitive abilities and physical disability did not influence consistency of the answers with test results and clinical opinion. CONCLUSIONS: One-question interview is a useful tool for screening for depression in people with multiple sclerosis as it confirms existing depression (sensitivity 91%), but the results should be treated with caution if the person denies mood problems.

Conservative bladder management in advanced multiple sclerosis.

Anticholinergics and intermittent catheterization are the cornerstones of bladder management in early multiple sclerosis (MS). In advanced MS however, bladder management is based more on tradition than on evidence. Nurses seem to deal with catheter problems and chronic incontinence. Despite the abundant use of indwelling catheters, there is a lack for guidelines on catheter-induced problems. The psychosexual and social impact of bladder problems in advanced MS is often neglected. The international multidisciplinary special interest group on sexual, urological and bowel dysfunction in MS (SUBDIMS) as a special interest group of the Rehabilitation in Multiple Sclerosis (RIMS) was confronted with a high variability in practice and a lack of guidelines. A literature review was prepared during three multidisciplinary expert meetings. This review will be the basis of further initiatives to improve the urological treatment of patients with advanced MS.

Decreased expression of phospholamban is not associated with lower beta-adrenergic activation in rat atria.

The aim of the study was to find out whether low phospholamban level in atria as compared with ventricles is associated with differences in sarcoplasmic reticular Ca2+-uptake and contractile performance. Relationship between phospholamban and beta-adrenergic stimulation in rat left atria and papillary muscles were examined by means of contractile measurements, sarcoplasmic reticular oxalate-supported Ca2+-uptake, and Western blotting of phosphorylated phospholamban. Phosphoprotein determination after beta-adrenergic stimulation demonstrated that the levels of Ser16 and Thr17 phosphorylated phospholamban in atria remained at about one-third of that in ventricles. However, comparison of sarcoplasmic reticular Ca2+-uptake in control and isoproterenol perfused preparations demonstrated that the effect of beta-adrenergic stimulation on sarcoplasmic reticular Ca2+-uptake was stronger in atrial preparations. Moreover, atria responded to isoproterenol with much larger increases in developed tension, contractility and relaxation rates than papillary muscles. Thus, despite lower level of phospholamban, the beta-adrenergic activation of sarcoplasmic reticular Ca2+-uptake and contractile indices are higher in atria.

Lack of dystrophin is associated with altered integration of the mitochondria and ATPases in slow-twitch muscle cells of MDX mice.

The potential role of dystrophin-mediated control of systems integrating mitochondria with ATPases was assessed in muscle cells. Mitochondrial distribution and function in skinned cardiac and skeletal muscle fibers from dystrophin-deficient (MDX) and wild-type mice were compared. Laser confocal microscopy revealed disorganized mitochondrial arrays in m. gastrocnemius in MDX mice, whereas the other muscles appeared normal in this group. Irrespective of muscle type, the absence of dystrophin had no effect on the maximal capacity of oxidative phosphorylation, nor on coupling between oxidation and phosphorylation. However, in the myocardium and m. soleus, the coupling of mitochondrial creatine kinase to adenine nucleotide translocase was attenuated as evidenced by the decreased effect of creatine on the Km for ADP in the reactions of oxidative phosphorylation. In m. soleus, a low Km for ADP compared to the wild-type counterpart was found, which implies increased permeability for that nucleotide across the mitochondrial outer membrane. In normal cardiac fibers 35% of the ADP flux generated by ATPases was not accessible to the external pyruvate kinase-phosphoenolpyruvate system, which suggests the compartmentalized (direct) channeling of that fraction of ADP to mitochondria. Compared to control, the direct ADP transfer was increased in MDX ventricles. In conclusion, our data indicate that in slow-twitch muscle cells, the absence of dystrophin is associated with the rearrangement of the intracellular energy and feedback signal transfer systems between mitochondria and ATPases. As the mechanisms mediated by creatine kinases become ineffective, the role of diffusion of adenine nucleotides increases due to the higher permeability of the mitochondrial outer membrane for ADP and enhanced compartmentalization of ADP flux.

Intracellular energetic units in red muscle cells.

The kinetics of regulation of mitochondrial respiration by endogenous and exogenous ADP in muscle cells in situ was studied in skinned cardiac and skeletal muscle fibres. Endogenous ADP production was initiated by addition of MgATP; under these conditions the respiration rate and ADP concentration in the medium were dependent on the calcium concentration, and 70-80% of maximal rate of respiration was achieved at ADP concentration below 20 microM in the medium. In contrast, when exogenous ADP was added, maximal respiration rate was observed only at millimolar concentrations. An exogenous ADP-consuming system consisting of pyruvate kinase (PK; 20-40 units/ml) and phosphoenolpyruvate (PEP; 5 mM), totally suppressed respiration activated by exogenous ADP, but the respiration maintained by endogenous ADP was not suppressed by more than 20-40%. Creatine (20 mM) further activated respiration in the presence of ATP and PK+PEP. Short treatment with trypsin (50-500 nM for 5 min) decreased the apparent K(m) for exogenous ADP from 300-350 microM to 50-60 microM, increased inhibition of respiration by PK+PEP system up to 70-80%, with no changes in MgATPase activity and maximal respiration rates. Electron-microscopic observations showed detachment of mitochondria and disordering of the regular structure of the sarcomere after trypsin treatment. Two-dimensional electrophoresis revealed a group of at least seven low-molecular-mass proteins in cardiac skinned fibres which were very sensitive to trypsin and not present in glycolytic fibres, which have low apparent K(m) for exogenous ADP. It is concluded that, in oxidative muscle cells, mitochondria are incorporated into functional complexes ('intracellular energetic units') with adjacent ADP-producing systems in myofibrils and in sarcoplasmic reticulum, probably due to specific interaction with cytoskeletal elements responsible for mitochondrial distribution in the cell. It is suggested that these complexes represent the basic pattern of organization of muscle-cell energy metabolism.

A questionnaire assessment of unmet needs for rehabilitation services and resources for people with multiple sclerosis: results of a pilot survey in five European countries. Needs Task group of MARCH (Multiple Sclerosis and Rehabilitation, Care and Health Services Research in Europe).

OBJECTIVE: To develop an international services and needs assessment instrument (SUN) for people with multiple sclerosis and their carers and to pilot this in different countries of the European Community. DESIGN: Interview study of people with multiple sclerosis, their carers and nominated key professionals examining the unmet needs of patients and carers. SETTING: Belgium, Estonia, Greece, Italy and the United Kingdom. MAIN OUTCOME MEASURES: Needs assessment questionnaire. RESULTS: The study comprised 137 people with multiple sclerosis, 125 carers and 111 professionals. Patients reported on average 2.9 unmet needs for themselves; their carers and professionals reported on average 2.4. Needs were categorized into seven broad categories. Due to difficulties experienced by the local researchers in distinguishing between needs and objectives a large proportion of needs had to be assigned to the 'other' category. CONCLUSIONS: The SUN is a valuable and practicable tool for the identification of unmet needs for people with multiple sclerosis and their carers. Formal validation and reliability testing of the different language versions is recommended.

Personality as a predictor of coping efforts in patients with multiple sclerosis.

The aim of the study was to explore personality traits as predictors of coping with disease-related distress in patients with multiple sclerosis (MS). All patients with clinically definite MS in a city with a population of approximately 100000 were asked to complete the NEO Personality Inventory and a multidimensional coping inventory (COPE). There was an 83% response rate yielding 49 patients for the study population and 49 controls, matched for age, gender and educational level to the MS-patients, were used as comparison. Only Neuroticism correlated significantly with emotion-focused coping in both groups. Extraversion and Openness to Experience were linked to task-oriented coping strategies in normal controls but not in the MS-group. Agreeableness was associated with avoidance-oriented coping strategies only in the MS-group. Thus, the relation of certain personality characteristics to the choice of strategies for coping with the disease-related distress appear to differ from coping with stressful problems in everyday life. As dispositional characteristics may interfere with adaptive coping responses, analysis of personality traits and coping strategies could contribute while attempting to relieve the consequences of chronic disease on everyday life.

The risk of motor neurone disease and multiple sclerosis is different in Estonians and Russians. Data from South Estonia.

Epidemiological studies were performed in South Estonia to establish the prevalence rate of multiple sclerosis (MS) and motor neurone disease (MND). The case finding method included information from the hospital records of the central hospital in the region-the University Hospital (for MS from 1942 to 1989), from all neurologists in the region, from the Estonian MS Society and Association of Muscular Disorders, and from nursing homes in the region. The prevalence day was 31 December 1989. MND incidence was established for the period of 1986-1995. The results demonstrated high prevalence rates of MS among native Estonians (55.3 per 100 000), somewhat lower prevalence among native-born representatives of other nationalities (43.6 per 100 000) and the lowest prevalence rate of MS among non-Estonian immigrants (26.6 per 100 000). The differences were not statistically significant. The results for MND demonstrated the opposite pattern. The mean annual incidence rate of MND for 10 years was statistically significantly higher among people of other nationalities (2.5 per 100 000) and Russians (2.6 per 100 000), and lower in native-born Estonians (1.1 per 100 000). No differences in health care or clinical picture were established. The reasons for the demonstrated differences in MND incidence remain unclear.

Mechanisms of thyroid hormone control over sensitivity and maximal contractile responsiveness to beta-adrenergic agonists in atria.

This paper discusses the mechanisms of two basic effects of thyroid hormones on atrial responses to beta-adrenergic agonists, i.e. increased inotropic sensitivity and decreased maximal contractile responsiveness. The increased sensitivity of atria to beta-adrenergic agonists under thyroid hormones appears to be related to increases in beta-adrenoceptor density and Gs/Gi protein ratio, leading to activation of Gs-mediated pathway, but suppression of Gi-mediated pathway of adenylate cyclase regulation. Therefore, the i/c concentrations of cAMP and corresponding inotropic responses achieve their maximums at lower doses of beta-adrenergic agonist. Thyroid hormones also decrease the expression of phospholamban, but increase the expression of sarcoplasmic reticulum Ca2+-pump. As a result, the basal activity of sarcoplasmic reticulum Ca2+-pump increases, but its beta-adrenergic activation through phosphorylation of phospholamban decreases. It is suggested that these changes are causal for decreased maximal inotropic and lusitropic responses of atria to beta-adrenergic agonists.

Motor neurone disease in South Estonia. Diagnosis and incidence rate.

The current study evaluated the diagnostic standards of MND and epidemiological markers of MND in Estonia. A total of 108 patients were referred to the University Hospital from 1986 to 1995 with the first suggested diagnosis or final diagnosis of amyotrophic syndrome, amyotrophic lateral sclerosis (ALS), progressive bulbar paralysis (PBP) or progressive muscular atrophy (PMA). In addition neurologists of the region and the National Society of Neuromuscular disorders were contacted. Some 94 patients satisfied the diagnostic criteria. The annual incidence rate in South Estonia and in the city of Tartu ranged from 0.5 to 2.8 per 100,000. The mean annual incidence rate in Tartu is 1.98 and in South Estonia in general 1.3. The highest incidence rate was 8.3 for men in the age group 60 to 64 years and 7.49 in the age group 70-74; among female patients the highest incidence rate -4.6 was in the age group from 65 to 69.

Thyroid hormones differentially affect sarcoplasmic reticulum function in rat atria and ventricles.

The present study was undertaken to compare the effects of hypothyroidism and hyperthyroidism on sarcoplasmic reticulum (SR) Ca(2+)-pump activity, together with assessment of the functional role of SR in providing activator Ca2+ under these altered thyroid states. In response to a shift from hypothyroid to hyperthyroid state, a 10 fold and 2 fold increase in SR Ca(2+)-pump activity in atria and ventricles, respectively, were observed. This was associated with the 8-9 fold increases in atrial contractility (+dT/dt) and relaxation (-dT/dt), but only with a 3-4 fold increase in their ventricular counterparts. Also, the recirculation fraction of activator Ca2+ (RFA) increased to a far greater extent in atria (4 fold) than in papillary muscles, and the relative increment in inhibition of developed tension by ryanodine became 3 times larger in atria than in papillary muscles. A positive force-frequency relationship (FFR) was observed in hypothyroid atria, whereas the hyperthyroid atria, hypothyroid and hyperthyroid papillary muscles showed a negative FFR. These results suggest the greater role of transsarcolemmal (SL) Ca2+ and smaller role of SR Ca2+ in activating contraction in hypothyroid atria compared to other preparations. Thyroid hormones decrease the contribution of SL and increase that of SR in providing activator Ca2+ to the greater extent in atria than in ventricles. This effect of thyroid hormones is based on larger stimulation of SR Ca(2+)-pump in atria compared to ventricles.

Sarcoplasmic reticulum function in determining atrioventricular contractile differences in rat heart.

The relationships between the contractile characteristics and the sarcoplasmic reticulum (SR) function of rat atrial and ventricular trabeculae were compared. The isometric developed tension (DT) and the rates of contraction (+ dT/dt) and relaxation (-dT/dt) normalized to cross-sectional area were 3.7, 2.2, and 1.8 times lower, respectively, in intact atrial strips compared with ventricular strips, whereas + dT/dt and -dT/dt (normalized to DT) were 2.3 and 2.8 times higher, respectively, in atria. Atria exhibited a maximal potentiation of DT after shorter rest periods than ventricles and a lower reversal for prolonged rest periods. Caffeine-induced tension transients in saponin-permeabilized fibers suggested that the Ca2+ concentration released in atrial myofibrils reached a lower maximum and decayed more slowly than in ventricular preparations. However, the tension-time integrals indicated an equivalent capacity of sequestrable Ca2+ in SR from both tissues. In atrial, as in ventricular myocardium, the SR Ca2+ uptake was more efficiently supported by ATP produced by the SR-bound MM form of creatine kinase (CK; MM-CK) than by externally added ATP, suggesting a tight functional coupling between the SR Ca2+ adenosinetriphosphatase (ATPase) and MM-CK. The maximal rate of oxalate-supported Ca2+ uptake was two times higher in atrial than in ventricular tissue homogenates. The SR Ca(2+)-ATPase 2a mRNA content normalized to 18S RNA was 38% higher in atria than in ventricles, whereas the amount of mRNA encoding the alpha-myosin heavy chain, calsequestrin, and the ryanodine receptor was similar in both tissues. Thus a lower amount of readily releasable Ca2+ together with a faster uptake rate may partly account for the shorter time course and lower tension development in intact atrial myocardium compared with ventricular myocardium.

Thyroid hormones increase the contractility but suppress the effects of beta-adrenergic agonist by decreasing phospholamban expression in rat atria.

OBJECTIVE: The aim of the present study was to characterize the relationships between the thyroid-hormone-dependent changes in sarcoplasmic reticulum (SR) Ca2+ handling and contractile performance in atria. METHODS: Hypothyroidism in rats was induced by adding 0.05% 6-n-propyl-2-thiouracil to their drinking water for 6 weeks. Hyperthyroidism was induced by daily subcutaneous injections of L-thyroxine (1 microgram/g body weight) to euthyroid rats for 1 week. Left atria from the hearts with different thyroid states were examined by means of contractile measurements, SR oxalate-supported Ca(2+)-uptake, and Western blot of SR proteins. RESULTS: The tissue level of SR Ca(2+)-pump protein decreased in hypothyroid (46 +/- 6%) atria, but remained unchanged in hyperthyroid (110 +/- 8%) atria as compared with euthyroid atria. Hypothyroidism was associated with increased phospholamban expression (141 +/- 25%), whereas it was drastically downregulated under hyperthyroidism (21 +/- 4%). The rate of SR Ca(2+)-uptake, measured in the presence of the protein kinase A inhibitor, H-89, was higher in hyperthyroid atria and lower in hypothyroid atria than in euthyroid atria (397 +/- 40, 55 +/- 6 and 194 +/- 17 nmol Ca2+/g protein/min, respectively). However, the stimulation of SR Ca(2+)-uptake by the catalytic subunit of protein kinase A was relatively weaker in hyperthyroid (130 +/- 20% over control level without catalytic subunit) and stronger in hypothyroid (640 +/- 60%) than in euthyroid atria (280 +/- 40%). The rates of inotropic contraction (+dT/dt) were higher in the hyperthyroid atria (133 +/- 10 mN/s), but lower in hypothyroid atria (15 +/- 3 mN/s) than in their euthyroid counterparts (95 +/- 13 mN/s). Inversely, hypothyroid atria responded to isoproterenol with much larger increases in contractility (883 +/- 164% over the control values for the same muscle before addition of isoproterenol) and hyperthyroid with smaller increases (25 +/- 9%) than euthyroid preparations (207 +/- 17%) CONCLUSIONS: Thyroid hormones increase the contractility, but decrease the inotropic response to isoproterenol through decreasing the phospholamban/SR Ca(2+)-pump ratio in rat atria.