Benzodiazepines and Cognitive Functioning in Older Adults. With Emphasis on Long-Term Use and Withdrawal

Benzodiazepines (BZD) and benzodiazepine related drugs (RD) are the most commonly used psychotropics among the aged. The use of other psychotropics taken concomitantly with BZD/ RD or their cognitive effects with BZD/RD have not been studied frequently. The aim of this academic thesis was to describe and analyse relationships between the use of BZD/RD alone or concomitantly with antipsychotics, antidepressants, opioids, antiepileptics, opioids and anticholinergics in the aged and their health. Especially, the relationships between long-term use of BZD/RD and cognitive decline were studied. Additionally, the effect of melatonin on BZD/RD withdrawal and the cognitive effects of BZD/RD withdrawal were studied. This study used multiple data sets: the first study (I) was based on clinical data containing aged patients (≥65 years; N=164) admitted to Pori City Hospital due to acute disease. The second data set (Studies II and III) was based on population-based data from the Lieto Study, a clinico-epidemiological longitudinal study carried out among the aged (≥65 years) in the municipality of Lieto. Follow-up data was formed by combining the cohort data collected in 1990-1991 (N=1283) and in 1998-1999 (N=1596) from those who participated in both cohorts (N=617). The third data set (Studies IV and V) was based on the Satauni Study’s data. This study was performed in the City of Pori in 2009-2010. In the RCT part of the Satauni Study, ninety-two long-term users of BZD/RD were withdrawn from their drugs using melatonin against placebo. The change of their cognitive abilities was measured during and after BZD/ RD withdrawal. BZD/RD use was related to worse cognitive and functional abilities, and their use may predict worse cognitive outcomes compared with BZD/RD non-users. Hypnotic use of BZD/RD could be withdrawn with psychosocial support in motivated participants, but melatonin did not improve the withdrawal results compared to those with placebo. Cognitive abilities in psychomotor tests did not show, or showed only modest, improvements for up to six months after BZD/RD withdrawal. This suggests that the cognitive effects of BZD/RD may be longlasting or permanent.

The Use of Nervous System Drugs and the Risk of Fractures in Old Adults

Hermostoon vaikuttavien lääkkeiden käyttö on yleistä iäkkäässä väestössä. Erityisen yleistä käyttö on pitkäaikaisessa laitoshoidossa asuvilla iäkkäillä. Hermostoon vaikuttavien lääkkeiden haittavaikutuksia on tutkittu paljon, ja useat hermostoon vaikuttavat lääkeaineryhmät on tunnistettu murtumien riskitekijöiksi. Aikaisemmin ei ole kuitenkaan tutkittu usean hermostoon vaikuttavan lääkkeen yhteiskäytön yhteyksiä murtuman riskiin 65 vuotta täyttäneillä. Väitöskirjatutkimuksessa havaittiin, että usean hermostoon vaikuttavan lääkeaineen yhtäaikainen käyttö oli hyvin yleistä Porin kaupunginsairaalan viidellä pitkäaikaisen laitoshoidon osastolla (n = 154) vuosien 2004 ja 2005 vaihteessa. Kolmasosa tutkituista käytti säännöllisesti kolmea tai useampaa hermostoon vaikuttavaa lääkettä samanaikaisesti. Kun huomioitiin myös tarvittaessa otettavat lääkkeet, vastaava luku oli 53 %. Tutkimuksessa havaittiin myös viitteitä lääkkeiden epäasianmukaisesta käytöstä, kun potilaiden käyttämiä lääkkeitä verrattiin heidän kognitiiviseen ja fyysiseen suorituskyynsä sekä asetettuihin diagnooseihin. Liedon kunnassa 1990-luvulla toteutettuun väestöpohjaiseen Liedon Iäkkäät -seurantatutkimukseen osallistui 1177 lietolaista 65 vuotta täyttänyttä. Lääkitystietoja sekä seuranta-aikana tapahtuneita murtumia analysoimalla havaittiin, että kahden tai useamman bentsodiatsepiinin sekä kahden tai useamman psykoosilääkkeen käyttö oli yhteydessä murtuman riskiin 65 vuotta täyttäneillä miehillä. Opioidin ja psykoosilääkkeen yhteiskäyttö sekä opioidin ja bentsodiatsepiinin yhteiskäyttö oli yhteydessä iäkkäiden miesten murtuman riskiin. Naisilla vastaavia tilastollisesti merkitseviä yhteyksiä ei havaittu. Väitöskirjatutkimuksen uusin osa-aineisto perustui Porissa vuosina 2009–2010 toteutetun Satauni-tutkimuksen aineistoon. Tutkimuksessa osoitettiin 89 potilaan aineistossa, että hallittu, yhden kuukauden aikana lääkärin ja hoitajan tuella toteutettu bentsodiatsepiinivieroitus paransi merkitsevästi 55 vuotta täyttäneiden naisten käden puristusvoimaa kuuden kuukauden seuranta-aikana. Vastaavaa yhteyttä ei havaittu miehillä. Bentsodiatsepiinivieroituksella ei ollut yhteyttä osallistujien tasapainotestin tulosten paranemiseen kuuden kuukauden seurantaaikana. Murtumilla on vakavia seurauksia sekä yksilötasolla että yhteiskunnallisesti iäkkäässä väestössä. Murtumien ehkäisy on hyvin tärkeää. Siinä tulee kiinnittää huomiota potilaan käyttämään lääkitykseen ja arvioida erityisesti usean hermostoon vaikuttavan lääkkeen yhteiskäytön tarpeellisuutta.

Heart rate variability in young adults - Reference values and associations with cardiometabolic risk factors and vascular properties. The Cardiovascular Risk in Young Finns Study.

Background: The function of the autonomic nervous system (ANS) can be evaluated with heart rate variability (HRV). Decreased HRV is associated with aging, the male sex, increased heart rate, and overall increased cardiometabolic risk. It has been hypothesized that early atherosclerotic vascular changes and ANS function are related. Aims: The aims were to assess reference values on HRV in young adults, and examine associations with HRV and cardiometabolic risk factors and metabolic syndrome (MetS) and to study relations between HRV and ultrasonographically measured vascular properties. Participants and methods: The present thesis is part of the Cardiovascular Risk in Young Finns Study. The thesis is based on the follow-up study in 2001, when the study individuals were 24-39 years of age. HRV data were available on 1 956 individuals. Results: HRV was inversely associated with age and heart rate (for all p<0.001). Highfrequency HRV (HF) was higher, and low-frequency HRV (LF) lower in women than men (p<0.0001 for both). MetS was associated with 11% decreased HF and 12% increased LF/HF-ratio in women, and 8% decreased HF and 4% increased LF/HF-ratio in men. Carotid artery distensibility was independently associated with HF and total HRV (for both p<0.05). Conclusions: The reference values in young adults were generated. Decreased HRV was associated with age, the male sex and increased heart rate. Women had higher HF and lower LF variability than men. MetS was related to decrease in HRV. The observed associations between carotid elasticity and HRV, supports the hypothesis that reduction in carotid elasticity may lead to decrease in autonomic cardiac control.

Levels of C-reactive protein in serum samples from healthy children and adults in São Paulo, Brazil

C-reactive protein (CRP) was measured by ELISA in the sera of 165 healthy blood donors and 125 normal children 1 to 14 years old. The serum levels of blood donors ranged from 0.05 to 57.6 mg/l with median and mean values of 1.8 mg/l and 4.86 mg/l, respectively. CRP levels ranged from 0.02 to 14.4 mg/l in the children's sera, the median being 0.45 mg/l and the mean 1.65 mg/l. No individual lacking CRP was detected. The high CRP levels observed in the present study suggest that the population of the State of São Paulo may usually be exposed to subacute infections and/or inflammation without presenting clinical symptoms

Serodiagnosis of Helicobacter pylori infection by Cobas Core ELISA in adults from Minas Gerais, Brazil

We evaluated the accuracy of a 2nd generation ELISA to detect Helicobacter pylori infection in adults from a developing country in view of variations in sensitivity and specificity reported for different populations. We studied 97 non-consecutive patients who underwent endoscopy for evaluation of dispeptic symptoms. The presence of H. pylori was determined in antral biopsy specimens by culture, by the preformed urease test and in carbolfuchsin-stained smears. Patients were considered to be H. pylori positive if at least two of the three tests presented a positive result or if the culture was positive, and negative if the three tests were negative. Sixty-five adults (31 with peptic ulcer) were H. pylori positive and 32 adults were H. pylori negative. Antibodies were detected by Cobas Core anti-H. pylori EIA in 62 of 65 H. pylori-positive adults and in none of the negative adults. The sensitivity, specificity and positive and negative predictive values of the test were 95.4, 100, 100 and 91.4%, respectively. The Cobas Core anti-H. pylori EIA presented high sensitivity and specificity when employed for a population in Brazil, permitting the use of the test both to confirm the clinical diagnosis and to perform epidemiologic surveys.

Familial predisposition to hypertension and the association between urinary sodium excretion and blood pressure in a population-based sample of young adults

The reasons for the inconsistent association between salt consumption and blood pressure levels observed in within-society surveys are not known. A total of 157 normotensive subjects aged 18 to 35 years, selected at random in a cross-sectional population-based survey, answered a structured questionnaire. They were classified as strongly predisposed to hypertension when two or more first-degree relatives had a diagnosis of hypertension. Anthropometric parameters were obtained and sitting blood pressure was determined with aneroid sphygmomanometers. Sodium and potassium excretion was measured by flame spectrophotometry in an overnight urine sample. A positive correlation between blood pressure and urinary sodium excretion was detected only in the group of individuals strongly predisposed to hypertension, both for systolic blood pressure (r = 0.51, P<0.01) and diastolic blood pressure (r = 0.50, P<0.01). In a covariance analysis, after controlling for age, skin color and body mass index, individuals strongly predisposed to hypertension who excreted amounts of sodium above the median of the entire sample had higher systolic and diastolic blood pressure than subjects classified into the remaining conditions. The influence of familial predisposition to hypertension on the association between salt intake and blood pressure may be an additional explanation for the weak association between urinary sodium excretion and blood pressure observed in within-population studies, since it can influence the association between salt consumption and blood pressure in some but not all inhabitants.

Immune and hormonal activity in adults suffering from depression

An association between depression and altered immune and hormonal systems has been suggested by the results of many studies. In the present study we carried out immune and hormonal measurements in 40 non-medicated, ambulatory adult patients with depression determined by CID-10 criteria and compared with 34 healthy nondepressed subjects. The severity of the condition was determined with the Hamilton Depression Rating Scale. Of 40 depressed patients, 31 had very severe and 9 severe or moderate depression, 29 (72.5%) were females and 11 (27.5%) were males (2.6:1 ratio). The results revealed a significant reduction of albumin and elevation of alpha-1, alpha-2 and ß-globulins, and soluble IL-2 receptor in patients with depression compared to the values obtained for nondepressed subjects (P<0.05). The decrease lymphocyte proliferation in response to a mitogen was significantly lower in severely or moderately depressed patients when compared to control (P<0.05). These data confirm the immunological disturbance of acute phase proteins and cellular immune response in patients with depression. Other results may be explained by a variety of interacting factors such as number of patients, age, sex, and the nature, severity and/or duration of depression. Thus, the data obtained should be interpreted with caution and the precise clinical relevance of these findings requires further investigation.

Malnutrition during lactation as a metabolic imprinting factor inducing the feeding pattern of offspring rats when adults: The role of insulin and leptin

The aim of the present study was to determine the impact of malnutrition during early postnatal life and the feeding pattern of rat offspring when adults (2 months and 1 year old). In comparison with rats normally fed during lactation, we observed that adult offspring displayed a faster process of feeding reduction when a protein-free diet was offered. In addition, we studied the concentration of insulin and leptin in the lactating pups (10 days) and when these offspring became adult after the onset of a new feeding pattern induced by the protein-free diet. When the diet was changed at 60 days, the offspring malnourished during lactation displayed, after 3 days, a food intake reduction around 41.4 vs 14.2% of the control group. At 10 days of life, plasma leptin and insulin were higher in the malnourished pups when compared with normally fed rats (leptin: 4.6 ± 0.8 vs 2.25 ng/ml; insulin: 0.73 ± 0.12 vs 0.22 ± 0.03 ng/ml) while at 60 days they showed reduction of both hormones when compared with the control group (leptin: 1.03 ± 0.25 vs 1.43 ± 0.5 ng/ml; insulin: 0.54 ± 0.3 vs 0.61 ± 0.4 ng/ml). Despite the different food intake reductions, the malnourished and control rats displayed a similar reduction of insulin and leptin after 3 days of protein-free diet (from 60 to 63 days). The data suggest that the high concentration of insulin and leptin found at 10 days in the malnourished pups may elicit a sustained long-term and unique feeding pattern.

p53 as a prognostic factor in adrenocortical tumors of adults and children

Mutations of the tumor suppressor gene p53 have been considered to be important determinants in several kinds of human cancer. Accumulation of p53 protein has been reported to correlate with more aggressive clinical behavior in some neoplasms. The role of p53 expression in adrenal cortical tumors (ACT) has not been elucidated but some studies have suggested its correlation with malignant behavior. Our objective was to determine if there is a correlation between the expression of immunoreactive p53 and the biological behavior of ACT. Fifty-seven ACT (21 from children and 36 from adults) were evaluated for p53 expression by immunohistochemistry in formalin-fixed paraffin-embedded tissue and analyzed in terms of outcome. The p53 parameter was utilized semiquantitatively. Tumors were classified as p53 negative when no positivity was observed, or when only few cells showed weak positivity (0/1+) and scored as p53 positive when there was a diffuse and strong nuclear positivity (2+/3+). In children, p53 positivity was associated with clinically malignant ACT and p53 negativity was associated with clinically benign ACT (P = 0.026). In adults' ACT, p53 positivity had an effect on disease-free survival (P<0.001) and also correlated with Weiss score, with a cutoff = 4 (P = 0.04). p53 expression was related to the clinical behavior of ACT in both children and adults and these findings seem to support a role for p53 in ACT progression.

Effects of physical activity and fitness on the psychological wellbeing of young men and working adults: associations with stress, mental resources, overweight and workability

Background: A positive association has been suggested to exist between physical activity and psychological wellbeing. However, the association between physical fitness, especially muscle fitness and psychological wellbeing, has not yet been fully elucidated. Aims: The objective of the present thesis was to assess the relationship between physical activity and physical fitness with stress symptoms, mental resources and workability among young men and working adults. Subjects and methods: Volunteers of young men (n=831, mean age 25-y (±4.0)), underwent a cardiorespiratory (CRF) and muscle fitness (MFI) test and completed leisure time physical activity (LTPA) and Occupational Stress Questionnaires (OSQ). The participants were divided into tertiles according to LTPA, CRF and MFI. A 12-month exercise intervention evaluated 371 working adults (exercise group, n=338, mean age 45-y (±8.8)); control group, n=33, mean age 41-y (±6.9)).The exercise group underwent a 12-month exercise program followed by a 12-month follow-up. The OSQ, Workability Index (WAI) and CRF were evaluated at baseline and at 4, 8, 12 and 24 months. Results: Physically inactive subjects reported more stress and less available mental resources than the subjects who reported high physical activity levels. Improved physical fitness was associated with less stress and more mental resources among normal weight men, but not in overweight men. After a 12-month exercise intervention, employees in the exercise group increased their physical activity, improved workability, decreased stress symptoms and improved their physical fitness and mental resources. After the follow-up year, workability and stress were improved compared to baseline. Conclusions: In this thesis, good physical fitness was associated with improved psychological wellbeing among young men and working adults.

Determinants of Bone Strength and Predictors of Hip Fracture among Finnish Adults. Results from the Health 2000 Survey and the Mini-Finland Health Survey

The objective of this thesis was to identify the determinants of bone strength and predictors of hip fracture in representative samples of Finnish adults. A secondary objective was to construct a simple multifactorial model for hip fracture prediction over a 10-year follow-up period. The study was based on the Health 2000 Survey conducted during 2000 to 2001 (men and women aged 30 years or over, n=6 035) and the Mini-Finland Health Survey conducted during 1978 to 1980 (women aged 45 years or over, n=2 039). Study subjects participated in health interviews and comprehensive health examination. In the Health 2000 Survey, bone strength was assessed by means of calcaneal quantitative ultrasound (QUS). The follow-up information about hip fractures was drawn from the National Hospital Discharge Register. In this study, age, weight, height, serum 25-hydroxyvitamin D (S-25(OH)D), physical activity, smoking and alcohol consumption as well as menopause and eventual HRT in women were found to be associated with calcaneal broadband ultrasound attenuation (BUA) and speed of sound (SOS). Parity was associated with a decreased risk of hip fracture in postmenopausal women. Age, height, weight or waist circumference, quantitative ultrasound index (QUI), S-25(OH)D and fall-related factors, such as maximal walking speed, Parkinson’s disease, and the number of prescribed CNS active medication were significant independent predictors of hip fracture. At the population level, the incremental value of QUS appeared to be minor in hip fracture prediction when the fall-related risk factors were taken into account. A simple multifactorial model for hip fracture prediction presented in this study was based on readily available factors (age, gender, height, waist circumference, and fallrelated factors). Prospective studies are needed to test this model in patient-based study populations.

Typing of Pseudomonas aeruginosa from hospitalized patients: a comparison of susceptibility and biochemical profiles with genotype

Typing techniques are essential for understanding hospital epidemiology, permitting the elucidation of the source of infection and routes of bacterial transmission. Although DNA-based techniques are the "gold standard" for the epidemiological study of Pseudomonas aeruginosa, antibiotic profiles and biochemical results are used because they are easy to perform and to interpret and relatively inexpensive. Antibiotypes (susceptibility profiles) and biotypes (biochemical profiles) were compared to genotypes established by DNA restriction enzyme analysis in 81 clinical isolates of P. aeruginosa from three hospitals in Porto Alegre, Brazil. The epidemiological relationship among patients was also evaluated. Susceptibility and restriction profiles were discrepant in more than 50% of the cases, and many antibiotypes were observed among isolates from the same genotype. Furthermore, susceptibility profiles did not allow the distinction of isolates from unrelated genotypes. Since a large number of isolates (63%) yielded the same biochemical results, only 10 biotypes were detected, showing that this typing method has a low discriminatory power. On the other hand, DNA restriction enzyme typing allowed us to establish 71 distinct types. Epidemiological data about the relation among P. aeruginosa isolates were not conclusive. The results of the present study indicate that the only method that can establish a clonal relation is DNA restriction enzyme typing, whereas the other methods may cause misleading interpretations and are inadequate to guide proper infection control measures.

Comparison of angular frequency contrast sensitivity in young and older adults

The aim of the present study was to measure contrast sensitivity curves for angular frequencies in the range between 2 and 96 cycles/360º in older human adult volunteers and to compare these measurements with the more usual contrast sensitivity functions for sine-wave gratings. All subjects were free of identifiable ocular disease and had normal acuity. We measured the contrast thresholds for young adults (N = 6; age range, 20-26 years) and older adults (N = 6; age range, 60-67 years) using the psychophysical forced-choice method. In this paradigm the volunteers had to choose the stimulus containing a test frequency at low contrast (e.g., either a sine-wave grating or an angular frequency stimulus), or another neutral stimulus at mean luminance (without any contrast). Older adults presented a loss in contrast sensitivity at high and medium angular frequencies compared to the young adults (i.e., from 8 to 96 cycles/360º). Contrary to expectation, contrast sensitivity at low angular frequencies, i.e., 2 and 4 cycles/360º, was better for the older group than for the younger group. On the other hand, contrast sensitivity for sine-wave gratings at 3 and 4 cpd was higher for young adults as expected. These results suggest age-related changes in the contrast sensitivity function for angular frequencies.

Age-related changes in radiation-induced micronuclei among healthy adults

The aim of the present study was to establish the extent of in vitro radioresponse of lymphocytes among 62 healthy adults of both genders and to estimate the distribution of baseline micronuclei and radiosensitivity among individuals of the study population using the cytochalasin block micronucleus test. A younger study group consisted of 10 males (mean age, 22.4 years; range, 21-27) and 12 females (mean age, 24.8 years; range, 20-29), whereas an older study group consisted of 18 males (mean age, 35.1 years; range, 30-44) and 22 females (mean age, 38.5 years; range, 30-48). For evaluation of radiosensitivity blood samples were irradiated in vitro using 60Co g-ray source. The radiation dose employed was 2 Gy, the dose rate 0.45 Gy/min. The study revealed a significant gender effect on baseline micronuclei favoring females (Z = 3.25, P < 0.001), while yields of radiation-induced micronuclei did not differ significantly (Z = 0.56, P < 0.56) between genders. The distribution of baseline micronuclei among the individuals tested followed Poisson distribution in both study groups and in both genders, whereas the distribution of radiosensitivity among individuals of the older study group did not fulfill Poisson expectations (Kolmogorov-Smirnof test, P < 0.01). In contrast to a nonsignificant difference in radiosensitivity between males and females of the same age group (Z = 1.97, P < 0.56), a statistically significant difference in radiosensitivity between younger and older group for both genders was found (Z = 3.03, P < 0.03). Since the individuals tested were healthy, the observed variability in radiation response is considered to be an early effect of ageing.

Mesopic radial frequency contrast sensitivity function for young and older adults

The objective of the present study was to determine contrast sensitivity curves of concentric circular patterns with radial frequencies of 0.25, 0.5, 1.0, 2.0, and 4.0 cycles per degree in young and older adult volunteers. These parameters were also compared with sensitivity contrasts for sine-wave gratings. All participants had normal acuity vision and were free of identifiable ocular illness. Contrast sensitivity was measured in 6 young adults aged 19 to 23 years and 6 older adults aged 60 to 69 years using the psychophysical forced-choice method. In this paradigm the volunteers had to decide which of two stimuli contained the above radial frequencies at low contrast levels. The other neutral stimulus was gray with homogeneous luminance. We detected a decline in contrast sensitivity for older adults at all radial frequencies compared to young adults. Also, contrast sensitivity for sine-wave gratings at all measured frequencies was better, as predicted, for all young adults. Maximum sensitivities in the radial frequency contrast sensitivity function and contrast sensitivity function occurred at 0.25 and 0.5 cycles per degree, respectively, for both young and older adults. These results suggest age-related changes in the contrast sensitivity function for concentric symmetrical stimuli.