Spatial memory deficits in mice induced by chemotherapeutic agents are prevented by acetylcholinesterase inhibitors.

PURPOSE: These studies determined whether the acetylcholinesterase inhibitors, donepezil and galantamine, both of which are approved for the treatment of cognitive deficits in Alzheimer's disease, can prevent or reverse spatial memory deficits in mice induced by cyclophosphamide and doxorubicin, cytotoxic agents commonly used to treat breast cancer. METHODS: Female BALB/C mice were trained in the Morris water maze to identify the location of a submerged platform, and, following baseline assessment of spatial memory, received injections of cyclophosphamide and doxorubicin once per week for 4 weeks to impair spatial memory. Saline or acetylcholinesterase inhibitors were administered daily either concurrent with the chemotherapy injections (prevention) or beginning 1 week following the final chemotherapy injections (reversal), and spatial memory was assessed weekly. RESULTS: Spatial memory declined during and following weekly injections of cyclophosphamide and doxorubicin, and was unaltered when the acetylcholinesterase inhibitors were administered following the manifestation of chemotherapy-induced deficits. In contrast, spatial memory of mice receiving the acetylcholinesterase inhibitors concurrent with chemotherapy did not differ from that at baseline. CONCLUSIONS: Results indicate that chemotherapy-induced spatial memory deficits in mice can be prevented, but not reversed by the use of acetylcholinesterase inhibitors concomitant with chemotherapy, suggesting that these agents should be investigated further for the prevention of chemobrain.

3-Acetylpyridine neurotoxicity in mice.

3-acetylpyridine (3-AP) is a metabolic antagonist used in research to decrease levels of nicotinamide (niacinamide) in laboratory animals. The administration of 3-AP followed by nicotinamide to rats leads to the selective destruction of neurons in the medial inferior olive, resulting in a loss of climbing fibers innervating cerebellar Purkinje cells and a consequent ataxia manifest by alterations in both balance and gait. Although 3-AP has also been administered to mice to destroy neurons in the inferior olive, there are limited studies quantifying the consequent effects on balance, and no studies on gait. Further, the relationship between 3-AP-induced lesions of the inferior olive and behavior has not been elucidated. Because 3-AP continues to be used for experiments involving mice, this study characterized the effects of this toxin on both balance and gait, and on the neuronal integrity of several brain regions involved in motor coordination. Results indicate that C57BL/6 mice are less sensitive to the neurotoxic effects of 3-AP than rats, and a dose more than 6.5 times that used for rats produces deficits in both balance and gait comparable to those in rats. This dose led to a significant (p<0.05) loss of NeuN(+) neurons in several subregions of the inferior olive including the rostral medial nucleus, dorsomedial cell column, ventrolateral protrusion, and cap of Kooy. Further, the number of NeuN(+) neurons in these subregions, with the exception of the dorsomedial cell column, was significantly (p<0.05) related to rotorod performance, implicating their involvement in this behavior.

Analysis of gait in rats with olivocerebellar lesions and ability of the nicotinic acetylcholine receptor agonist varenicline to attenuate impairments.

Studies have demonstrated that administration of the neuronal nicotinic receptor agonist varenicline to rats with olivocerebellar lesions attenuates balance deficits on a rotorod and balance beam, but the effects of this drug on gait deficits have not been investigated. To accomplish this, male Sprague-Dawley rats were trained to walk on a motorized treadmill at 25 and 35 cm/s and baseline performance determined; both temporal and spatial gait parameters were analyzed. A principal component analysis (PCA) was used to identify the key components of gait, and the cumulative gait index (CGI) was calculated, representing deviations from prototypical gait patterns. Subsequently, animals either remained as non-lesioned controls or received injections of 3-acetylpyridine (3-AP)/nicotinamide to destroy the climbing fibers innervating Purkinje cells. The gait of the non-lesioned group was assessed weekly to monitor changes in the normal population, while the gait of the lesioned group was assessed 1 week following 3-AP administration, and weekly following the daily administration of saline or varenicline (0.3, 1.0, or 3.0mg free base/kg) for 2 weeks. Non-lesioned animals exhibited a 60-70% increased CGI over time due to increases in temporal gait measures, whereas lesioned animals exhibited a nearly 3-fold increased CGI as a consequence of increases in spatial measures. Following 2 weeks of treatment with the highest dose of varenicline (3.0mg free base/kg), the swing duration of lesioned animals normalized, and stride duration, stride length and step angle in this population did not differ from the non-lesioned population. Thus, varenicline enabled animals to compensate for their impairments and rectify the timing of the gait cycle.

Gait analysis and the cumulative gait index (CGI): Translational tools to assess impairments exhibited by rats with olivocerebellar ataxia.

Deviations from 'normal' locomotion exhibited by humans and laboratory animals may be determined using automated systems that capture both temporal and spatial gait parameters. Although many measures generated by these systems are unrelated and independent, some may be related and dependent, representing redundant assessments of function. To investigate this possibility, a treadmill-based system was used to capture gait parameters from normal and ataxic rats, and a multivariate analysis was conducted to determine deviations from normal. Rats were trained on the treadmill at two speeds, and gait parameters were generated prior to and following lesions of the olivocerebellar pathway. Control (non-lesioned) animals exhibited stable hindlimb gait parameters across assessments at each speed. Lesioned animals exhibited alterations in multiple hindlimb gait parameters, characterized by significant increases in stride frequency, braking duration, stance width, step angle, and paw angle and decreases in stride, stance, swing and propulsion durations, stride length and paw area. A principal component analysis of initial hindlimb measures indicated three uncorrelated factors mediating performance, termed Rhythmicity, Thrust and Contact. Deviation in the performance of each animal from the group mean was determined for each factor and values summed to yield the cumulative gait index (CGI), a single value reflecting variation within the group. The CGI for lesioned animals increased 2.3-fold relative to unlesioned animals. This study characterizes gait alterations in laboratory rats rendered ataxic by destruction of the climbing fiber pathway innervating Purkinje cells and demonstrates that a single index can be used to describe overall gait impairments.

Neuronal nicotinic receptor agonists improve gait and balance in olivocerebellar ataxia.

Clinical studies have reported that the nicotinic receptor agonist varenicline improves balance and coordination in patients with several types of ataxia, but confirmation in an animal model has not been demonstrated. This study investigated whether varenicline and nicotine could attenuate the ataxia induced in rats following destruction of the olivocerebellar pathway by the neurotoxin 3-acetylpyridine (3-AP). The administration of 3-AP (70 mg/kg followed by 300 mg niacinamide/kg; i.p.) led to an 85% loss of inferior olivary neurons within one week without evidence of recovery, and was accompanied by a 72% decrease in rotorod activity, a 3-fold increase in the time to traverse a stationary beam, a 19% decrease in velocity and 31% decrease in distance moved in the open field, and alterations in gait parameters, with a 19% increase in hindpaw stride width. The daily administration of nicotine (0.33 mg free base/kg) for one week improved rotorod performance by 50% and normalized the increased hindpaw stride width, effects that were prevented by the daily preadministration of the nicotinic antagonist mecamylamine (0.8 mg free base/kg). Varenicline (1 and 3 mg free base/kg daily) also improved rotorod performance by approximately 50% following one week of administration, and although it did not alter the time to traverse the beam, it did improve the ability to maintain balance on the beam. Neither varenicline nor nicotine, at doses that improved balance, affected impaired locomotor activity in the open field. Results provide evidence that nicotinic agonists are of benefit for alleviating some of the behavioral deficits in olivocerebellar ataxia and warrant further studies to elucidate the specific mechanism(s) involved.

Effect of preventive health screening on long-term primary health care utilization. A randomized controlled trial.

BACKGROUND: Regular preventive health screenings are a feature of primary health care in several countries. Studies of the effect of regular preventive health checks have reported different results regarding primary health care utilization. OBJECTIVE: To analyse the effect of preventive health screening and health discussions on contacts to general practice. METHODS: A randomized controlled trial with all GPs in the district of Ebeltoft, Denmark. All middle-aged residents registered with a GP in the district of Ebeltoft were included (n = 3464). A random sample of 2030 subjects was selected for invitation to participate in health screening or health screening and discussions. The remaining 1434 subjects were never contacted and served as an external control group. Main outcome measure was number of daytime consultations in general practice. RESULTS: The annual rate ratios for daytime consultations showed a very clear time trend (P < 0.0001) with a high rate of contacts among invited compared with non-invited subjects during the first year (P = 0.001) followed by a gradual decrease to a lower level after eight years (P = 0.037). The total rate ratio for daytime consultations was 1.01 (95% CI 0.93 to 1.10). CONCLUSION: We observed no differences between the invited group and the non-invited group in any type of contact to general practice when the entire follow-up period was considered. There was a significant trend in rate ratios for daytime consultations with an initial rise followed by a gradual decrease in rate ratios. More investigations are needed to confirm and explore reasons for this trend.

Markers of fetal growth and serum levels of insulin-like growth factor (IGF) I, -II and IGF binding protein 3 in adults.

Fetal growth has been linked with increased risk of cancer and cardiovascular disease later in life. The insulin-like growth factor (IGF) axis has recently been proposed as a predictor of risk of subsequent cancer and cardiovascular disease. However, only few data are available on the possible association between fetal growth and levels of IGFs later in life. We examined the association between markers of fetal growth, i.e. birth weight, birth length and Ponderal Index, from birth records and serum IGF-I, IGF-II, and IGF binding protein 3 (IGFBP-3) levels in 545 middle-aged Danish men and women. We fitted separate multivariate models including birth weight, birth length, Ponderal Index and serum IGF-I, IGF-II, and IGFBP-3, respectively. After adjustment for age, alcohol intake, smoking, diabetes mellitus, systolic and diastolic blood pressure, serum total cholesterol and current height and weight, we found negative associations between birth weight and Ponderal Index, respectively, and serum IGF-II in men, i.e. the mean regression coefficients were -49.41 (95% CI: -87.06-11.77) (microg/l)/kg and -3.49 (95% CI: -6.73-0.25) (microg/l)/(kg/m3), respectively. Furthermore, in men birth weight was negatively associated with the (IGF-I + IGF-II)/IGFBP-3 and IGF-II/IGFBP-3 ratios, which are believed to be indicators of bioavailable IGF and IGF-II, respectively. However, no other associations were found in any of the models. Between 1 and 16% of the variance in serum IGF-I, IGF-II, and IGFBP-3, respectively, could be explained by the statistical models used in the analyses. We found very little support to the hypothesis of an association between fetal growth and the IGF axis throughout life.

Fetal growth and urinary albumin excretion among middle-aged Danes.

OBJECTIVE: Impaired fetal growth has been linked with cardiovascular disease and different cardiovascular risk factors. Few studies have examined the association between fetal growth and urinary albumin excretion, an important predictor of vascular disease in both diabetic and non-diabetic subjects. MATERIAL AND METHODS: We examined the association between markers of fetal growth, ie, birth weight, birth length and Ponderal Index, from birth records and urinary albumin excretion in 545 middle-aged men and women who had taken part in a population-based follow-up study in the municipality of Ebeltoft, Denmark. The outcome was the urinary albumin-creatinine ratio. RESULTS: Three men (1.1%) and 10 women (3.6%) had a albumin-creatinine ratio above 2.5/3.5 mg/mmol, which is considered abnormal and diagnostic of microalbuminuria. The strength of the associations between birth weight, birth length, Ponderal Index and albumin-creatinine ratio were fitted in separate multivariate models, but no associations were found in any model. CONCLUSIONS: Our study did not support the hypothesis of an association between fetal growth and adult albumin-creatinine ratio. Studies with larger numbers of microalbuminuric subjects are required in order to further clarify the relationship between fetal growth and later renal function.

The association between physical workload and low back pain clouded by the "healthy worker" effect: population-based cross-sectional and 5-year prospective questionnaire study.

STUDY DESIGN: A population-based cross-sectional and 5-year prospective questionnaire study. OBJECTIVE: To investigate self-reported physical workload as a risk factor for low back pain. SUMMARY OF BACKGROUND DATA: Both physical and psychosocial workplace factors are considered risk factors for low back pain. However, today no consensus has been reached regarding the exact role of these factors in the genesis of low back pain. METHODS: Questionnaire data were collected at baseline for 1397 (and after 5 years for 1163) men and women aged 31--50 years at baseline. Low back pain ("any low back pain within the past year," "low back pain < or = 30 days in total during the past year," "low back pain > 30 days in total during the past year") was analyzed in relation to physical workload (sedentary, light physical, and heavy physical work) using logistic regression and controlling for age, gender, and social group. The proportions of workers changing between the workload groups over the 5-year period were analyzed in relation to low back pain status. RESULTS: At baseline no statistically significant differences in low back pain outcomes were found for workers exposed to sedentary, light physical, or heavy physical work. This was true for all age, gender, and social groups. At follow-up there was a statistically significant dose-response association between any low back pain and longstanding low back pain within the past year and increasing physical workload at baseline also after controlling for age, gender, and social group. Subjects with heavy physical workload at baseline changed statistically significantly more often to sedentary work if they experienced low back pain for more than 30 days out of the past year. CONCLUSIONS: Having a sedentary job might have a protective or neutral effect in relation to low back pain, whereas having a heavy physical job constitutes a significant risk factor. Because of migration between exposure groups (the "healthy-worker" effect), longitudinal studies are necessary for investigating the associations between physical workload and low back pain.

A randomised controlled trial of screening for adult hearing loss during preventive health checks.

BACKGROUND: Prophylactic strategies to counter acquired hearing impairment may involve routine audiometric screening of asymptomatic working-age adults attending general practice for regular health checks. AIM: To evaluate the effect of adult hearing screening on subsequent noise exposure and hearing. DESIGN OF STUDY: A randomised controlled population-based study of health checks and health discussions in general practice. SETTING: The project was initiated in the district of Ebeltoft, Aarhus county, Denmark. METHOD: Intervention group participants' hearing thresholds were determined audiometrically at 0.5, 1, 2, 3, and 4 kHz in each ear. Participants were advised to get their ears checked if the average hearing loss exceeded 20 dB hearing level (dBHL) in either ear. Noise avoidance was emphasised when thresholds exceeded 25 dBHL bilaterally at 4 kHz. Follow-up included questionnaires and audiometry. RESULTS: Hearing loss was observed among 18.9% of the study sample at baseline. At the five-year follow-up we recorded no significant differences between the control and the intervention groups regarding subjective or objective hearing, or exposure to occupational noise. However, there was a tendency towards reduction in exposure to leisure noise among intervention participants (P = 0.045). Approximately 20% reported hearing problems; 16.5% reported tinnitus-related complaints; 0.8% used hearing aids; 35.0% reported frequent noise exposure; and occluding wax was suspected in 2.1%. CONCLUSION: Preventive health checks with audiometry did not significantly affect hearing, but leisure noise exposure tended to become less frequent. The poor effect may be ascribed to inadequate audiological counselling or a higher priority to other advice, e.g. on cardiovascular risk or lifestyle.

Validation of psychiatric patients' statements on coercive measures.

OBJECTIVE: To investigate the accuracy of psychiatric patients' statements on coercive measures compared with medical file information using empirical methodology, and relating the statements to patients' psychopathology. METHOD: One hundred and forty-three in-patients were identified consecutively, and interviewed using a structured questionnaire. Psychopathology was measured using BPRS, and social functioning using GAF. Patients' statements about coercion were compared with information in the medical files. RESULTS: In general, patients stated to have been subjected to more coercion than was evident from the files. In particular, statements about forced medication, earlier involuntary commitments and present legal status showed low accordance with information in the files. Low accordance was related to the severity of psychopathology and being schizophrenic. CONCLUSION: The existence of a 'grey zone' between patients' and doctors' perception of coercion was confirmed. Knowledge of patients' psychopathology seems essential when considering medical, legal and ethical aspects of the use of coercion.

Fetal growth and blood pressure in a Danish population aged 31-51 years.

During the past decade, studies have shown an inverse association between birth weight and blood pressure and risk of coronary heart disease in adult life. From old public archives we were able to trace the birth records of 545 out of 905 persons (60.2%) aged 31-51 years who participated in the Ebeltoft Health Promotion Project in Denmark. We examined the associations between birth weight, length at birth, Ponderal Index and systolic and diastolic blood pressure. No associations were found for women. For men, the mean systolic blood pressure fell from 131.1 mmHg with a birth weight of less than 3300 g to 129.6 mmHg with a birth weight of more than 4000 g, and for diastolic blood pressure 81.6 mmHg to 80.3 mmHg, respectively. For men, the mean systolic blood pressure fell from 135.7 mm Hg with a birth length of 30-51 cm to 131.6 with a birth length of 55-62 cm, and for diastolic blood pressure 83.0 mmHg to 78.8 mmHg, respectively. The associations may reflect organ programming in fetal life.

A five-year longitudinal study of hearing in a Danish rural population aged 31-50 years.

This paper aims to report changes in hearing sensitivity over five years in a rural population aged 31-50 years and to identify risk factors associated with hearing deterioration. The study is prospective and based on data from pure tone audiometry and questionnaires in the Ebeltoft Health Promotion Project in Denmark. A representative sample of 705 subjects had a complete follow-up, including audiometry. The median hearing deterioration was 2.5 dB at 3-4 kHz and 0 dB at 0.5-2 kHz. There was a high degree of individual variability in deterioration. The overall deterioration of hearing sensitivity of the population was largely predicted from the cross-sectional findings reported previously. In the analysis of risk factors, hearing deterioration was defined as an average deterioration 10 dB/5 years at 3-4 kHz in at least one ear. Deterioration was present in 23.5% of the sample. The 41-50-year-olds had a relative risk of deterioration of 1.32 (95% CI 1.01-1.73) compared with the 31-40-year-olds. Males had a relative risk of 1.35 (1.03-1.76) compared with females. The risk was not significantly elevated for a range of other possible risk factors confirmed by logistic regression analysis. In conclusion, deterioration in hearing sensitivity on population level can be predicted on the basis of cross-sectional findings. Hearing sensitivity deteriorated mainly at 3-4 kHz. The deterioration increased with age and was higher in males than in females. Other risk factors were not found. The present study does not support the hypothesis that hypertension or tobacco smoking is associated with deterioration in hearing.

Inverse association between birth weight, birth length and serum total cholesterol in adulthood.

OBJECTIVES: To investigate whether impaired fetal growth, measured by low birth weight and short birth length, is linked with raised levels of serum lipids and increased risk and mortality of coronary heart disease. DESIGN: The association between birth length, birth weight, Ponderal Index and total serum cholesterol was examined in 545 Danish men and women aged 31 to 51 years who participated in the Ebeltoft Health Promotion Project in Denmark. RESULTS: No associations were found in women. For men, a negative association was found between birth weight and serum total cholesterol, with a fall in mean serum total cholesterol from 6.03 mmol/l at birth weight below 3300 g to 5.64 mmol/l at birth weight above 4000. A similar association was found between birth length and serum cholesterol, with a mean value of 6.23 mmol/l at birth length below 51 cm and a mean value of 5.56 mmol/l at birth length above 54 cm. No associations were found for Ponderal Index. Between 3% and 8% of the variance in serum total cholesterol could be explained by the statistical models used in this study. CONCLUSION: Our findings support the hypothesis of a negative association between birth weight, birth length and elevated serum cholesterol in adult life, but only in men.

Somatization in primary care. Prevalence, health care utilization, and general practitioner recognition.

To study the prevalence of somatoform disorders (SDs) in primary care, a questionnaire including the modified 25-item version of the Symptom Checklist-90 was administered to 191 patients consecutively consulting their family physician. A stratified sample of the patients was interviewed with the Schedules for Clinical Assessment in Neuropsychiatry. The study showed that 22.3% (confidence interval [CI]: 95%: 16.4-28.1) of the patients fulfilled the diagnostic criteria for an International Classification of Diseases--10th Revision (ICD-10) SD, excluding SD, unspecified, and 57.5% (CI: 95%: 50.5-64.5) for DSM-IV SD. But 30.3% met the criteria (CI: 95%: 23.8-36.9) when the DSM-IV Not Otherwise Specified (NOS) diagnostic group is excluded. The most frequent ICD-10 diagnosis was autonomous dysfunction, for which 14.1% of the patients fulfilled the criteria, whereas the prevalence of the other somatoform diagnosis was between 3.0% and 8.1%. The most frequent DSM-IV diagnoses were SD NOS and undifferentiated SD, which 29.93% and 27.3% of the interviewed patients, respectively, received, whereas the prevalence of the other diagnoses was between 1.0% and 8.1%. A high comorbidity between SDs and other mental disorders was found. The general practitioners identified between 50% and 71% of the patients with an ICD-10 SD and between 36% and 48%, according to DSM-IV criteria. Patients with SDs used more nonpsychiatric health care facilities than other patients (P = 0.01).

Screening for somatization and hypochondriasis in primary care and neurological in-patients: a seven-item scale for hypochondriasis and somatization.

The aim of this study was to investigate the internal and external validity of the Whiteley Index as a screening instrument for somatization illness. A 14-item version of the Whiteley Index for hypochondriacal traits was given to 99 of 191 consecutive primary care patients, aged 18-65 years, and to 100 consecutive patients, aged 18-60 years, admitted for the first time to a neurological ward. The primary care sample was, in addition, interviewed by means of the SCAN (Schedules for Clinical Assessment in Neuropsychiatry) psychiatric interview. The GPs and the neurologists were asked to rate various characteristics of the patients that might indicate somatization. The internal validity of the Whiteley Index was tested by means of latent structure analysis. On this basis, a reduced seven-item scale (Whiteley-7 scale) and two subscales (i.e., an Illness Conviction and Illness Worrying scale, each with three items) were constructed. All three had a high internal validity fitting into the very restricted Rasch statistical model (p>0.05) and an acceptable transferability between most of the subpopulations investigated. In the primary care population, the Whiteley-7 and the Illness Conviction scales at cut-point 0/1 showed 1.00 and 0.87 sensitivity and 0.65 and 0.87 specificity, respectively, using as "gold standard" the fulfillment of criteria for at least one ICD-10 somatoform disorder, and 0.71 and 0.63 sensitivity and 0.62 and 0.87 specificity, respectively, as gold standard for the fulfillment of criteria for at least one DSM-IV somatoform disorder, excluding the NOS diagnostic group. The Illness Worrying subscale showed less impressive performance in this respect. The agreement between the Whiteley-7 scale including the two subscales and neurologists' rating and the GPs' rating and the somatization subscale on the SCL-90 was modest or worse. It may be concluded that the Whiteley-7 scale and the Illness Conviction subscale had acceptable psychometric profiles, and both seem to be promising screening tools for not only hypochondriasis but also for somatoform disorders in general.