[Anticholinergic scales: Use in psychiatry and update of the anticholinergic impregnation scale]. / Les échelles anticholinergiques : usage en psychiatrie et mise à jour de l'échelle d'imprégnation anticholinergique.

Anticholinergic properties are well known to prescribers, notably in mental health, as a therapeutic strategy for i.e. extrapyramidal syndrome but also as a source of numerous adverse side effects. Herein, we propose a narrative literature review describing: (i) cholinergic pharmacology and anticholinergic properties; (ii) the importance of anticholinergic therapeutic properties in psychiatry; (iii) the existing anticholinergic drug scales and their usage limitations in Psychiatry and; last (iv) an update to the anticholinergic drug impregnation scale, designed for the French psychiatry practice. The anticholinergic side effects can appear both in the peripheral level (dry mouth, constipation, etc.) and in the central level (especially as cognitive deficits). Many of the so called « anticholinergic ¼ drugs are in fact entirely or mostly antimuscarinic and act essentially as parasympathetic system antagonists. Overall, anticholinergic/antimuscarinic side effects are usually attributed to psychotropic medications: to certain antipsychotics, notably classical neuroleptics such as phenothiazine and also to tricyclic antidepressants. In practice, the impact of anticholinergic toxicity treatments is often highlighted due to their excessively prolonged use in patients on antipsychotics. Interestingly, these antipsychotic treatments are better known for their anticholinergic side effects, especially cognitive ones, with an early onset specially in elder patients and/or in the case of polymedication. In order to evaluate anticholinergic side effects, metrics known as anticholinergic burden scales were created in the last few decades. Nowadays, 13 different scales are documented and accepted by the international academic community, but only three of them are commonly used: the Anticholinergic Drug Scale (ADS), the Anticholinergic Risk Scale (ARS) and the Anticholinergic Burden Scale (ACB). All of them are based on a similar principle, consisting of grading treatments individually, and they are normally scored from 0 - no presence of side effects - to 3 - anticholinergic effects considered to be strong or very strong. Using these scales enables the calculation of the so-called "anticholinergic burden", which corresponds to the cumulative effect of using multiple medications with anticholinergic properties simultaneously. The application of anticholinergic scales to patients with psychiatric disorders has revealed that schizophrenic patients seem to be especially sensitive to anticholinergic cognitive side effects, while elder and depressed patients were more likely to show symptoms of dementia when exposed to higher anticholinergic burden. Unfortunately, these tools appear to have a low parallel reliability, and so they might induce large differences when assessing side effects predictability. In addition, the capacity of these scales to predict central adverse effects is limited due to the fact they poorly or do not differentiate, the ability of treatments to cross the blood-brain barrier. Finally, one last limitation on the validity of these scales is prescription posology is not accounted for side effects considered to be dose dependent. Recently, the MARANTE (Muscarinic Acetylcholine Receptor ANTagonist Exposure) scale has incorporated an anticholinergic burden weighting by posology. Nevertheless, this new model can be criticized, due to the limited number of medications included and due to testing a limited number of potency ranges and dosages for each treatment. Herein, we propose an update to the Anticholinergic Impregnation Scale, developed specifically for the French Psychiatry practice. The scale validation was based on an evaluation of the prescriptions correcting anticholinergic peripheral side effects (constipation, xerostomia and xeropthalmia). This indirect evaluation allowed us to show patients with an anticholinergic impregnation score higher than 5 received significantly more treatments for constipation and xerostomia. This strategy bypasses the bias of a cognitive evaluation in patients with severe mental health disorders. Moreover, the relevance of a tool developed specifically for French psychiatry is justified by the fact that some highly prescribed treatments for mental illness in France (cyamemazine and tropatemine) are strong anticholinergics, and also by the fact they are rarely included in the existing anticholinergic scales. This update of the original scale, published in 2017, includes information whether prescribed drugs cross the blood-brain barrier and thus makes possible a more accurate assessment when evaluating anticholinergic central side effects. Finally, the anticholinergic impregnation scale will soon be integrated into a prescription help software, which is currently being developed to take into consideration dose dependent adverse effects.

Asparaginase and MOPP treatment of dogs with lymphoma.

BACKGROUND: Dogs with multicentric lymphoma are treated with various cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy protocols with variable success. OBJECTIVES: To describe the progression-free survival (PFS) time and overall survival time (OST) of dogs with T-cell lymphoma or hypercalcemic lymphoma treated with L-asparaginase and mechlorethamine, vincristine, prednisone, procarbazine (MOPP). ANIMALS: Fifty dogs with T-cell lymphoma, hypercalcemic lymphoma, or both treated at 3 referral veterinary hospitals. METHODS: Retrospective study. Case were selected based on histologic or cytologic diagnosis of lymphoma; presence of the T-cell phenotype, presence of hypercalcemia or both; and absence of previous chemotherapy. The T-cell phenotype was determined by flow cytometry, immunocytochemistry, immunohistochemistry, or polymerase chain reaction of antigen receptor rearrangement. RESULTS: The overall response rate was 98% (78% complete response, 20% partial response). The median PFS for the entire study population was 189 days with 25% PFS at 939 days. The median OST for the entire study population was 270 days with 25% surviving 939 days. Twenty percent of the dogs required hospitalization for treatment related complications. CONCLUSIONS AND CLINICAL IMPORTANCE: L-Asp/MOPP chemotherapy might result in longer PFS and OST for dogs with multicentric T-cell lymphoma, dogs with hypercalcemic lymphoma or both, than achieved with CHOP.

Coupling of the thrombin receptor to G12 may account for selective effects of thrombin on gene expression and DNA synthesis in 1321N1 astrocytoma cells.

In 1321N1 astrocytoma cells, thrombin, but not carbachol, induces AP-1-mediated gene expression and DNA synthesis. To understand the divergent effects of these G protein-coupled receptor agonists on cellular responses, we examined Gq-dependent signaling events induced by thrombin receptor and muscarinic acetylcholine receptor stimulation. Thrombin and carbachol induce comparable changes in phosphoinositide and phosphatidylcholine hydrolysis, mobilization of intracellular Ca2+, diglyceride generation, and redistribution of protein kinase C; thus, activation of these Gq-signaling pathways appears to be insufficient for gene expression and mitogenesis. Thrombin increases Ras and mitogen-activated protein kinase activation to a greater extent than carbachol in 1321N1 cells. The effects of thrombin are not mediated through Gi, since ribosylation of Gi/Go proteins by pertussis toxin does not prevent thrombin-induced gene expression or thrombin-stimulated DNA synthesis. We recently reported that the pertussis toxin-insensitive G12 protein is required for thrombin-induced DNA synthesis. We demonstrate here, using transfection of receptors and G proteins in COS-7 cells, that G alpha 12 selectively couples the thrombin receptor to AP-1-mediated gene expression. This does not appear to result from increased mitogen-activated protein kinase activity but may reflect activation of a tyrosine kinase pathway. We suggest that preferential coupling of the thrombin receptor to G12 accounts for the selective ability of thrombin to stimulate Ras, mitogen-activated protein kinase, gene expression, and mitogenesis in 1321N1 cells.

Validation of a Multiplexed Gene Signature Assay for Diagnosis of Canine Cancers from Formalin-Fixed Paraffin-Embedded Tissues.

BACKGROUND: Use of molecular-based diagnostics for companion animals is impeded by availability of technology platforms, tissue acquisition requirements, and species-specific reagents. HYPOTHESIS/OBJECTIVES: To validate a quantitative nuclease protection assay (qNPA) to simultaneously measure RNA expression of multiple genes in archived formalin-fixed paraffin-embedded (FFPE) tumors from dogs. ANIMALS: All tumor biopsy samples were collected retrospectively from surgical biopsies and in the care of veterinarians. METHODS: Retrospective case series. A qNPA 96-well ArrayPlate was built using 30 canine-specific genes, 5 housekeeping genes, positive and negative controls with qualified gene-specific oligonucleotides. Pearson's correlation, coefficient of variation (CV), and multivariate analysis were used to determine analytical performance using 40 FFPE dog tumors. Once validated, 70 FFPE dog tumors were analyzed for differences in gene expression using hierarchical clustering and analysis of variance of log transformed data. Immunohistochemistry (IHC) was performed to correlate gene expression and protein expression in a subset of tumors. RESULTS: The assay was linear with decreasing sample input (R2 = 0.978), reproducible within and between 96-well plates (r = 0.988 and 0.95, respectively) and between different laboratories (CV = 0.96). Hierarchical cluster analysis showed grouping of tumors by histogenesis and oncogenes. Significant differences were found between BCl2, E2F transcription factor 1, MDM2, COX-2, MET proto-oncogene receptor kinase, and other biologically relevant gene expression in tumor subtypes. Immunohistochemistry confirmed protein expression. CONCLUSIONS AND CLINICAL IMPLICATIONS: Because this technology works reliably on FFPE specimens, it can help expedite the broad introduction of multiplexed genomic information for improved diagnostics and discovery of new targets for therapies in veterinary oncology.

Recurrence rates and clinical outcome for dogs with grade II mast cell tumours with a low AgNOR count and Ki67 index treated with surgery alone.

Grade II mast cell tumours (MCT) are tumours with variable biologic behaviour. Multiple factors have been associated with outcome, including proliferation markers. The purpose of this study was to determine if extent of surgical excision affects recurrence rate in dogs with grade II MCT with low proliferation activity, determined by Ki67 and argyrophilic nucleolar organising regions (AgNOR). Eighty-six dogs with cutaneous MCT were evaluated. All dogs had surgical excision of their MCT with a low Ki67 index and combined AgNORxKi67 (Ag67) values. Twenty-three (27%) dogs developed local or distant recurrence during the median follow-up time. Of these dogs, six (7%) had local recurrence, one had complete and five had incomplete histologic margins. This difference in recurrence rates between dogs with complete and incomplete histologic margins was not significant. On the basis of this study, ancillary therapy may not be necessary for patients with incompletely excised grade II MCT with low proliferation activity.

Clinical presentation, treatment and outcome in 31 dogs with presumed primary colorectal lymphoma (2001-2013).

The objective of this multicentre retrospective study was to describe clinical presentation, treatment and outcome and to determine prognostic factors for dogs with presumed primary colorectal lymphoma (PCRL). A total of 31 dogs were included. The predominant features of PCRL were high grade (n = 18) and immunophenotype B (n = 24). Most dogs were substage b (n = 25) with higher prevalence of haematochezia (n = 20). One dog had surgery only. Thirty dogs received chemotherapy; amongst them 13 had surgery or radiotherapy. Progression free survival (PFS) was 1318 days and disease-related median survival time (MST) was 1845 days. Fourteen dogs were alive at the end of the study with a median follow-up time of 684 days (3-4678 days). Younger dogs had longer PFS (P = 0.031) and disease-related MST (P = 0.01). Presence of haematochezia corresponded with longer PFS (P = 0.02). Addition of local treatment to chemotherapy did not significantly improve the outcome (P = 0.584). Canine PCRL has considerably longer PFS and MST than other forms of non-Hodgkin's lymphoma.

Alternating Rabacfosadine/Doxorubicin: Efficacy and Tolerability in Naïve Canine Multicentric Lymphoma.

BACKGROUND: Standard of care treatment for multicentric lymphoma in dogs remains doxorubicin (DOX)-based combination chemotherapy, but owners may hesitate to commit the time and financial resources to complete such a protocol, typically requiring 12-16 visits. Rabacfosadine (RAB), a double prodrug of the nucleotide analog 9-(2-phosphonylmethoxyethyl) guanine, has substantial single-agent activity in dogs with lymphoma, and a different mechanism of action than DOX. HYPOTHESIS/OBJECTIVES: Our objective was to evaluate the efficacy and adverse effect (AE) profile of alternating doses of RAB and DOX in dogs with naïve multicentric lymphoma. ANIMALS: Fifty-four dogs with previously untreated lymphoma. METHODS: Open-label, multicenter prospective clinical trial. Dogs received alternating RAB (1.0 mg/kg IV weeks 0, 6, 12) and DOX (30 mg/m2 IV weeks 3, 9, 15). Dogs that achieved complete response (CR) were followed by monthly evaluations. Complete clinicopathological evaluation and assessment of remission and AEs were performed every 21 days. RESULTS: The overall response rate was 84% (68%; CR; 16%; partial response [PR)]. The overall median progression-free interval (PFI) was 194 days (216 for CR and 63 for PR). Most AEs were mild and self-limiting: gastrointestinal and hematologic AEs were most common. Thirteen dogs experienced dermatologic AEs, and 2 dogs developed grade 5 pulmonary fibrosis. CONCLUSIONS AND CLINICAL IMPORTANCE: Alternating RAB/DOX generally was well tolerated and resulted in PFIs comparable to standard DOX-based multi-agent protocols, with fewer treatment visits. Most adverse events were mild or moderate and self-limiting. Further studies are warranted to explore long-term outcome and other RAB chemotherapy combinations.

Geographical differences in survival of dogs with non-Hodgkin lymphoma treated with a CHOP based chemotherapy protocol.

BACKGROUND: In humans geographical differences in the incidence and presentation of various cancers have been reported. However, much of this information has not been collected in veterinary oncology. AIM: The purpose of this study was to determine if a geographic difference in progression free survival exists for dogs with lymphoma treated within the US. MATERIALS AND METHODS: Medical records of 775 cases of canine lymphoma from 3 US regions (west, south and north), treated with CHOP chemotherapy, were retrospectively evaluated. Cases were collected from referral institutions and were required to have received at least one doxorubicin treatment and have follow up information regarding time to progression. RESULTS: Significant differences in sex (p = 0.05), weight (p = 0.049), stage (p < 0.001), immunophenotype (p = <0.001), and number of doxorubicin doses (p = 0.001) were seen between regions. Upon univariate analysis, progression free survival (PFS) differed by region (p = 0.006), stage (p = 0.009), sub-stage (p = 0.0005), and immunophenotype (p = 0.001). A multivariable Cox regression model showed that dogs in the western region had a significantly shorter PFS when compared to the south and east. CONCLUSION: PFS was significantly affected by stage, sub-stage and phenotype.

Weight-bearing activity during youth is a more important factor for peak bone mass than calcium intake.

In a 15 year longitudinal study (Amsterdam Growth and Health Study) is evaluated the effect of daily calcium intake (CAI) during adolescence and young adulthood on the development of peak bone mass at age 27 when the influence of weight-bearing activity (WBA) and body weight was accounted for. A group of 84 males and 98 females were measured longitudinally from age 13 until age 28. Measurements were taken six times of anthropometric characteristics. Lifestyle was also evaluated six times by cross-check interviews of CAI and WBA. Bone mineral density (BMD) of the lumbar spine was determined at age 27 by dual x-ray absorption. Three periods were considered, that is, the adolescent period, the period 13-21 years, and the total period (13-27 years). In multiple linear regression analyses, only WBA and body weight were significant positive contributors to the final model of lumbar BMD at age 27. In all three periods WBA was the best predictor in males and body weight in females. ANOVA was performed on BMD and the highest and lowest quartiles of calcium intake with the significant predictor variables of the linear regression model as covariates. Again calcium intake appeared not a significant predictor of BMD in the three periods in both sexes. Regular weight-bearing exercise and at least a normal age-related body weight in adolescence and young adulthood are of key importance in reaching the highest lumbar peak bone mass at the age of 27 years.

Behavioral variables and development of a central pattern of body fat from adolescence into adulthood in normal-weight whites: the Amsterdam Growth and Health Study.

Associations were investigated between the amount of physical activity, energy and macronutrient intake, smoking behavior, alcohol intake, and a central pattern of body fat (subscapular skinfold thickness and waist circumference) measured six times between the mean ages of 13 and 27 y in a healthy white population. Subjects (84 males, 98 females) were participants in the longitudinal Amsterdam Growth and Health Study. In longitudinal analyses, alcohol intake was positively associated with the subscapular skinfold thickness (beta = 0.09, 95% CI: 0.01, 0.16) in males. In females, the subscapular skinfold thickness was negatively associated with physical activity (beta = -0.10. 95% CI: -0.15, -0.05) and, unexpectedly, energy intake (beta = -0.25, 95% CI: -0.31,-0.19), whereas a positive association was found with carbohydrate intake (beta = 0.09. 95% CI: 0.02, 0.16). In both sexes, the mean value of behavioral variables, obtained from the mean value in adolescence and the values obtained at 21 and 27 y of age was not significantly associated with the subscapular skinfold thickness or waist circumference at the mean age of 27 y, except for a small positive association between physical activity and the subscapular skinfold thickness in males (R2 = 2.3%).

A fifteen-year longitudinal study in young adults on the relation of physical activity and fitness with the development of the bone mass: The Amsterdam Growth And Health Longitudinal Study.

Although positive effects of physical activity are often reported, there are still uncertainties about the type, intensity, duration, and frequency of these activities that are most effective for (re)modeling bone mass during youth. In the Amsterdam Growth and Health Longitudinal Study, daily physical activity and fitness were monitored from age 13 to 29 years in a group of 182 males and females. At a mean age of 28 years, bone mineral density (BMD) was measured at three sites with dual X-ray absorptiometry (DXA): in the lumbar region (lumbar BMD), the femoral neck (hip BMD), and the distal radius (wrist BMD). Physical activity (PA) was estimated from a cross-check activity interview taking in consideration all daily physical activities during the last 3 months; PA was scored in two different ways: (1) metabolic physical activity score (METPA) by weighting the intensity (multiples of basic metabolic rate [METs]) and duration (minutes per week); and (2) mechanic physical activity score (MECHPA) by weighting the peak strain (ground reaction forces as multiples of body mass) irrespective of frequency and duration of the physical activities. Physical fitness was measured with a neuromotor fitness test (composite of six strength, flexibility, and speed tests) and as cardiopulmonary fitness (maximal oxygen uptake). The physical activity and fitness scores were calculated over two age periods: during adolescence (13-16 years) and during adulthood (21-27 years). The standardized regression coefficients (corrected for gender, biological age, body composition, and calcium intake) show that weight, physical activity (both METPA and MECHPA), and neuromotor fitness during adolescence and in young adulthood are significantly and positively related with the lumbar BMD (beta = 0. 11-0.40) and hip BMD (beta = 0.18-0.26), measured at the mean age of 28 years. This was not the case for cardiorespiratory fitness. No significant correlations at all are found with wrist BMD, a bone site that is less involved in physical activity and fitness. It can be concluded that daily physical activity during adolescence and in the young adult period is significantly related to the BMD at the lumbar spine and femoral neck at age 28 of males and females. Only neuromotor fitness and not cardiopulmonary fitness during adolescence and young adulthood is related to the BMD of males and females at age 28 years.

Relation between the longitudinal development of lipoprotein levels and lifestyle parameters during adolescence and young adulthood.

The longitudinal relationship between serum levels of lipoproteins and lifestyle measures (e.g., intake of cholesterol, carbohydrates, saturated fatty acids [SFA], polyunsaturated fatty acids [PUFA], the PUFA/SFA (P:S) ratio, alcohol consumption, smoking behavior, and daily physical activity) was investigated over a period of 15 years in a cohort study (the Amsterdam Growth and Health Study). Members of the cohort were 13 years of age at commencement of the study and were 27 years old at termination. The unique feature of the study presented is that the longitudinal relations were analyzed with generalized estimating equations, a statistical technique in which the relations at different time-points are tested simultaneously. The development of the total serum cholesterol (TC) level was positively related to the intake of cholesterol and negatively to the P:S ratio. The development of high-density-lipoprotein cholesterol (HDL) level was positively related to alcohol consumption and daily physical activity and negatively to smoking behavior. The development of the TC:HDL ratio was negatively related to alcohol consumption and positively to both smoking behavior and carbohydrate intake.

Clustering of risk factors for coronary heart disease. the longitudinal relationship with lifestyle.

PURPOSE: The purpose of this study was to investigate whether or not clustering of biological coronary heart disease (CHD) risk factors exists and to investigate the longitudinal relationship between lifestyle parameters (dietary intake, daily physical activity, smoking behaviour, alcohol consumption) and a biological CHD risk factor clustering score. This was defined as belonging to one or more gender specific 'high risk' quartiles for the following CHD risk factors: ratio between total serum cholesterol and high density lipoprotein cholesterol (TC:HDL), mean arterial blood pressure (MABP), body fatness [sum of skinfolds (SSF)], and cardiopulmonary fitness (VO2-max). METHODS: The data were derived from the Amsterdam Growth and Health Study, an observational longitudinal study in which six repeated measurements were carried out over a period of 15 years covering adolescence and young adulthood. The longitudinal relationships were analysed with generalized estimating equations. RESULTS: The results showed significant clustering for the TC:HDL ratio, SSF, and VO(2)-max. MABP was not significantly associated with the other CHD risk factors. Daily physical activity and alcohol consumption (only for males) were both inversely related to the clustering score. None of the other lifestyle parameters showed significant relationships with the clustering score. CONCLUSIONS: Based on this small longitudinal study, it can be stated that during adolescence and young adulthood both daily physical activity and alcohol consumption were related to a healthy CHD risk profile.

Cyclosporine nephrotoxicity is minimized by adjusting dosage on the basis of drug concentration in blood.

Two immunosuppressive regimens-cyclosporine plus prednisone and azathioprine plus prednisone-were compared in 78 renal transplantation patients (39 in each treatment group) who were successfully managed for more than 15 months. In patients who received cyclosporine, the dosage was adjusted to achieve trough whole blood concentrations of 100 to 250 ng/ml measured by liquid chromatography. A greater number of haplotypes matched in the azathioprine-treated group than in the cyclosporine-treated group (P less than 0.026). Graft survival was similar in patients who received azathioprine (95%) and those given cyclosporine (94%). The azathioprine group had a higher mortality (7%) than the cyclosporine group (2%). In a comparison of the two treatment groups, no statistically significant difference was found in posttransplant renal function, based on either serum creatinine or iothalamate clearance. We conclude that renal toxicity due to cyclosporine can be minimized to statistical nonsignificance by using cyclosporine dosages that provide trough whole blood concentrations in the range of 150 to 250 ng/ml during the first 4 months of therapy and 80 to 200 ng/ml thereafter.

Comparison of a quantitative dairy questionnaire with a dietary history in young adults.

BACKGROUND: There is growing interest in the potential role of calcium in the prevention of osteoporosis. Therefore a quantitative dairy questionnaire (DQ) was developed to estimate the calcium intake from dairy products. The aim of this study was to evaluate the relative validity and reproducibility of the DQ in 27-29 year old males and females. METHODS: The DQ was validated against a cross-check dietary history method (DH) in 160 subjects, and the reproducibility was assessed in 29 subjects by repeating the administration of the DQ with a one-year interval. RESULTS: In the validity study, the nutrient calcium and the food groups cheese and milk and milk products measured by the DQ tend to show higher intakes as compared to the results of the DH. However, only for the calcium intake was the difference between the DQ and DH (7%) significant. The Bland-Altman plot showed that this bias was constant over the range of calcium intakes. The Pearson correlation coefficients between the DQ and the DH varied from 0.58 to 0.65. On average, about 52% of the subjects were classified in the same quartile in the DQ and the DH for the intake of calcium as well as dairy products. The weighted kappas were between 0.60 and 0.67. In the reproducibility study, the Pearson correlation coefficient for the calcium intake assessed by the DQ one year apart was 0.78. CONCLUSIONS: These data indicate that the DQ is reasonably accurate in young adults as a means of assessing the calcium intake from dairy products.

Genitourinary leiomyomas.

Leiomyomas may originate from any anatomic location of smooth muscle in the genitourinary system but are uncommon neoplasms. Five unusual cases of leiomyomas arising from the renal pelvis, bladder, spermatic cord, and glans penis are presented. The leiomyoma arising from the glans penis in a three-year-old boy is the first case of a leiomyoma in that location noted in the literature. A review of leiomyomas from each genitourinary structure of origin is presented.

Leukemic infiltration of penis.

Leukemic infiltration of the urinary tract is most common in the kidneys. Other areas are involved much less frequently. We report a case of leukemic infiltration of the penis.

Pathways and roadblocks in muscarinic receptor-mediated growth regulation.

In some cell systems muscarinic receptor stimulation can induce proliferation or transformation. This phenomenon is subtype-specific (only m1 and m3 receptors are effective) and cell type dependent. In 1321N1 astrocytoma cells activation of m3 receptors stimulates phospholipase C, but does not induce DNA synthesis. In contrast the thrombin receptor, which also couples to phospholipase C, is strongly mitogenic and induces AP-1-dependent gene expression. Various experimental findings indicate that this discrepancy is not due to muscarinic receptor desensitization or blockade of growth stimulatory pathways. Muscarinic receptor number may be limiting, in particular for receptor coupling to the pertussis toxin-insensitive G-protein G12. This G-protein is required for thrombin-induced mitogenesis in 1321N1 cells and may couple selectively to the thrombin versus muscarinic receptor. In cardiomyocytes hypertrophic cell growth is induced by heterologously expressed m1 or m3 receptors but not by the endogenous m2 receptors. Studies using chimeric receptors confirm that induction of hypertrophy requires signalling through phospholipase C, but indicate that additional signals are needed to induce the morphological features of this response. We suggest that small G-proteins of the Rho subfamily, in addition to G12, mediate growth responses to G-protein-coupled receptors.

Physical activity of young people: the Amsterdam Longitudinal Growth and Health Study.

PURPOSE: To describe the natural development of habitual physical activity behavior (HPA) of young Dutch male and female subjects between the ages of 13 and 27, using data from the Amsterdam Longitudinal Growth and Health Study. METHODS: HPA was measured by means of a structured interview at ages 13, 14, 15, 16, 21, and 27 and concerned all activities (at work, school, during leisure, organized and nonorganized sports, and active transportation) exceeding a level of intensity of 4 METs. Complete longitudinal data concern 98 female and 83 male subjects. MANOVA for repeated measurements were done for total HPA (expressed in min x wk(-1) and in METs x wk(-1)). Similar analyses were done for organized sports activities, leisure time activities, and all "other" activities separately (also min x wk(-1) and METs x wk(-1)), as well as for weekly time at three different levels of intensity of HPA, i.e. 4-7 MET (moderate), 7-10 MET (vigorous), and >10 MET (very vigorous). RESULTS: Our data showed regarding total HPA (min x wk(-1)) in male, but not in female, subjects a significant decrease in weekly time spent on HPA between the ages of 13 and 27. Regarding the three different levels of intensity in male and female subjects, a significant increase was found in time spent on moderate activities, where female subjects were spending significantly more time on moderate activities than male subjects; both in male and female subjects, a significant decrease was found in time spent on vigorous activities: in male subjects a significant decrease was found in time spent on very vigorous activities, whereas in female subjects time spent at this level of activity remained more or less stable. For the total weighted activity score (METs x wk(-1)), a significant decrease was found for both male (42%) and female subjects (17%). This decrease was significantly greater for male than for female subjects. Regarding more specific activities, it was found that in the course of time organized sports activities became relatively more important contributors to both weekly HPA time and energy expenditure, both in male and female subjects. CONCLUSIONS: Our data show a considerable decrease in HPA over a 15-yr period of time, both in male and female subjects. Differences between male and female subjects are predominantly caused by differences in time spent in moderate and very vigorous activities. In the course of time, organized sports activities became a relatively more important contributor of weekly HPA.

Nutrient intake and biological maturation during adolescence. The Amsterdam growth and health longitudinal study.

The study evaluates the association of the food intake and the rate of biological maturation of 200 boys and girls in Amsterdam during their adolescence. The subjects were followed in a longitudinal survey over a period of 9 years, between the ages of 13 and 22 years. In the first four years (1976-1980) annual measurements were performed (school period). In 1985 a fifth measurement was made at the age of 21 years. Biological maturation was estimated from X-ray photographs of the left hand and wrist and rated according to the Tanner-Whitehouse II method. On the basis of the annual measurements in the first four years a distinction was made between late maturers (LMs) and early maturers (EMs). The individual food intake was obtained with a cross-check dietary history method: a dietitian interviewed the entire range of foods and drinks, making allowance for regular meals as well as in-between meals, separately for normal schooldays and weekend days. Analysis of variance was used to test the effects of maturation (M), time of measurement (T) and interaction (M x T). The results show that EMs of both sexes consumed less energy and protein per kg body weight, but were fatter at young adult age and showed less habitual physical activity than LMs during the whole period of observation. The conclusion could be drawn that late maturation seems to coincide with an energy intake that is more appropriate to their higher activity pattern than early maturation during adolescence. This results in a significantly lower body fat mass in late maturing boys and girls compared to early maturers.