Negative symptoms in schizophrenia: considerations for clinical trials

There is little agreement about the methodology of clinical trials of antipsychotic drugs in patients with negative symptoms. A literature review revealed wide variation in experimental design, rating scales and study duration. This reflects differing views as to the definition and response to treatment of negative symptoms. Some degree of standardization would improve comparability of studies and aid the development of new compounds. Patients included in such studies should have displayed negative symptoms for at least 6 months. Depressive symptoms, positive schizophrenic symptoms and extrapyramidal signs may all influence or be confused with negative symptoms and may respond to treatment; they should be at a low level at baseline and should be measured during the study period. Studies should last at least 8 weeks. Several scales are available for measuring negative symptoms and are reviewed; a global impression score should be used additionally.     

Heart rate analysis in 24 patients treated with 150 mg amitriptyline per day

Twenty-four patients treated with 150 mg amitriptyline per day for an episode of major depression underwent a standardized heart rate analysis (HRA) before therapy and after 14 days. The battery of cardiovascular reflex tests included the determination of the coefficient of variation (CV) while resting and during deep respiration, a spectral analysis of heart rate, the heart rate response to standing, and the Valsalva manoeuvre. The results of the initial HRA did not differ from a group of 24 normal control subjects matched for age and sex. On day 14 of treatment the patients showed significantly reduced values of heart rate variability in all tests (P<0.0001), probably due to the anticholinergic side effects of amitriptyline. Heart rate increased form 78.1 to 93.6 bpm on average (P<0.0001). Abnormal CV at rest was registered in 96% of the patients; during deep respiration 29% showed abnormal CV results. An abnormal spectral analysis was found in 100% of the cases (low frequency peak: 42%, mid-frequency peak: 100%, high frequency peak: 79%). The heart rate response to standing was abnormal in 75% and the Valsalva test in 33% of the cases. Eighty-eight percent of the patients fulfilled the criteria of a cardiovascular autonomic neuropathy under the conditions of amitriptyline therapy. As yet, the consequences of these changes for the patients have not been sufficiently elucidated.     

Heart rate response to breathing: dependency upon breathing pattern

Summary. Heart rate responses to stepwise and periodic changes in lung volume were studied in seven young healthy males. Stepwise inspiration and expiration both resulted in an increase in heart rate followed by a rapid decrease in heart rate. The fastest heart rate was reached in 1·6 ± 0·5 s and in 3·6 ± 1·4 s in response to inspiration and expiration, respectively (P < 0·01). The slowest heart rate was reached in 4·8± 1·0 s and in 7·6± 1·9 s in response to inspiration and expiration, respectively (P < 0·01). Following this biphasic change the heart rate returned to a steady level. The difference between the fastest and the slowest heart rates was significantly larger in response to inspiration (21·7 ± 7·3 beats per minute) than in response to expiration (12·0±7·3 beats per minute; P < 0·01). Periodic changes in lung volume were performed with frequencies from 3·0 to 12·0 respirations per minute (r.p.m.). The changes in heart rate showed a constant amplitude in the frequency range below 5·5 r.p.m. Maximal heart rate changes were found at frequencies of 5·5 to 7·0 r.p.m. Changes in heart rate decreased in a linear manner on a log-log scale in the frequency range above 7·0 r.p.m. The relation between frequency and changes in heart rate is explained by interference between the transient changes in heart rate induced both by inspiration and by expiration. It is concluded that if heart rate changes in response to periodic changes in lung volume are to be used as a measure of vagal function a number of factors have to be taken into consideration and to simplify the analysis of heart rate responses to breathing we recommend, instead, the use of the transient changes in heart rate induced by stepwise changes in lung volume.     

Are nonresorbing osteoclasts sources of bone anabolic activity?

Some osteopetrotic mutations lead to low resorption, increased numbers of osteoclasts, and increased bone formation, whereas other osteopetrotic mutations lead to low resorption, low numbers of osteoclasts, and decreased bone formation. Elaborating on these findings, we discuss the possibility that osteoclasts are the source of anabolic signals for osteoblasts. In normal healthy individuals, bone formation is coupled to bone resorption in a tight equilibrium. When this delicate balance is disturbed, the net result is pathological situations, such as osteopetrosis or osteoporosis. Human osteopetrosis, caused by mutations in proteins involved in the acidification of the resorption lacuna (ClC-7 or the a3-V-ATPase), is characterized by decreased resorption in face of normal or even increased bone formation. Mouse mutations leading to ablation of osteoclasts (e.g., loss of macrophage-colony stimulating factor [M-CSF] or c-fos) lead to secondary negative effects on bone formation, in contrast to mutations where bone resorption is abrogated with sustained osteoclast numbers, such as the c-src mice. These data indicate a central role for osteoclasts, and not necessarily their resorptive activity, in the control of bone formation. In this review, we consider the balance between bone resorption and bone formation, reviewing novel data that have shown that this principle is more complex than originally thought. We highlight the distinct possibility that osteoclast function can be divided into two more or less separate functions, namely bone resorption and stimulation of bone formation. Finally, we describe the likely possibility that bone resorption can be attenuated pharmacologically without the undesirable reduction in bone formation.     

Maternal glycated haemoglobin, pre-gestational weight, pregnancy weight gain and risk of large-for-gestational-age babies: a Danish cohort study of 209 singleton Type 1 diabetic pregnancies.

AIMS: To examine the association between maternal glycated haemoglobin in the second half of diabetic pregnancies and the relative risk of delivering large-for-gestational-age (LGA) babies, controlling for maternal body mass index (BMI) before pregnancy, weight gain, age, White class and smoking habits. METHODS: We identified all pregnant diabetic women in North Jutland County, Denmark from 1985 to 2003. Data on HbA(1c) values from the 20th gestational week to term were collected from medical records and the babies were classified as large, normal or small for gestational age. The association between glycated haemoglobin (HbA(1c)) and relative risk of delivering an LGA baby was quantified based on logistic regression models and stratified analysis controlling for the five covariates. RESULTS: We included 209 singleton pregnancies with assessable HbA(1c) values of which 59%[95% confidence interval (CI) 52-65%] terminated with an LGA baby. Increasing levels of HbA(1c), BMI and weight gain were all associated with increasing risk of delivering an LGA baby. Analyses stratified according to maternal BMI showed that the association between HbA(1c) and risk of delivering an LGA baby was restricted to pregnancies with pre-pregnancy BMI > 23 kg/m(2). We found no association between HbA(1c) and risk of delivering an LGA baby in pregnancies with lower BMI. CONCLUSION: The positive association between glycated haemoglobin and birth of an LGA baby seems to be restricted to women with BMI > 23 kg/m(2).     

Treatment of age-related macular degeneration by laser photocoagulation. Visual results 2-8 weeks and 2-4 years after initial laser treatment

Laser treatment with blue-green argon, green argon and/or krypton red was performed on 578 eyes in 443 patients with neovascular age-related macular degeneration (AMD). The visual acuity was examined in all eyes 2 to 8 weeks after initial treatment and in 204 eyes in 167 patients 2 to 4 years after initial treatment. The short term results were as follow: 91/578 eyes (16%) had improved (greater than or equal to 2 lines on Snellen's charge or equivalent steps), 445/578 eyes (77%) remained unchanged and 42/578 eyes (7%) had deteriorated visual acuity (greater than or equal to 2 lines on Snellen's chart or equivalent steps). The reduction in visual acuity, may in about half of the 42 eyes be caused by too intensive laser application in the beginning of this study in 1983 and 1984 where treatment was applied with blue-green argon, which has now been abandoned. In the group with an observation time of 2 to 4 years, 42/204 eyes (21%) had improved, 119/204 eyes (58%) remained unchanged and 43/204 eyes (21%) had a deteriorated visual acuity. In the 204 eyes the subretinal neovascular lesion(s) were located extrafoveally in 52 eyes, juxtafoveally in 114 eyes and subfoveally in 38 eyes. It is to be pointed out, that even patients with a pre-laser visual acuity of 6/60 or worse obtained an improvement of visual acuity in 12/27 eyes. About 40% of the eyes needed re-treatment from 1 to 8 times. It is unknown whether the obtained results are to be considered marginal or more substantial.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anal sphincter size measured by endosonography in healthy volunteers. Effect of age, sex, and parity.

The anal sphincter muscles consist of the circular internal and external sphincters together with the sling-shaped associated puborectalis muscle. Ten men, 10 women with no vaginal deliveries, and 10 women with one or more vaginal deliveries were studied with anal endosonography using a 7 MHz multiplanar endoprobe. The thickness of the internal sphincter and the thickness, length, and cross-sectional area of the external sphincter were measured and related to age, sex, and parity. Reproducibility was assessed by similar measurements on different days in 10 volunteers. Anal sphincter size was the same in men and women and was not affected by the number of child births. Internal sphincter muscle thickness increased with age. Anal manometry and electromyography with an anal sponge were performed in all volunteers but the results did not correlate to any of the anal sphincter dimensions. Our conclusion is that although there are some limitations, endosonography can be used to determine the size of the anal sphincter muscles.     

Transient cyst-like cortical defects following fractures in children. Medullary fat within the subperiosteal haematoma

Asymptomatic cyst-like cortical defects appearing after fractures in children have been occasionally reported. Typically, these defects appear during fracture consolidation, within the newly formed subperiosteal bone, proximal to the fracture line, do not enlarge, and progressively disappear. We have previously shown a fatty density on CT scan within the early cortical defect. We now present two additional cases in which early CT scans appeared to confirm that these transient cortical defects may consist of fat, and probably result from the inclusion of medullary fat within the subperiosteal haematoma.