Need for symptomatic management in advanced multiple sclerosis.

OBJECTIVE: A majority of patients with advanced multiple sclerosis (MS) need symptomatic treatment. Many MS-related symptoms may not be recognized and thus are not treated. We conducted a study to estimate the prevalence of inadequate symptomatic treatment of patients with advanced MS. METHODS: Patients with advanced MS admitted to a specialist MS rehabilitation clinic were included in this study. Severity was assessed using the Expanded Disability Status Scale (EDSS). The information we collected included age of onset, initial course, time to sustained disability, pharmacological treatment, degree of spasticity, pain and bladder dysfunction, and unmet needs of symptomatic treatment. RESULTS: In total, we assessed demographic and clinical characteristics in 129 patients with a mean age of 56 years and a median EDSS of 7.5. The proportion with inadequate symptom treatment was regarding spasticity 46%, pain 28%, and bladder dysfunction 23%. DISCUSSION: This study showed that a large proportion of patients with advanced MS had lack of symptomatic treatment. These patients probably underuse neurological specialist services. Better symptomatic treatment could contribute to improving quality of life of people with MS.

Very long-term mortality after ischemic stroke: predictors of cardiovascular death.

BACKGROUND: The purpose of this article is to find possible predictors associated with long-term mortality and long-term cardiovascular death after stroke. METHODS: A cohort of 550 patients with acute stroke admitted to a single hospital within 24 h of a stroke were recruited consecutively. Patients were followed for 12 years or until death. Information on death was collected through linkage with the National Population Register of Statistics Norway, an official register containing name, date of birth, address, and date of death, and the National Register of Cause of Death. Cardiovascular deaths were defined as ICD 9 codes 390 to 448 and ICD 10 codes I00 to I99. RESULTS: The proportion of cardiovascular deaths was 71%. In multivariate Cox regression analysis of cardiovascular mortality, stroke severity (HR 2.78; 95% CI 2.13-3.57), hemorrhagic stroke (2.0; 1.43-2.78), diabetes (1.85; 1.37-2.50), male gender (1.69; 1.31-2.17), ischemic heart disease (1.56; 1.16-2.13), age (1.06; 1.04-1.08), and right hemispheric stroke (1.49; 1.16-1.89) were significant predictors. DISCUSSION: This study shows that age, male gender, stroke severity, hemorrhagic stroke, diabetes, ischemic heart disease, and right hemispheric stroke are predictors associated with increased risk of long-term cardiovascular mortality. Neither atrial fibrillation, antihypertensive treatment on admission, smoking, or living alone was risk factors for late cardiovascular deaths.

Survival over 12 years following acute stroke: initial treatment in a stroke unit vs general medical wards.

BACKGROUND: Few studies have assessed the influence of the organization of stroke care on long-term survival. AIMS OF THE STUDY: To compare survival over 12 years after stroke between subjects treated in an acute stroke unit (SU) and those treated in general medical wards (GMW). METHODS: In total, 550 subjects ≥60 years of age with acute stroke were prospectively allocated according to date of birth (day of the month) to treatment in a SU with relatively short length of stay or GMWs. We assessed survival through a link to the register of Statistics Norway. Groups were compared using Kaplan-Meier analysis on an intention-to-treat basis. RESULTS: Of the 550 eligible subjects, 271 were allocated to a SU and 279 to GMWs. There still was no difference in mortality over 12 years between the groups (P = 0.15, log-rank test) CONCLUSIONS: An acute SU offering early treatment and rehabilitation did not offer better long-term mortality after stroke in patients ≥60 years old than initial treatment in GMWs.

Delirium in acute stroke--prevalence and risk factors.

BACKGROUND: Delirium is frequently seen as a major complication among elderly stroke patients. Few studies have prospectively studied delirium as a complication of acute stroke. In these studies, the results are conflicting regarding risk factors and estimated prevalence. The aims of the present study are to assess the prevalence of delirium in patients with acute stroke treated in an acute Stroke Unit, identify characteristics of patients with delirium and important factors associated with the development of delirium. METHODS: We conducted a prospective study of patients with delirium and acute stroke consecutively admitted to a Stroke Unit. The diagnosis of delirium was based on Confusion Assessment Method (CAM). CAM is devised from DSM-III-R criteria based on the diagnosis of delirium, and is a simple test with high sensitivity and specificity. RESULTS: One hundred and seventy-eight patients with a diagnosis of stroke were eligible for the study. The prevalence of delirium in acute stroke in our study was 10% (18 of 178 patients). Patients with delirium had significantly longer length of stay in the Stroke Unit (12.3 vs 8.5 days, P < 0.004). Prestroke dementia [odds ratio (OR) 18.7], hemianopsia (OR 12.3), apraxia (OR 11.0), higher age (OR 5.5) and infection (UTI or pneumonia) (OR 4.9) during in-hospital stay were associated with increased risk of delirium. CONCLUSION: One of 10 stroke patients had delirium. This is the lowest prevalence of delirium shown in acute stroke patients. In our study, all patients were treated in a Stroke Unit. A Stroke Unit like the Scandinavian model may be beneficial in preventing delirium.

Abnormal craniofacial development and expression patterns of extracellular matrix components in transgenic Del1 mice harboring a deletion mutation in the type II collagen gene.

OBJECTIVE: To analyze the effect of a type II collagen mutation on craniofacial development in transgenic Del1 mice. DESIGN: Samples from homozygous (+/+) and heterozygous (+/-) transgenic Del1 mice harboring mutations in the type II collagen gene as well as non-transgenic (-/-) littermates were collected at days 12.5, 14.5, 16.5 and 18.5 of gestation. The cartilaginous and bony elements of the craniofacial skeleton were analyzed after staining with alcian blue, alizarin red S and von Kossa. The expression patterns of type II, IX and X collagens and aggrecan were analyzed by immunohistochemistry and in situ hybridization. RESULTS: Several abnormalities were observed in the craniofacial skeleton of transgenic Del1 mice. These include an overall retardation of chondrogenesis and osteogenesis in Del1 +/+ mice, and to a lesser extent also in Del1+/- mice. Characteristic findings in Del1 +/+ mice included a reduced anterioposterior length, a smaller size of the mandible, a palatal cleft and a downward bending snout. We also detected retarded ossification of calvarial bones in Del1 +/+ and +/- mice when compared with Del1 -/- mice. A surprising finding was the presence of both type II and X collagens and their mRNAs in the periosteum of the cranial base. CONCLUSION: The present study confirms the important role of type II collagen mutation in craniofacial development and growth. In addition to affecting endochondral ossification, the type II collagen mutation also disturbs intramembranous ossification in the developing craniofacial skeleton.

Distribution of insulin-like growth factor-I mRNA in the mandibular condyle and rib cartilage of the rat during growth.

This study makes a molecular biological comparison of primary and secondary cartilage at an early phase of postnatal development. The distribution of insulin-like growth factor-I (IGF-I) mRNA expression in the mandibular condyle and rib cartilage of 1-28-day-old rats was examined after in situ hybridisation using an oligo probe cocktail for IGF-I mRNA. In the condyle, expression was localised to a narrow strip under the articular layer where the cells are undifferentiated. Essentially, no differences were found in IGF-I synthesis within three samples from the same age group or between different age groups. In rib cartilage, IGF-I mRNA was localised within the germinative, proliferative and early hypertrophic cell layers in 1-28-day-old rats. Again, there were no differences in expression among animals of the same age or as a function of age. This pattern of IGF-I mRNA expression indicates that IGF-I synthesis during growth of the mandibular condylar cartilage is different from that of costal cartilage. The findings shed light on the problem of overgrowth often associated with the use of costochondral grafts to replace defective mandibular condyles.

Induced leukemia and antineoplastic agent carmustine cause permanent changes in craniofacial growth of immature rats.

OBJECTIVES: The purpose of the present study was to investigate the possible effects of untreated terminal leukemia on craniofacial growth (Study I), and also the effects of the antineoplastic agent carmustine on craniofacial growth in both leukemic and healthy rats (Study II). MATERIAL: A total of 367 inbred Piebald variegated rats was used. METHOD: Transmission of leukemic cells was carried out intraperitoneally at 30 days of age, and without treatment (Study I), the rats reached the terminal phase within 17 +/- 1 days. Rats with induced leukemia was cured with 10 mg/kg carmustine (BCNU) given on days 6 and 13 following cell transmission (Study II), the rats remaining in remission until they were killed at 100 days of age. Final weight was recorded and 12 craniofacial dimensions and tibial length were measured with a digital sliding caliper. RESULTS: The results showed that the effect of untreated terminal rat leukemia (Study I) on craniofacial growth differed between the genders. Male rats showed clearly reduced dimensions of facial structures and also retarded general body growth, whereas females showed differences mainly in general body growth. The effect of cured leukemia (Study II) as such was minor, while BCNU had a strong and permanent reducing effect on both craniofacial and general body growth in both genders. CONCLUSION: We suggest that the results in Study I came both from a direct effect of leukemia and an indirect effect of untreated terminal leukemia through malnutrition. The alkylating agent BCNU seemed to be the main cause of permanent craniofacial and general growth retardation in Study II.

Distribution of fibroblast growth factors (FGFR-1 and -3) and platelet-derived growth factor receptors (PDGFR) in the rat mandibular condyle during growth.

OBJECTIVES: To elucidate the role of the fibroblast growth factors 1 and 3 (FGFR-1, -3) and the platelet derived growth factor (PDGFR) in the growth of the mandibular condylar cartilage in the rat. SETTING AND SAMPLE POPULATION: Institute of Dentistry and Department of Biostatistics, University of Turku, Turku, Finland. The material consisted of 1- to 21-day-old Long-Evans/Turku rats (total of 24 animals, three in each age group). DESIGN: An immunohistological in vivo study combined with histomorphometry and biostatistical analysis. EXPERIMENTAL VARIABLE: The animals were killed with an overdose of carbon dioxide and thereafter decapitated. Heads were fixed in 4% paraformaldehyde, decalcified in 12.5% ethylenediaminetetraacetic acid, cut sagittally into two halves and sectioned sagittally at 6 microns. In order to detect FGFR-1, -3 and PDGFR the sections were treated with H2O2/methanol (1:100), after which FGFR-1 and PDGFR monoclonal and FGFR-3 polyclonal antibodies were applied. The reaction products were visualized by using the Vectastain ABC Elite Kit using peroxidase substrate kit DAB as substrate. Negative and positive controls were also prepared. The sections were counterstained with hematoxylin. OUTCOME MEASURE: In order to measure the depth of the cell layer labeled with FGF-1, -3 and PDGF receptors, the condylar head was divided into four regions: anterior, superior, posterosuperior and posterior. The measurements were made perpendicular to the articular surface using a computerized image analysis system, the images being acquired by means of a microscope connected to a CCD camera. The mean of five equally distributed measurements of each region was used to indicate the depth of the cell layers secreting the receptors. Regression analysis was used to evaluate the association between the depth of the labeled cell layer in relation to total depth of the condylar head, as a function of age. RESULTS: Our results show that the depth of the cell layer labeled for FGFR-1, -3 and PDGFR increase significantly as a function of age in the mandibular condylar head of rats. CONCLUSION: Increase in the cell layer labeled for FGFR-1, -3 and PDGFR occurs during the stage when the articular function of the mandibular condyle intensifies. FGFR-1, -3 and PDGFR evidently have an important role in the growth regulation of the condylar cartilage during the most rapid growth period in the rat.

Incidence and predictors for post-stroke epilepsy. A prospective controlled trial. The Akershus stroke study.

The aim of the study was to assess the incidence and identify predictors for post-stroke epilepsy (PSE), in particular the possible influence of treatment in a stroke unit (SU). Patients with PSE were identified between 4 weeks and 1 year after the stroke. Different parameters were studied as possible predictors. Twelve patients (2.5%) developed PSE during 12 months. Four of the patients (33%) were treated in an SU and eight of the patients (67%) were treated in general medical wards (GMWs) (P=0.50). Mean age in those with PSE was 75 and 76 in those without (P=0.57). Four out of 363 patients (1.1%) with minor stroke [Scandinavian Stroke Scale (SSS)-score >30] developed PSE. Seven out of 104 patients (6.3%) with severe stroke developed PSE (P=0.004). In the multivariate analysis SSS-score scores below 30 was a significant predictor for incidence of PSE (odds ratio=6.1, P=0.003). At 12 months the incidence of PSE was 2.5%. SSS-score below 30 was a significant predictor for PSE, whilst age and treatment in SU versus GMW were not.

Craniofacial morphology in preschool children with sleep-related breathing disorder and hypertrophy of tonsils.

UNLABELLED: The purpose of this study was to examine craniofacial morphology, pharyngeal airway space and hyoid bone position in preschool children with sleep-related breathing disorder associated with hypertrophy of tonsils (SBDT). Thirty-eight preschool children, mean age 4.7 y, with SBDT and with an apnoea index (AI) of 0 < AI < 5, were divided into two groups. One consisted of 15 children with sleep-related breathing disorder (SBD) and more than 75% of the tonsils visible (GIII) and the other of 23 children with SBD and 25-75% of the tonsils visible (GII). The control group consisted of 31 children without ear, nose and throat disease and with GI (barely visible) tonsils. Compared with the controls, GIII children had a retrognathic mandible, a large posterior facial height, a large interincisal angle with retroclined lower incisors, a narrow pharyngeal airway space, an anterior tongue base position and a long soft palate. Compared with the controls, GII children had a large anterior lower facial height and a short nasal floor. However, like the controls, GII children did not have a retrognathic mandible. CONCLUSION: The findings show that children with SBDT display a characteristic facial appearance at an early age. Since the condition has an effect on growth, it needs to be prevented by controlling morphology and function at the preschool age.

Survival of unselected stroke patients in a stroke unit compared with conventional care.

BACKGROUND: Recent meta-analyses have reported a beneficial effect of stroke units compared with traditional care, both on patient survival and on dependency after one year. AIM: To determine whether these results can be reproduced outside a clinical trial setting. SETTING: A medium-sized general hospital. METHODS: From 1993 to 1998, all patients aged >60 years with suspected acute stroke were allocated either to a stroke unit or general medical wards according to date of birth (day of the month). Patients were identified retrospectively, using a discharge diagnosis of ICD-9 codes 431, 434 and 436. We assessed 30-day and 1-year survival. RESULTS: In the stroke unit, 926/1128 patients survived at 30 days, vs. 905/1141 in the general medical wards (p=0.08). Beyond the first 30 days, there was no difference in survival (p=0.27). Under Cox regression analysis, there was a 20% reduction in mortality in the stroke unit after 30 days compared with the general medical wards (RR 0.80, p=0.02) after adjusting for age, gender, stroke type and season of the year. DISCUSSION: In this, the largest single-centre study to evaluate the survival benefit of a stroke unit, survival at 30 days was increased, although not significantly so. Survival at one year was unchanged.

Growth hormone and insulin-like growth factor I receptors in the temporomandibular joint of the rat.

While there are numerous investigations on hormonal control of long bone epiphyseal growth, corresponding knowledge is sparse concerning the condylar cartilage. We investigated the distribution of growth hormone (GH) and insulin-like growth factor I (IGF-I) receptors in the temporomandibular joint (TMJ), especially the condyle, and compared the findings with information of long bone epiphyseal plates. The localization of the receptors was examined in vivo by immunohistochemical methods in one- to 21-day-old rats. GH receptors were detected in various components of the TMJ, but not in the fibrous articular surface or in the cartilage layers of the condyle. IGF-I receptors were found in the fibrous articular surface of the condyle and particularly in the superior and posterosuperior regions of the condylar cartilage, the depth of the labeled cell layer increasing significantly with age. It is evident that the expression of GH and IGF-I receptors is area-specific in the TMJ. Early post-natal growth and development of the mandibular condylar cartilage seem to be IGF-I-dependent but not directly dependent on GH.

Disturbances in craniofacial morphology in children treated for solid tumors.

Because of increased survival rates in childhood cancer, special interest has been focused on the side-effects of the therapy and the quality of life in long-term survivors. Our aim was to investigate craniofacial growth in children who had received different kinds of antineoplastic therapies for solid tumors. A total of 40 children treated in the Turku University Central Hospital were examined and divided into three different groups. Group 1 comprised 18 children treated for intracranial tumors with cranial irradiation (CRI) and chemotherapy (CT) including alkylating agents. Seven children out of 18 in this group received growth hormone (GH) therapy. In Group 2, 11 children with extracranial solid tumors also received multiagent CT including alkylating agents, but no CRI. Group 3 consisted of 11 children treated for Wilm's tumor with CT, which did not include alkylating agents or CRI. A total of 19 linear and four angular variables from the lateral cephalograms of the subjects were measured. Most deviations in craniofacial structures were found in children treated with combined CRI and multiagent CT. All disturbances were seen in the vertical measurements which were reduced when compared to the matched controls. It seems reasonable to assume that impaired growth following combined radio- and chemotherapy, as well as GH treatment, particularly affects cartilage-mediated growth. However, the deviations seen in the present study were fairly minor and did not usually require clinical consideration.

The benefit of an acute stroke unit in patients with intracranial haemorrhage: a controlled trial.

OBJECTIVES: Patients with stroke receiving organised inpatient (stroke unit) care after stroke are more likely to be alive and independent compared with patients offered conventional care. The objective was to determine the effect of an acute stroke unit on patients with primary intracranial haemorrhage. METHODS: In a prospective controlled study, the effect of an acute stroke unit was examined on 30 day and 1 year mortality in patients with primary intracranial haemorrhage. Patients treated in general medical wards served as controls. RESULTS: Of 121 patients included, 56 were allocated to an acute stroke unit and 65 to a general medical ward. The 30 day mortality rate was 39% in the acute stroke unit compared with 63% in the general medical wards, and the 1 year mortality rates were 52% and 69%, respectively. There was a difference between the 30 day and 1 year survival curves between the groups (p=0.007 and 0.013, respectively); however, there was no difference in survival between 30 and 365 days. There was no difference in risks of being discharged home or to long term care between the groups. CONCLUSIONS: In this study admission to an acute stroke unit reduced mortality 30 days and 1 year after primary intracranial haemorrhage, which could be attributed to a large difference in survival during the first 30 days.

Craniofacial growth of immature rats following administration of vincristine and doxorubicin.

The aim of the present study was to investigate the possible short-term effect of two anti-neoplastic drugs, vincristine and doxorubicin, on the craniofacial skeleton in young rats. On the basis of findings from pilot experiments, one dose of 0.0375 mg/kg vincristine or 1.0 mg/kg doxorubicin was given parenterally to inbred Long-Evans/Turku rats at 10 or 30 days of age, and followed up until 30 or 50 days, respectively. Some 30-day-old rats received two additional doses of the drugs, 3 and 6 days after the first injection. Controls were given physiological saline. A total of 310 rats were used: 40 for the pilot study, 180 medicated, and 90 control animals for the experiment itself. The weights of the rats were recorded, a number of craniofacial dimensions were measured, and the neurocranial volume determined in the case of the most severely affected rats. The weight gain of the younger rats was retarded, as was that of the older rats that received repeated drug injections. Most dimensions of the craniofacial skeleton were significantly smaller in the vincristine-treated young animals, and following multiple injections of vincristine or doxorubicin also in the older ones when compared with the controls. Contrary to the general pattern, the measurements of the foramen magnum increased in the older rats, a feature associated with the decrease in brain cavity volume observed in those that received vincristine. These findings indicate that anti-neoplastic agents can have a short-term adverse effect on the craniofacial growth and that the morphological changes are differential, rather than uniform.

Catch-up growth and craniofacial dimensions following administration of the antineoplastic agent vincristine to young rats.

Decreased linear growth is a common problem during childhood anticancer therapy. Although catch-up growth may occur, short stature is sometimes permanent. A macroscopic experimental study was performed to investigate the catch-up growth of body and craniofacial structures of growing rats subjected to the antineoplastic agent vincristine. A total of 150 Long-Evans/Turku strain rats were randomly divided into one of two treatment or control groups. A group of 10-d-old rats was given a single s.c. injection of 0.0375 mg/kg vincristine, while another treatment group of 30-d-old rats received three injections of 0.05 mg/kg vincristine. All rats were killed at the age of 100 d. Twelve different craniofacial dimensions, tibia and body length, and final weight were recorded. Female and male groups were analyzed separately. As an expression of catch-up growth, most of the body and craniofacial structures returned to the control level by 100 d of age. A clear sex-dependency was seen in the measurements which remained reduced so that females seemed to catch-up better than males. The timing of the first injection was found to be important for the catch-up growth in the neurocranial area.

Advanced dental maturity in children with juvenile rheumatoid arthritis.

The subjects of the investigation comprised 95 girls and 73 boys with juvenile rheumatoid arthritis (JRA), and 102 girls and 66 boys representing healthy controls, all with a chronological age from 6.3 to 14.4 yr. The dental development was assessed from panoramic radiographs using a seven-tooth model. The radiographs were evaluated on three separate occasions with a minimum interval of one month in a randomized order, and blind with respect to absence or presence of JRA. In both JRA patients and healthy controls, dental maturity was ahead of chronological age. In addition, dental maturity was significantly advanced in JRA patients with 0.26 yr in girls and 0.28 yr in boys. It is tentatively suggested that the advanced dental development in JRA patients compared with healthy children was partly an effect of treatment with cortisone, while the influence of the disorder per se remains to be elucidated.

Collagen I and II mRNA distribution in the rat temporomandibular joint region during growth.

The distribution of type I and II collagen synthesis in the temporomandibular joint (TMJ) area of 1- to 28-day-old rats was studied after hybridization with probes to pro alpha1(I) and pro alpha1(II) collagen mRNA, and stain intensity through the various cartilaginous zones of the mandibular condyle and other areas of TMJ was assessed. The pro alpha(I) collagen mRNA was detected in the perichondrium/periosteum, in the fibrous and undifferentiated cell layers of the mandibular condyle, in the articular disc, and in all bone structures and muscles. The pro alpha1(II) collagen mRNA was found in the condylar cartilage and the articular fossa. Intensity in the condyle was highest in the chondroblastic layer and decreased towards the lower hypertrophic layer. In the condylar cartilage of the 21- to 28-day-old rats the chondroblastic cell zone was relatively narrow compared with the younger animals, whereas the reverse seems to be the case in the cartilage of the articular fossa. Changes in the pro alpha1(II) collagen mRNA were observed in the osseochondral junction area of the primary spongiosa, in that at the age of 5 days intense staining was found, whereas no staining was observed by 14 days. In the mineralizing zone, however, the majority of osteoblastic cells gave a positive signal with the pro alpha1(I) collagen probe. In conclusion, type II collagen synthesis of the mandibular condyle is restricted to its upper area. This differs from the long bone epiphyseal plate, where this type of collagen is produced virtually throughout the cartilage. Type II collagen synthesis of the fossal cartilage seems to increase as a function of age.

[Should patients with acute stroke routinely receive supplemental oxygen?]. / Skal pasienter med akutt hjerneslag rutinemessig ha ekstra oksygentilførsel?

BACKGROUND: Supplemental oxygen is often given routinely to all patients suffering from an acute stroke, although clinical evidence for its efficacy is not available. The object of this study was to study the impact on mortality, impairment and disability of supplemental oxygen given the first 24 hours after an acute stroke. MATERIAL AND METHODS: Patients admitted to hospital with acute stroke were randomly allocated to two groups: one group received supplemental oxygen (100% atmospheres, 3 litres/minute) for 24 hours (n = 292); whereas a control group did not receive additional oxygen (n = 258). RESULTS: One-year survival was 69% in the oxygen group and 73% in the control group (odds ratio 0.82; 95% CI 0.57-1.19; p = 0.30). Impairment scores and disability scores were comparable seven months after stroke. Among patients with Scandinavian Stroke Scale (SSS) > or = 40.82% in the oxygen group and 91% in the control group survived (odds ratio 0.45; 95% CI 0.23-0.90; p = 0.02). For patients with SSS < 40, 53% in the oxygen group and 48% in the control group survived (odds ratio 1.26; 95% CI 0.76-2.09; p = 0.54). INTERPRETATION: The study indicates that supplemental oxygen should not be given routinely to non-hypoxic stroke victims with minor or moderate strokes. Further research is needed for giving conclusive advice concerning oxygen supplementation for patients with severe strokes.

Effect of methotrexate alone and in combination with vincristine on craniofacial morphology in growing rats.

Craniofacial growth in young Long-Evans/Turku strain rats was studied following administration at different intervals of the antineoplastic agent methotrexate (MTX) and of a combination of two agents, MTX and vincristine (VCR). The 10-day-old rats tolerated only 1 subcutaneous injection of 0.75 mg/kg MTX, while single and repeated doses of 1.0 mg/kg MTX, or of the combination of MTX (1.0 mg/kg) and VCR (0.05 mg/kg), could be used for the 30-day-old rats. The rats were killed 20 days after the start of the experiment, i.e. at 30 or 50 days of age, respectively; their weights were recorded and a total of 12 craniofacial dimensions were measured. Owing to the relatively few significant sex differences, the dimensions recorded for the females and males were pooled. Administration of MTX alone or combined with VCR caused disturbed craniofacial growth, which was already evident following 1 single injection of MTX in the younger rats (10 to 30 days) and after repeated injections (every third day) of MTX alone or combined with VCR in the older rats (30 to 50 days). The body weights of all the medicated rats were initially retarded and catch-up growth, i.e. a return to control body weight levels, occurred by the end of the experiment only in the rats that received a single injection of MTX, but not after repeated injections. We conclude that the antineoplastic agent MTX alone or in combination with VCR administered at short intervals with pharmacologically adjusted doses has a short-term effect on the craniofacial skeleton of growing rats.