Postoperative cognitive dysfunction and its relationship to cognitive reserve in elderly total joint replacement patients.

Whether total joint replacement (TJR) patients are susceptible to postoperative cognitive dysfunction (POCD) remains unclear due to inconsistencies in research methodologies. Moreover, cognitive reserve may moderate the development of POCD after TJR, but has not been investigated in this context. The current study investigated POCD after TJR, and its relationship with cognitive reserve, using a more rigorous methodology than has previously been utilized. Fifty-three older adults (aged 50+) scheduled for TJR were assessed pre and post surgery (6 months). Forty-five healthy controls matched for age, gender, and premorbid IQ were re-assessed after an equivalent interval. Cognition, cognitive reserve, and physical and mental health were all measured. Standardized regression-based methods were used to assess cognitive changes, while controlling for the confounding effect of repeated cognitive testing. TJR patients only demonstrated a significant decline in Trail Making Test Part B (TMT B) performance, compared to controls. Cognitive reserve only predicted change in TMT B scores among a subset of TJR patients. Specifically, patients who showed the most improvement pre to post surgery had significantly higher reserve than those who showed the greatest decline. The current study provides limited evidence of POCD after TJR when examined using a rigorous methodology, which controlled for practice effects. Cognitive reserve only predicted performance within a subset of the TJR sample. However, the role of reserve in more cognitively compromised patients remains to be determined.

Depression and anxiety after total joint replacement among older adults: a meta-analysis.

OBJECTIVE: Patients usually experience good physical recovery after total joint replacement (TJR); however, it is unclear whether mood also improves. The current meta-analysis examined changes in depression and anxiety following TJR in older (≥50 years) patients in order to address this gap in the literature. METHODS: Data from 26 studies (4045 TJR, 55 controls) that assessed depression and/or anxiety pre- and post-surgery in TJR patients, with or without a control group, were analyzed. Prevalence rates and Cohen's d effect sizes were used to evaluate changes in the prevalence and severity of depression/anxiety, respectively. RESULTS: Approximately 23% of TJR patients had clinically significant levels of depression prior to surgery, which decreased to 13% one year later. The prevalence of anxiety could not be evaluated due to the limited available data. TJR patients did not show any clinically meaningful reductions in symptoms of depression or anxiety, following surgery. Compared to controls, there was no difference in symptom progression over time; although only one study examined this. CONCLUSIONS: TJR patients appear to have higher rates of clinically significant symptoms of depression before and after surgery, compared to the general population, however more research with adequate control groups is needed to confirm this. Only a modest improvement in the severity of depression and anxiety symptoms was noted post-surgery. However, existing research is limited; preventing definite conclusions regarding the impact of TJR on mood.

The ontogeny of the chin: an analysis of allometric and biomechanical scaling.

The presence of a prominent chin in modern humans has been viewed by some researchers as an architectural adaptation to buttress the anterior corpus from bending stresses during mastication. In contrast, ontogenetic studies of mandibular symphyseal form suggest that a prominent chin results from the complex spatial interaction between the symphysis and surrounding soft tissue and skeletal anatomy during development. While variation in chin prominence is clearly influenced by differential growth and spatial constraints, it is unclear to what degree these developmental dynamics influence the mechanical properties of the symphysis. That is, do ontogenetic changes in symphyseal shape result in increased symphyseal bending resistance? We examined ontogenetic changes in the mechanical properties and shape of the symphysis using subjects from a longitudinal cephalometric growth study with ages ranging from 3 to 20+ years. We first examined whether ontogenetic changes in symphyseal shape were correlated with symphyseal vertical bending and wishboning resistance using multivariate regression. Secondly, we examined ontogenetic scaling of bending resistance relative to bending moment arm lengths. An ontogenetic increase in chin prominence was associated with decreased vertical bending resistance, while wishboning resistance was uncorrelated with ontogenetic development of the chin. Relative to bending moment arm lengths, vertical bending resistance scaled with significant negative allometry whereas wishboning resistance scaled isometrically. These results suggest a complex interaction between symphyseal ontogeny and bending resistance, and indicate that ontogenetic increases in chin projection do not provide greater bending resistance to the mandibular symphysis.

Incidence of delirium following total joint replacement in older adults: a meta-analysis.

OBJECTIVE: Delirium is common in older adults following total joint replacement (TJR) of the hip and knee. However, reports of the incidence of delirium vary widely, limiting their usefulness. The current meta-analysis therefore examined (1) the incidence of delirium in older patients who underwent TJR and (2) whether these rates vary according to the (a) joint (hip/knee replacement), (b) inclusion/exclusion of patients who underwent simultaneous bilateral surgery, (c) inclusion/exclusion of patients with preexisting cognitive impairments, (d) type of anesthesia (regional/general), (e) method/frequency of assessment, and (f) postoperative interval. METHOD: Data from 24 studies (2,895 patients) that measured postsurgical delirium following TJR were analyzed. Mean weighted proportions were calculated using a random-effects model to assess the overall incidence of delirium and whether the rate varied according to the aforementioned variables. RESULTS: Overall, 17% of patients who underwent TJR developed delirium during hospital admission. Individual estimates varied from 0% to 82%, but this variability was not adequately explained by the variables that were examined. CONCLUSIONS: Delirium is relatively common following TJR; however, it remains unclear why individual estimates vary so widely. Health professionals working with these patients should remain alert to the presentation, diagnosis and management of delirium to optimize postsurgical outcomes.

The adaptive significance of mandibular symphyseal fusion in mammals.

The mandibular symphyseal joint is remarkably variable across major mammalian clades, ranging in adults from unfused (amphiarthrosis) to partially fused (synarthrosis) to completely ossified (synostosis). Experimental work conducted on primates suggests that greater ossification of the symphysis is a response to increased recruitment of the balancing-side (i.e. nonchewing side) jaw-adductor muscles during forceful unilateral biting and chewing, with increased fusion strengthening the symphysis against correspondingly elevated joint stresses. It is thus expected that species with diets composed primarily of foods that require high-magnitude bite forces and/or repetitive loading to process will be characterized by greater degrees of symphyseal ossification than species with relatively easy-to-process diets (i.e. food items typified by low toughness and/or low stiffness). However, comparative support for this idea is limited. We tested this hypothesis in four dietarily diverse mammalian clades characterized by variation in symphyseal fusion - the Strepsirrhini, Marsupialia, Feliformia, and Caniformia. We scored fusion in adult specimens of 292 species, assigned each to a dietary category based on literature accounts, and tested for an association between these two variables using Pagel's test for the correlated evolution of binary characters. Results indicate that greater fusion is associated with diets composed of resistant items in strepsirrhines, marsupials, and feliforms, providing some support for the hypothesis. However, no such relationship was detected in caniforms, suggesting that factors other than dietary mechanical properties influence symphyseal ossification. Future work should focus on such factors, as well as those that favour an unfused mandibular symphysis.

Defining MAP3 kinases required for MDA-MB-231 cell tumor growth and metastasis.

Analysis of patient tumors suggests that multiple MAP3 kinases (MAP3Ks) are critical for growth and metastasis of cancer cells. MAP3Ks selectively control the activation of extracellular signal-regulated kinase 1/2 (ERK1/2), Jun N-terminal kinase (JNK), p38 and ERK5 in response to receptor tyrosine kinases and GTPases. We used MDA-MB-231 cells because of their ability to metastasize from the breast fat pad to distant lymph nodes for an orthotopic xenograft model to screen the function of seven MAP3Ks in controlling tumor growth and metastasis. Stable short hairpin RNA (shRNA) knockdown was used to inhibit the expression of each of the seven MAP3Ks, which were selected for their differential regulation of the MAPK network. The screen identified two MAP3Ks, MEKK2 and MLK3, whose shRNA knockdown caused significant inhibition of both tumor growth and metastasis. Neither MEKK2 nor MLK3 have been previously shown to regulate tumor growth and metastasis in vivo. These results demonstrated that MAP3Ks, which differentially activate JNK, p38 and ERK5, are necessary for xenograft tumor growth and metastasis of MDA-MB-231 tumors. The requirement for MAP3Ks signaling through multiple MAPK pathways explains why several members of the MAPK network are activated in cancer. MEKK2 was required for epidermal growth factor receptor and Her2/Neu activation of ERK5, with ERK5 being required for metastasis. Loss of MLK3 expression increased mitotic infidelity and apoptosis in vitro. Knockdown of MEKK2 and MLK3 resulted in increased apoptosis in orthotopic xenografts relative to control tumors in mice, inhibiting both tumor growth and metastasis; MEKK2 and MLK3 represent untargeted kinases in tumor biology for potential therapeutic development.

25-year analysis of a dental undergraduate research training program (BSc Dent) at the University of Manitoba Faculty of Dentistry.

Research in the context of the dental school has traditionally been focused on institutional/faculty accomplishments and generating new knowledge to benefit the profession. Only recently have significant efforts been made to expand the overall research programming into the formal dental curriculum, to provide students with a baseline exposure to the research and critical thinking processes, encourage evidence-based decision-making, and stimulate interest in academic/research careers. Various approaches to curriculum reform and the establishment of multiple levels of student research opportunities are now part of the educational fabric of many dental schools worldwide. Many of the preliminary reports regarding the success and vitality of these programs have used outcomes measures and metrics that emphasize cultural changes within institutions, student research productivity, and student career preferences after graduation. However, there have not been any reports from long-standing programs (a minimum of 25 years of cumulative data) that describe dental school graduates who have had the benefit of research/training experiences during their dental education. The University of Manitoba Faculty of Dentistry initiated a BSc Dent program in 1980 that awarded a formal degree for significant research experiences taking place within the laboratories of the Faculty-based researchers and has continued to develop and expand this program. The success of the program has been demonstrated by the continued and increasing demands for entry, the academic achievements of the graduates, and the numbers of graduates who have completed advanced education/training programs or returned to the Faculty as instructors. Analysis of our long-term data validates many recent hypotheses and short-term observations regarding the benefits of dental student research programs. This information may be useful in the design and implementation of dental student research programs at other dental schools.

The effect of elevated dietary cholesterol on pulmonary surfactant function in adolescent mice.

It has been established that phospholipids and cholesterol interact in films of pulmonary surfactant (PS). Generally it is thought that phospholipids increase film stability whereas cholesterol increases film fluidity. To study this further, we modified dietary cholesterol in mice which received either standard rodent lacking cholesterol (sd), or high cholesterol (2%) diet (hc) for 1 month. Phospholipid stability was investigated by a capillary surfactometer (CS), which measures airflow resistance and patency. PS was collected by bronchiolar lavage and centrifuged to obtain the surface-active film (SAF). Results showed that the hc-SAF had significantly more cholesterol than sd-SAF. CS analyses at 37 degrees C showed no significance differences in airflow resistance between hc-SAF and sd-SAF. However, at 37 degrees C, sd-SAF showed greater ability to maintain patency compared to hc-SAF, whereas at 42 degrees C hc-SAF showed patency ability similar to sd-SAF. The results suggested that increased cholesterol in hc-SAF induced less stability in the SAF possibly due to cholesterol's fluidizing effect on phospholipids at physiological temperatures.

In vitro dissolution of tritium-loaded particles from the JET fusion machine.

With the experimental evolution of fusion power the levels of tritium used will increase as will the potential for human exposure. Tritium-loaded carbon particles produced during the experimental operation of the Joint European Torus fusion tokamak have been characterised in terms of size, elemental composition and specific activity of tritium elsewhere. The aim of this study was to characterise the dissolution of tritium from these particles in order to derive dose coefficients for this material and provide guidance on monitoring procedures should it be inhaled accidentally. The dissolution of tritium was measured for 100 d in lung serum simulant from two batches of materials, SG1 and SG2, which were obtained from carbon tiles originating from different positions in the reactor. Retention over this period followed a three-component exponential. About 1-5% dissolved within a minute, and up to a further 20% dissolved over 100 d for the SG1 materials but <1% for the SG2 materials. Dissolution between the SG1 materials varied greatly, whereas the SG2 materials were similar. As a result of this variability, the assessed dose from urinary excretion could be in error by up to two orders of magnitude depending on the material inhaled. It is recommended that (i) the dissolution is measured for a wider range of materials, preferably dusts collected in working areas, and (ii) in vivo studies are performed to characterise fully the urine excretion of tritium from these materials. This information could be used to provide improved guidance on dose assessment after special or routine monitoring, taking account of the likely variation of particle size and biological retention half times.

DNA fragmentation in developing lung fibroblasts exposed to Stachybotrys chartarum (atra) toxins.

Stachybotrys chartarum (atra) is a toxic mold that grows on water-damaged cellulose-based materials. Research has revealed also that inhalation of S. chartarum spores caused marked changes in respiratory epithelium, especially to developing lungs. We analyzed the epigenetic potential of S. chartarum spore toxins on developing rat lung fibroblasts using single cell gel electrophoresis (comet assay). Isolated fetal lung fibroblasts were exposed to S. chartarum spore toxins for 15 min, 3, 14, or 24 hr and control cells were exposed to saline under the same conditions. Cells were embedded in agarose, electrophoresed under alkaline conditions and silver stained. DNA damage was assessed in terms of fragmentation as measured by comet tail length (DNA migration) and intensity (% DNA contained within head and tail). Upon visual inspection, control fibroblasts showed no DNA fragmentation whereas S. chartarum-treated cells had definable comets of various degrees depending upon the time-course. Analyses of the comets revealed that exposure to S. chartarum spore toxins for at least 15 min to 14 hr, induced increased DNA fragmentation in a time-dependent manner. The fact that exposure to toxins for 24 hr showed less damage suggested that developing lung fibroblasts may have the capability of repairing DNA fragmentation.

Anti-Müllerian hormone inhibits initiation of growth of human primordial ovarian follicles in vitro.

BACKGROUND: Anti-Müllerian hormone (AMH) inhibits the initiation of the development and early growth of mouse ovarian follicles. Furthermore, the ovarian follicle pool diminishes prematurely in AMH-knockout mice. In this study, we examined whether AMH plays a similar role in humans, controlling ovarian follicle growth. METHODS: Human ovarian cortical tissue biopsy specimens were cut into small pieces and cultured for 7 days in medium containing rat recombinant AMH at 0, 10, 30 or 100 ng/ml. The developmental stages and viability of the follicles were evaluated from histological sections. RESULTS: Similar to previous studies, significant initiation of follicle growth was observed in almost all culture media, as demonstrated by a significantly smaller proportion of primordial follicles (14-26%) compared with non-cultured control tissue (56%). The exception was tissue in medium supplemented with AMH at 100 ng/ml. Here, the proportion of primordial follicles was not significantly different from that in non-cultured tissue; furthermore, it was significantly greater than that in vehicle control cultures and cultures containing AMH at 10 ng/ml, indicating the inhibition of growth initiation. Viability was unaffected by the presence of AMH when compared with tissues in control media. CONCLUSIONS: Recombinant AMH at a concentration of 100 ng/ml has an inhibitory effect on early human ovarian follicular development in vitro, suppressing the initiation of primordial follicle growth.

Doses from the consumption of Cardiff Bay flounder containing organically bound tritium.

ICRP dose coefficients for the ingestion of organically bound tritium (OBT) by adults and children are intended for general application to unspecified forms in diet and may not be applicable to intakes of a specific form of OBT. To obtain information relating to OBT in fish from Cardiff Bay, the retention of tritium in adult rats was determined after administration as either tritiated water (HTO) or dried flounder flesh containing OBT. Two components of retention were obtained in each case. The first component, attributable to tritium equilibrating with body water, had a half-time of retention of 3 days in each case, and accounted for 97% of the intake as HTO and 70% after intake of OBT in flounder. Results were consistent with rapid catabolism of a large proportion of flounder OBT to HTO. The second component of retention, attributable to OBT in rat tissues, accounted for 3% of tritium intake as HTO and 30% after intake as flounder OBT; the half-times of retention were 10 days and 25 days, respectively. The results obtained after administration as HTO are consistent with published animal data and correlate with the ICRP assumptions for adult man of half-times of 10 days for 97% behaving as HTO in body tissues and 40 days for 3% incorporated into OBT in body tissues. The results obtained after administration of flounder OBT suggest that appropriate assumptions for retention in adult man are 70% with a 10 day half-time and 30% with a 100 day half-time. These assumptions result in an ingestion dose coefficient of 6 x 10(-11) Sv Bq(-1). This compares with the ICRP value for OBT ingestion by adults of 4.2 x 10(-11) Sv Bq(-1), based on half-times of 10 days and 40 days applied to equal proportions of retained tritium. It is proposed that a dose coefficient of 6 x 10(-11) Sv Bq(-1) should be applied to tritium in flounders from Cardiff Bay. It is further proposed that this dose coefficient should be applied to all ingestion intakes by adults relating to this source of exposure, unless specific information is available showing that a significant proportion of the intake is HTO. The same proposals apply to dose coefficients derived here for flounder OBT consumption by children.

Stachybotrys chartarum alters surfactant-related phospholipid synthesis and CTP:cholinephosphate cytidylyltransferase activity in isolated fetal rat type II cells.

Stachybotry chartarum, a fungal contaminant of water-damaged buildings commonly grows on damp cellulose-containing materials. It produces a complex array of mycotoxins. Their mechanisms of action on the pulmonary system are not entirely clear. Previous studies suggest spore products may depress formation of disaturated phosphatidylcholine (DSPC), the major surface-active component of pulmonary surfactant (PS). If S. chartarum can indeed affect formation of this phospholipid, then mold exposure may be a significant issue for pulmonary function in both mature lung and developing fetal lung. To address this possibility, fetal rat type II cells, the principal source of DSPC, were used to assess effects of S. chartarum extract on formation of DSPC. Isolated fetal rat lung type II cells prelabeled with 3H-choline and incubated with spore extract showed decreased incorporation of 3H-choline into DSPC. The activity of CTP:cholinephosphate cytidylyltransferase (CPCT), the rate-limiting enzyme in phosphatidylcholine synthesis was reduced by approximately 50% by a 1:10 dilution of spore extract. Two different S. chartarum extracts (isolates from S. chartarum (Cleveland) and S. chartarum (Hawaiian)) were used to compare activity of CPCT in the presence of phosphatidylglycerol (PG), a known activator. PG produced an approximate two-fold increase in CPCT activity. The spore isolate from Hawaii did not alter enzyme activity. S. chartarum (Cleveland) eliminated the PG-induced activation of CPCT. These results support previous observations that mold products alter PS metabolism and may pose a risk in developing lung, inhibiting surfactant synthesis. Different isolates of the same species of fungus are not equivalent in terms of potential exposure risks.

Medium-term dexa analysis of an uncemented femoral component.

We investigated the bone remodelling around the AML uncemented femoral component using DEXA analysis and plain radiography in 19 patients at a mean of 89 months from operation. All patients had previously been analysed at a mean of 32 months after surgery. We found a decrease in bone mineral density around the AML implant between the two scans in Gruen zones 1,2 and 6 of up to 8%, but an increase in zones 4,5 and 7 of up to 36%. The increase in zones 4 and 5 were statistically significant (P>0.05). The relative difference between the operated and unoperated hips also showed a reduction in the bone density ratio with time, except in zones 4 and 5 where an increase was seen. We confirm the results of previous studies of proximal stress shielding and distal loading around the AML implant and demonstrate that bone remodelling continues in the medium term. (Hip International 2004; 14: 182-8).

Risk of congenital anomalies near the Byker waste combustion plant.

BACKGROUND: The aim of this study was to determine whether the risk of congenital anomalies in a population resident close to a waste combustion plant located at Byker in the city of Newcastle upon Tyne, United Kingdom, was higher than in a population resident further away. METHODS: A geographical study was carried out on the prevalence of congenital anomalies in residents living within 3 km (inner zone) of the Byker combustion plant compared with those living 3-7 km (outer zone) from the plant. There were 81255 live births (1985-1999) and 1508 cases with chromosomal and non-chromosomal congenital anomalies. The cases were identified from the Northern Region Congenital Abnormality Survey. RESULTS: After the site commenced operation the estimated rate ratio (inner versus outer zone) was 1.11 (95 per cent confidence interval (CI) 0.96-1.28) adjusted for socio-economic deprivation. There was significant heterogeneity across years and an increasing trend, of marginal significance (p = 0.07), in the rate ratio. The inner zone rate approached or became significantly higher than that in the outer zone in some of the later years. CONCLUSIONS: No significant overall association between the number of congenital anomalies and proximity of residence to the Byker waste combustion plant has been found in this study. Significantly increased rates near the site during the later years may suggest a possible risk but are difficult to interpret. More comprehensive, multi-site investigations around other waste combustion plants are indicated.

Elasticity in extracellular matrix 'shape modules' of tendon, cartilage, etc. A sliding proteoglycan-filament model.

Connective tissues (CTs), which define bodily shape, must respond quickly, robustly and reversibly to deformations caused by internal and external stresses. Fibrillar (elastin, collagen) elasticity under tension depends on molecular and supramolecular mechanisms. A second intra-/inter-molecular pair, involving proteoglycans (PGs), is proposed to cope with compressive stresses. PG interfibrillar bridges ('shape modules'), supramolecular structures ubiquitously distributed throughout CT extracellular matrices (ECMs), are examined for potential elastic properties. L-iduronate residues in shape module decoran PGs are suggested to be molecular springs, cycling through alternative conformations. On a larger scale, anionic glycosaminoglycan (AGAG) interfibrillar bridges in shape modules are postulated to take part in a sliding filament (dashpot-like) process, which converts local compressions into disseminated tensile strains. The elasticity of fibrils and AGAGs, manifest at molecular and larger-scale levels, provides a graduated and smooth response to stresses of varying degrees. NMR and rheo NMR, computer modelling, electron histochemical, biophysical and chemical morphological evidence for the proposals is reviewed.

The first and second 'laws' of chemical morphology, exemplified in mammalian extracellular matrices.

Tissues are supramolecular organisations. The permanent and semi-permanent biopolymers therein function collaboratively in specifically bonded frameworks of macromolecules according to the physico-chemical laws that govern the behaviour of all molecules. In this paper two 'laws' or principles are discussed which give insights into the development and function of tissues, particularly the extracellular matrices (ECMs) of connective tissues. The first 'law' is qualitative;- The shape of a tissue is implicit in the shapes of the biopolymers from which it is constructed. The tissue biopolymers are jigsaw pieces, if they don't fit precisely, there is no picture. The second 'law' is quantitative;-The composition of a tissue is determined by the stable, specific interactions between the macromolecules of which it is constructed. These basic ideas underlie the discipline of chemical morphology. The term chemical morphology implies both the chemistry of shape and the shape of chemicals. The first meaning is well exemplified in the ECMs of connective tissues, in which the shape of an organism is defined and maintained. Specific relationships between the fibrillar (collagenous) components and the soluble polymers (proteoglycans) are set in the context of the first law. Tissue electron histochemistry (the morphology of the tissue) and knowledge of secondary and tertiary structures of the participating biopolymers (the shapes of the chemicals) together provide a model susceptible to quantitative testing. Simple calculation shows that the amount of any ligand (e.g. a proteoglycan) specifically bound at a single binding site per unit of collagen fibril length (the D period) increases linearly with the fibril diameter. Given the amount of collagen (measured as hydroxyproline) and its density, the constant of proportionality is approximately 42. Comparisons of the quantitative relationship between collagen and proteoglycans predicted from the model agree well with those obtained by biochemical analyses of different tendons from three species at all stages of development. Thus, the second 'law' appears to hold in this case.

Fetal, perinatal, and infant death with congenital renal anomaly.

AIMS: To ascertain why 19.6% of pregnancies in which a fetal renal anomaly has been detected fail to produce a surviving child, and whether antenatal diagnostic accuracy has altered since specialised fetal medicine units were established in 1995. METHODS: An analysis of deaths was conducted among fetuses and babies with a congenital abnormality in the urinary tract notified to the Northern Region Congenital Abnormality Survey (NorCAS). There were 560 deaths among 2857 cases with an anomaly in the urinary tract delivered between 19 February 1984 and 21 March 2000. RESULTS: Renal anomaly was the cause of death in 323 (57.7%) cases. Excluding 10 which were not screened, 126 (60%) of 210 pre-1995 had been suspected antenatally and 81 (78.6%) of 103 post-1995. No abnormality had been suspected in 39 (18.6%) cases pre-1995 and four (3.9%) post-1995. Postnatal death occurred in 89 (41.4%) pre-1995 and in 13 (12%) post-1995. There were 209 cases of death caused by anomalies in other systems but with a renal anomaly present, of which 66 (31.6 %) were chromosomal and 36 (54.5%) had a horseshoe kidney. Of the cases with a horseshoe kidney, 56.3% had a chromosomal anomaly. CONCLUSIONS: The antenatal diagnosis of renal anomalies which cause death did not improve significantly in the second period of this study. However, the number of false positive antenatal diagnoses and the number of postnatal deaths were significantly lower and the number of pregnancy terminations were significantly higher. This reduced the risk of delivering a live baby with an unexpected fatal renal anomaly.

Tetrahydrocannabinol (THC) alters synthesis and release of surfactant-related material in isolated fetal rabbit type II cells.

Over the years, there has been a great deal of interest in the biological consequences of marijuana use. While evidence indicates that cannabinoids may have therapeutic uses in alleviating certain disease discomfort, there is little recent information on potential health risks, particularly related to the developing fetus. The present study was undertaken to determine the effects of delta 9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana on fetal lung development specifically related to surfactant production. The rationale for the choice of this model lies in the importance of adequate lung development and surfactant production for the successful transition of the fetus to an air-breathing environment. Lung type II cells, the source of pulmonary surfactant, were isolated from fetal rabbit lungs on the 24th gestational day and incubated concurrently with various concentrations of THC and [3H]choline to label disaturated phosphatidylcholine (DSPC) the major surface-active phospholipid of surfactant. Under these conditions THC significantly reduced radiolabelling of DSPC and at the highest concentration (10(-4) M) induced release of DSPC. Pulse-chase studies were also conducted. Cells were prelabelled with [3H]choline, removed to fresh medium with THC (10(-4) M) and incubated for various time periods. Aqueous- and organic-soluble intermediates of DSPC formation were isolated. THC induced a significant increase in radiolabelling of CDPcholine, the rate-limiting conversion in DSPC synthesis. Radiolabelling of total phosphatidylcholine and DSPC was also significantly increased. Assay of CTP: cholinephosphate cytidylyltransferase which enzymatically converts cholinephosphate to CDPcholine showed that THC and phosphatidylglycerol (PG) both induced activation of the enzyme in fetal lung cytosol but not in the membranes. This effect of THC and PG was not additive. THC activated the enzyme only in fetal and not adult rabbit lung. The ability of THC to induce release of surfactant related material was also examined. In cells prelabelled with [3H]choline, THC induced release of [3H]DSPC in both cultured and freshly isolated fetal type II cells. These results suggest THC reduces formation of surfactant DSPC, probably through alterations in membrane dynamics. However, intracellular THC may actually increase formation of DSPC through an effect on the rate-limiting enzyme. THC also increases release of previously formed surfactant-related material.

Chromosomal congenital anomalies and residence near hazardous waste landfill sites.

Previous findings of the EUROHAZCON study showed a 33% increase in risk of non-chromosomal anomalies near hazardous waste landfill sites. Here, we studied 245 cases of chromosomal anomalies and 2412 controls who lived near 23 such sites in Europe. After adjustment for confounding by maternal age and socioeconomic status, we noted a higher risk of chromosomal anomalies in people who lived close to sites (0-3 km) than in those who lived further away (3-7 km; odds ratio 1.41, 95% CI 1.00-1.99). Our results suggest an increase in risk of chromosomal anomalies similar to that found for non-chromosomal anomalies.