Time trends in neural tube defects prevalence in relation to preventive strategies: an international study

OBJECTIVE: To examine time trends in neural tube defects (NTD) prevalence from 1987 to 1996 in relation to the primary prevention policies for folic acid supplementation strategies in different countries. DESIGN: Retrospective time trends analysis of NTD prevalence. SETTING: 11 birth defect registries of congenital malformations participating in the International Clearinghouse for Birth Defects Monitoring System, in the period from 1 July 1987 to 30 June 1996. SUBJECTS: 8207 live births, stillbirths and terminated pregnancies affected by anencephaly or spina bifida registered by the 11 participating centres 1987-1996. OUTCOME MEASURES: Prevalence rate ratios based on the annual rates, using the Poisson regression model. RESULTS: During the study period a significant fall in prevalence rates for all NTD is present in Atlanta (USA), England and Wales, Hungary and Japan, and a significant rise in Norway and South America. After adjusting for the secular trends observed in the earlier years of the study, no significant trend can be attributed to preventive strategies. Data on NTD prevalence are supplemented with information on folate awareness among some of the populations studied. CONCLUSION: There is no evidence that, up to the middle of 1996, any change in time trend was attributable to the introduction of national folate supplementation policies. The possible effectiveness of folate supplementation policies for the reduction of NTD clearly needs to be tried and studied for several more years. Considering that in the Western world about 50% of pregnancies are unplanned, a policy that rests on action taken before conception can only have limited success. Strategies based on food enrichment, such as was introduced in the USA from the beginning of 1998, may prove to be more successful.     

Thermal conduction effects in human skin.

To determine the maximum permissible temperature any material may attain without causing pain or burn on contact with bare skin, over 2000 observations were made of pain threshold during contact with materials at elevated temperatures. Six materials were used representing the full range of thermal properties from good conductors to good insulators. Time to pain threshold was converted to time to threshold blister on the basis of the relationship between pain and burn established earlier for radiant and for convective heating. Calculated times to blister were used to predict the material temperatures causative of "touch-burn". Experimentally produced threshold blisters at the predicted temperature-times verified the predictions. Graphs and equations were generated for determining safe temperatures for any material in contact with bare skin for 1-5 s solely from a knowledge of its thermal properties. Conversely, the thermal inertia (k rho c) of the optimal material for a specific use and skin contact can be predicted from a knowledge of the maximum material temperature and length of contact time anticipated.     

Two-year syndromal and functional recovery in 219 cases of first-episode major affective disorder with psychotic features

OBJECTIVE: Psychotic affective disorders are the most prevalent idiopathic psychoses, but their outcome from onset has rarely been studied. In this study, the authors determined the rate and latency of syndromal recovery and rates of functional recovery after first lifetime hospitalization in patients with first-episode psychotic affective disorders. METHOD: From first lifetime hospitalization in 1989-1996, 219 patients with a DSM-IV psychotic affective illness were assessed at intervals over 24 months. Time to syndromal recovery (no longer meeting DSM-IV episode criteria) was assessed by survival analysis, and functional recovery (regaining baseline vocational and residential status) was rated. Factors associated with recovery were identified by bivariate and multivariate methods. RESULTS: By 3, 6, 12, and 24 months after first hospitalization, syndromal recovery was attained by 65.1%, 83.7%, 91.1%, and 97.5%, respectively, of subjects. Time to syndromal recovery (6.1 weeks to 50% of subjects recovered) was shorter for patients who had bipolar disorder, were married, were age 30 or older at onset, lacked comorbidity, required relatively brief hospitalization, and received fewer medicines. Functional recovery by 6 (30.4%) and 24 months (37. 6% of patients) was 2.6-2.7 times less likely than syndromal recovery; 63.1% of those recovering syndromally did not recover functionally by 2 years. Functional recovery was associated with older age at onset and shorter hospitalization. Annual recovery rates remained stable as mean hospital length of stay decreased 3. 6-fold over the 8-year study period. CONCLUSIONS: Syndromal recovery was attained by most psychotic affective disorder patients soon after hospitalization, but only one-third recovered functionally by 24 months. The findings suggest that these very common psychotic illnesses can carry a grave functional prognosis from the initial episode and first hospitalization.     

Effects of in utero exposure to finasteride on androgen-dependent reproductive development in the male rat.

Finasteride is a specific inhibitor of type II 5alpha-reductase, the enzyme that converts testosterone (T) to the more potent androgen receptor agonist dihydrotestosterone (DHT). In utero exposure to androgen receptor antagonists and T biosynthesis inhibitors have induced permanent effects on androgen-sensitive end points such as anogenital distance (AGD), nipple retention, and malformations of the male rat reproductive tract. The objectives of this study were to (1) characterize the dose response of finasteride-mediated alterations in androgen-dependent developmental end points, (2) determine whether prenatal exposure to finasteride permanently decreases AGD or results in nipple retention, and (3) evaluate whether AGD or nipple retention is predictive of adverse alterations in the male reproductive tract. Pregnant Crl:CD(SD)BR rats (n=5-6/group) were gavaged with either vehicle or finasteride at 0.01, 0.1, 1.0, 10, or 100 mg/kg/day on gestation days 12 to 21. All male offspring were monitored individually until necropsy on postnatal day (PND) 90. The present study design has been used previously for other antiandrogens and is sensitive to perturbations of the male rat reproductive tract. Decreases in AGD on PND 1 and increases in areolae-nipple retention on PND 13 were significantly different from controls in all finasteride-exposed male rats. Finasteride-induced changes in AGD and nipple retention were permanent in male rats exposed to finasteride at and above 0.1 mg/kg/day. On PND 90, dorsolateral and ventral prostate lobes were absent in 21 to 24% of rats exposed to 100 mg/kg/day finasteride and weighed significantly less at and above 10 mg/kg/day. In the highest dose group, 73% of animals had ectopic testes, much higher than previously reported. The most sensitive malformation other than decreased AGD and nipple retention was the dose-dependent increase in hypospadias. The lowest observed adverse effect level (LOAEL) for finasteride-induced permanent effects in this study was 0.1 mg/kg/day based on permanent changes in AGD and nipple retention. Finasteride-induced changes in AGD and retention of nipples were highly predictive of hypospadias, ectopic testes, and prostate malformations even though some animals with retained nipples or decreased AGD may not have had other reproductive tract malformations. In summary, prenatal exposure to finasteride specifically inhibited DHT-mediated development with little to no change in T-mediated development.     

Dietary plasma protein reduces small intestinal growth and lamina propria cell density in early weaned pigs

ABSTRACT We quantified the effects of a diet containing animal plasma protein on small intestinal growth and mucosal morphology in early weaned pigs. Ninety-six pigs [14 d old, 4 kg body weight (BW)] were assigned in groups of 32 to three dietary treatments as follows: 1) free access to control diet (C), 2) free access to plasma protein diet (P), and 3) plasma protein, pair-fed to C (PPF). Eight pigs from each group were killed at 2, 4, 8 or 16 d. Over a 16-d period, weight gain in the P group was 43% greater (P < 0.05) than that in C pigs; weight gain was similar in C and PPF groups. Protein intake in the P group was 33% higher (P < 0.05) than that in the PPF group; no significant difference was observed between the C and P groups. Dietary protein conversion efficiencies in both the P and PPF groups were approximately 18% greater (P < 0.05) than those in the C group. Intestinal masses in the three groups did not differ at 2, 4 and 8 d. By 16 d, the jejunal and ileal protein and DNA masses (mg/kg BW) in both the P and PPF groups were lower than those in the C group (P < 0.05). Dietary plasma protein did not affect crypt cell proliferation, crypt depth or villous height in either the jejunum or ileum. However, the intravillous lamina propria cell density in the jejunum was significantly lower (P < 0.05) in P and PPF pigs than in C pigs. Plasma urea concentrations were also 40 and 42% lower (P < 0.05) in the P and PPF groups, respectively, than in the C group. Our results indicate that dietary plasma protein reduces the cellularity of the lamina propria, but not epithelial cell surface of the small intestine. Feeding plasma protein also increased the efficiency of dietary protein utilization, in part, by decreasing amino acid catabolism.     

Altered gene expression during rat Wolffian duct development following di(n-butyl) phthalate exposure.

Di(n-butyl) phthalate (DBP) is a common plasticizer and solvent that disrupts androgen-dependent male reproductive development in rats. In utero exposure to 500 mg/kg/day DBP on gestation days (GD) 12 to 21 decreases androgen biosynthetic enzymes, resulting in decreased fetal testicular testosterone levels. One consequence of prenatal DBP exposure is malformed epididymides in adult rats. Reduced fetal testosterone levels may be responsible for the malformation, since testosterone is required for Wolffian duct stabilization and their development into epididymides. Currently, little is understood about the molecular mechanisms of Wolffian duct differentiation. The objective of this study was to identify changes in gene expression associated with altered morphology of the proximal Wolffian duct following in utero exposure to DBP. Pregnant Crl:CD(R) (SD) rats were gavaged with corn oil vehicle or 500 mg/kg/day DBP from GD 12 to GD 19 or 21. There were only small morphological differences between control and DBP-exposed Wolffian ducts on GD 19. On GD 21, 89% of male fetuses in the DBP dose group showed marked underdevelopment of Wolffian ducts, characterized by decreased coiling. RNA was isolated from Wolffian ducts on GD 19 and 21. Together with empirical information, cDNA microarrays were used to help identify candidate genes that could be associated with the morphological changes observed on GD 21. These candidate genes were analyzed by real-time RT-PCR. Changes in mRNA expression were observed in genes within the insulin-like growth factor (IGF) pathway, the matrix metalloproteinase (MMP) family, the extracellular matrix, and in other developmentally conserved signaling pathways. On GD 19, immunolocalization of IGF-1 receptor protein demonstrated an increase in cytoplasmic expression in the mesenchymal and epithelial cells. There was also a variable decrease in androgen receptor protein in ductal epithelial cells on GD 19. This study provides insight into the effects of antiandrogens on the molecular mechanisms involved in Wolffian duct development. The altered morphology and changes in gene expression following DBP exposure are suggestive of altered paracrine interactions between ductal epithelial cells and the surrounding mesenchyme during Wolffian duct differentiation due to lowered testosterone production.     

Health-related quality of life and post-traumatic stress disorder in patients after cardiac surgery and intensive care treatment

OBJECTIVES: Health-related quality of life and patient satisfaction have become important end points in cardiac surgery. Post-traumatic stress disorder has been described in patients with life-threatening heart disease. In this study, we investigated the occurrence of post-traumatic stress disorder in a sample of patients after cardiac surgery and compared health-related quality of life and patient satisfaction between patients with and without evidence of post-traumatic stress disorder. METHODS: We studied 80 patients serially admitted to the intensive care unit after cardiac surgery (bypass grafting, n = 51; aortic valve replacement, n = 29). Health-related quality of life was assessed with the use of the SF-36 Health Status Questionnaire. Post-traumatic stress disorder was measured with a previously validated instrument (the Post-Traumatic Stress Syndrome 10-Questions Inventory), and 20 different aspects of life satisfaction were quantified on a scale ranging from 0 to 10. For measurements of health-related quality of life and post-traumatic stress disorder, age- and gender-comparable healthy individuals, as well as patients with cardiovascular diseases, served as control groups. RESULTS: Patients who had cardiac surgery described high life satisfaction summary scores (156 of a maximum of 200 points) and only small impairments in physical and mental SF-36 summary scores when compared with healthy control groups (median reduction 7.15, P <.05). Patients with evidence of post-traumatic stress disorder (n = 15) reported the lowest SF-36 mental health summary scores when compared with patients without stress disorder (38.3 vs 48.4, P =.004) and rated their life satisfaction lower (121.5 vs 162.0, P =.002). CONCLUSIONS: Patients who have had cardiac surgery demonstrate a high life satisfaction with an acceptable degree of physical and mental health-related quality of life. Impairments in psychosocial function and life satisfaction were found in a subgroup of patients with evidence of post-traumatic stress disorder.     

Treatment failures secondary to drug interactions with divalent cations and fluoroquinolone

We observed four cases of therapeutic failures while patients were simultaneously taking medications that contained divalent cations and oral fluoroquinolones. Patients improved after conversion to the intravenous formulation of the same antibiotics, proper spacing of the divalent cation, or conversion to a different antibiotic class. Patients prescribed oral fluoroquinolones should receive instructions on proper separations of these antibiotics with divalent cations. Health care professionals should be cognizant of these interactions and educated on their potential deleterious effect.     

PSTPIP1‐associated myeloid‐related proteinemia inflammatory syndrome: A rare cause of childhood neutropenia associated with systemic inflammation and hyperzincemia

Neutropenia in pediatric patients can be due to a variety of disorders. We describe two patients who underwent extensive evaluation over many years for arthralgias and moderate neutropenia of unclear etiology. Genetic testing identified a pathogenic variant in PSTPIP1 (proline‐serine‐threonine phosphatase‐interacting protein 1) in both patients. Markedly elevated inflammatory markers and zinc levels confirmed the rare diagnosis of PSTPIP1‐associated myeloid‐related proteinemia inflammatory (PAMI) syndrome, tailoring treatment. Neutropenia is common in patients with PAMI syndrome. Unique mutations seen in PAMI syndrome may account for the specific phenotypic features of this disorder.