Teriparatide increases bone formation in modeling and remodeling osteons and enhances IGF-II immunoreactivity in postmenopausal women with osteoporosis.

Transiliac bone biopsies were obtained from 55 women treated with teriparatide or placebo for 12-24 months. We report direct evidence that modeling bone formation at quiescent surfaces was present only in teriparatide-treated patients and bone formation at remodeling sites was higher with teriparatide than placebo. INTRODUCTION: Recombinant teriparatide [human PTH(1-34)], a bone formation agent for the treatment of osteoporosis when given once daily subcutaneously, increases biochemical markers of bone turnover and activation frequency in histomorphometry studies. MATERIALS AND METHODS: We studied the mechanisms underlying this bone-forming action of teriparatide at the basic multicellular unit by the appearance of cement lines, a method used to directly classify surfaces as modeling or remodeling osteons, and by the immunolocalization of IGF-I and IGF-II. Transiliac bone biopsies were obtained from 55 postmenopausal women treated with teriparatide 20 or 40 microg or placebo for 12-24 months (median, 19.8 months) in the Fracture Prevention Trial. RESULTS: A dose-dependent relationship was observed in modeling and mixed remodeling/modeling trabecular hemiosteons. Trabecular and endosteal hemiosteon mean wall thicknesses were significantly higher in both teriparatide groups than in placebo. There was a dose-dependent relationship in IGF-II immunoreactive staining at all bone envelopes studied. The greater local IGF-II presence after treatment with teriparatide may play a key role in stimulating bone formation. CONCLUSIONS: Direct evidence is presented that 12-24 months of teriparatide treatment induced modeling bone formation at quiescent surfaces and resulted in greater bone formation at remodeling sites, relative to placebo.     

Executive function impairments in children with attention-deficit hyperactivity disorder: do they differ between school and home environments?

OBJECTIVE: The primary purpose of this study was to compare parent and teacher reports of executive function (EF), as measured by the Behavior Rating Inventory of Executive Function (BRIEF), on a sample of children who had been diagnosed with attention-deficit hyperactivity disorder (ADHD). If differences were found, the secondary purpose was to explore these differences by determining which of the 8 BRIEF scales, each representing a different EF, would best predict symptoms of ADHD by the 2 proxy reporters. METHOD: We performed a secondary data analysis on the assessment information pertaining to 240 children, aged 5 to 15 years, accessing services at an urban Toronto psychiatric program specializing in ADHD. We compared parent and teacher ratings and applied logistical binary regressions to predict the probability of a child's meeting the criteria for clinically significant inattention and hyperactivity-impulsivity on the ADHD Rating Scale-IV. RESULTS: As expected, teachers reported more variety and severity of EF impairments than did parents. In addition, teachers used inhibition, organization of materials, and planning and organizing as predictors of ADHD symptoms, whereas parents relied predominantly on inhibition, working memory, and planning and organizing as the risk factors. CONCLUSION: Consistent with the current theory, EF impairments, particularly in inhibition, appear to underlie the behavioural manifestation of ADHD. However, parents and teachers do not always agree when reporting EF impairments at home and in school. Thus information from both types of informants is essential for understanding and treating children with this disorder.     

TNF alpha and Fas mediate tissue damage and functional outcome after traumatic brain injury in mice.

Tumor necrosis factor-alpha (TNFalpha) and Fas are induced after traumatic brain injury (TBI); however, their functional roles are incompletely understood. Using controlled cortical impact (CCI) and mice deficient in TNFalpha, Fas, or both (TNFalpha/Fas-/-), we hypothesized that TNFalpha and Fas receptor mediate secondary TBI in a redundant manner. Compared with wild type (WT), TNFalpha/Fas-/- mice had improved motor performance from 1 to 4 days (P<0.05), improved spatial memory acquisition at 8 to 14 days (P<0.05), and decreased brain lesion size at 2 and 6 weeks after CCI (P<0.05). Protection in TNFalpha/Fas-/- mice from histopathological and motor deficits was reversed by reconstitution with recombinant TNFalpha before CCI, and TNFalpha-/- mice administered anti-Fas ligand antibodies had improved spatial memory acquisition versus similarly treated WT mice (P<0.05). Tumor necrosis factor-alpha/Fas-/- mice had decreased the numbers of cortical cells with plasmalemma damage at 6 h (P<0.05 versus WT), and reduced matrix metalloproteinase-9 activity in injured brain at 48 and 72 h after CCI. In immature mice subjected to CCI, genetic inhibition of TNFalpha and Fas conferred beneficial effects on histopathology and spatial memory acquisition in adulthood (both P<0.05 versus WT), suggesting that the beneficial effects of TNFalpha/Fas inhibition may be permanent. The data suggest that redundant signaling pathways initiated by TNFalpha and Fas play pivotal roles in the pathogenesis of TBI, and that biochemical mechanisms downstream of TNFalpha/Fas may be novel therapeutic targets to limit neurological sequelae in children and adults with severe TBI.     

Fat absorption in premature infants: medium-chain triglycerides and long-chain triglycerides are absorbed from formula at similar rates

Fat absorption from two different premature infant formulas and one full-term formula containing three different fat blends was investigated in two groups of premature infants. The first group of nine infants (gestational age, 29.1 +/- 0.88 weeks; postnatal age, 3.13 +/- 0.71 weeks) was fed alternately for 1 week each SMA preterm formula containing either high levels (50%) of medium-chain triglycerides (MCT) (6:0, 8:0, and 10:0) or high levels (86%) of long-chain triglycerides (LCT) (greater than or equal to C12). Except for fat blends, the formulas were otherwise identical. The second group of 11 infants (gestational age, 30.5 +/- 0.77 weeks, studied at a postnatal age of 4.33 +/- 0.91 weeks) was fed for 1 week a full-term infant formula, S-26, containing 98% LCT. Fat absorption (studied during a 3-day fat balance period) was similar irrespective of fat blend: 89.08 +/- 2.37% during feeding of preterm SMA, 50% MCT; 87.0 +/- 3.81% during feeding of preterm SMA, 86% LCT; and 83.00 +/- 2.89% during feeding of S-26, 98% LCT. Weight gain (grams per day) and increase in length (centimeters per day) were 23.2 +/- 1.7, 21.20 +/- 1.7, and 14.28 +/- 2.9, and 0.17 +/- 0.06, 0.16 +/- 0.04, and 0.22 +/- 0.07 during feeding of the three fat blends, respectively. Lipase activity levels in fasting gastric aspirates were higher during feeding of the LCT than the MCT formula. The possible stimulation of gastric lipase secretion secondary to long-chain fatty acid stimulation of cholecystokinin secretion might be related to the efficient digestion of formula fat, irrespective of triglyceride-fatty acid chain length.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic mapping of functional activity in the olfactory system of normal and hypogonadal (hpg) mice

The hypogonadal mouse, which lacks gonadotropin-releasing hormone, has been suggested as an animal model of Kallmann's syndrome, one symptom of which is hyposmia. We have determined the metabolic activity of the olfactory system, in normal and hypogonadal mice, using [14C]-2-deoxyglucose quantitative autoradiography. In the olfactory lobes, deoxyglucose uptake was greatest in the glomerular and granule cell layers and low in the olfactory nerve layer and bulb core. The pattern of uptake was similar in both hypogonadal and normal mice breathing filtered air. Exposure of normal mice to ethyl acetoacetate significantly increased deoxyglucose uptake in the olfactory nerve layer and glomerular layer, but not in the granule cell layer. Several foci of intense metabolic activity were produced, apparently corresponding to small groups of activated glomeruli. There were no changes in the secondary or tertiary projections of the olfactory system. In hypogonadal mice, ethyl acetoacetate failed to increase the number of foci and the density of labelling in the olfactory nerve layer and glomerular layer. These data show that the functional activity of the olfactory system in hypogonadal mice breathing air is apparently normal. However, the olfactory response to ethyl acetoacetate is significantly less in hypogonadal mice. Whether this is due to their lack of gonadotropin-releasing hormone requires further experimentation.     

Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an Italian series of patients affected by Paget's disease of bone (PDB).

PDB is genetically heterogeneous. Mutations of the sequestosome1 gene have been reported in sporadic and familial forms of Paget's in patients of French Canadian and British descent. Mutational analyses in different ethnic groups are needed to accurately investigate hereditary diseases. We describe two novel mutations of sequestosome1 in 62 Italian sporadic patients, confirming the role of the encoded protein in this disorder. INTRODUCTION: Paget's disease of bone (PDB) is a relatively common disease of bone metabolism reported to affect up to 3% of whites over 55 years of age. The disorder is genetically heterogeneous, and at present, there is scientific evidence that at least eight different human chromosomal loci are correlated with its pathogenesis. Mutations of the sequestosome1 (SQSTM1) gene were identified as responsible for most of the sporadic and familial forms of Paget in patients of French Canadian and British descent. Such mutations were located at exon 7 and 8 levels, encoding for the ubiquitin protein-binding domain (UBA) and representing a mutational hot spot area. MATERIALS AND METHODS: To verify the involvement of this gene in Italian subjects affected by PDB, we performed mutational analysis in 62 sporadic PDB cases. RESULTS: We described three different mutations at exon 8 level: P392L, already described in the French Canadian population and families predominantly of British descendent, and two novel mutations consisting of the amino acid substitutions M404V and G425R. No significant differences in the clinical history of PDB have been observed in patients with SQSTM1 mutations in respect to those without. CONCLUSIONS: Even though our findings suggest a minor involvement of the SQSTM1 gene in the pathogenesis of sporadic Italian Paget's cases, the identification of different significant mutations within the SQSTM1 gene in unrelated, but clinically similar individuals, offers extremely convincing evidence for a causal relationship between this gene and PDB. Longitudinal studies are needed to assess the penetrance of genotype/phenotype correlations. Our findings confirm the evidence of a clustered mutation area at this level in this disorder.     

Physical complaints and symptoms of somatizing patients.

The purpose of the study was to describe the physical complaints and symptoms of persistent somatization patients. Individuals in the general population (age 17-49 yr) with at least 10 general admissions during an 8-yr period were studied. Persistent somatizers (i.e. patients with more than six medically unexplained general admissions) were compared with patients whose admissions could be ascribed to well-defined somatic disorders. Somatizers were characterized by multiple symptoms from many organ systems, and their physical complaints simulated most types of somatic disorder. Although some symptoms were more common than others, none were infrequent, so neither 'classic' conversion symptoms nor pain symptoms were found to be especially characteristic of the persistent somatizer. Gender had no influence on number of registered symptoms, whereas the number increases with age. The finding question the use of a predefined symptom checklist in the diagnostic criteria for somatizing disorder. The major part of the somatizers present a different illness picture when admitted with medically unexplained disorders compared with admission for which no adequate medical explanation could be found. However, one fifth had, when admitted with a medically explained diagnosis, also been admitted with the diagnosis medically unexplained at another admission. One fifth of the persistent somatizers had been admitted at least once for factitious illness, but apart from the fact that they had more symptoms and admissions, they did not differ from the other persistent somatizers.     

CROHN'S DISEASE: A COLON AND RECTAL DEPARTMENT EXPERIENCE

This study reviewed a series of patients with Crohn's disease managed by surgeons of the Department of Colon and Rectal Surgery, St Vincent's Hospital, Melbourne, since 1978. There were 306 patients: 171 males and 135 females. The mean age at diagnosis was 33.4 years (range 11–93). The distribution of the disease was small bowel 32.3%, small bowel and colon 26.5%, colon 39.9%, and anal disease alone 1.6%. A total of 416 abdominal operations were performed on 204 patients. The commonest indications for surgery were failed medical therapy (21.9%), small bowel obstruction (15.9%), enteric tistula (10.1%), and intra-abdominal abscess (10.1%). The most frequently performed procedures were ileocolic resection with anastomosis (28.8%), small bowel resection (9.4%), and total colectomy and ileostomy (7.0%). Postoperative complications included anastomotic leaks in 4.0%. intra-abdominal abscess formation in 3.6%, and enterocutaneous fistulae developed in 6%. Three patients died during the review period. During follow up (mean 84.4). 30% of patients developed recurrence requiring further surgery at a mean of 72.7 months postoperatively. The most frequent site for a recurrence was the pre-anastomotic terminal ileum (61.7%). In conclusion. the majority of patients with Crohn's disease will require resectional surgery at some stage. This can be performed with a low mortality and morbidity, and a recurrence rate of around 5% per year.