Sodium/myo‐inositol cotransporter 1 and myo‐inositol are essential for osteogenesis and bone formation

myo‐Inositol (MI) plays an essential role in several important processes of cell physiology, is involved in the neural system, and provides an effective treatment for some psychiatric disorders. Its role in osteogenesis and bone formation nonetheless is unclear. Sodium/MI cotransporter 1 (SMIT1, the major cotransporter of MI) knockout (SMIT1^?/?) mice with markedly reduced tissue MI levels were used to characterize the essential roles of MI and SMIT1 in osteogenesis. SMIT1^?/? embryos had a dramatic delay in prenatal mineralization and died soon after birth owing to respiratory failure, but this could be rescued by maternal MI supplementation. The rescued SMIT1^?/? mice had shorter limbs, decreased bone density, and abnormal bone architecture in adulthood. Deletion of SMIT1 resulted in retarded postnatal osteoblastic differentiation and bone formation in vivo and in vitro. Continuous MI supplementation partially restored the abnormal bone phenotypes in adult SMIT1^?/? mice and strengthened bone structure in SMIT1^+/+ mice. Although MI content was much lower in SMIT1^?/? mesenchymal cells (MSCs), the I(1,4,5)P₃ signaling pathway was excluded as the means by which SMIT1 and MI affected osteogenesis. PCR expression array revealed Fgf4, leptin, Sele, Selp, and Nos2 as novel target genes of SMIT1 and MI. SMIT1 was constitutively expressed in multipotential C3H10T1/2 and preosteoblastic MC3T3‐E1 cells and could be upregulated during bone morphogenetic protein 2 (BMP‐2)–induced osteogenesis. Collectively, this study demonstrated that deficiency in SMIT1 and MI has a detrimental impact on prenatal skeletal development and postnatal bone remodeling and confirmed their essential roles in osteogenesis, bone formation, and bone mineral density (BMD) determination. © 2011 American Society for Bone and Mineral Research.     

The contribution of employer characteristics to continued employment of employees with residual work capacity: evidence from register data in The Netherlands

Objectives:This study aimed to examine the contribution of employer characteristics to continued employment of employees with residual work capacity. Moreover, we examined whether the contribution of employer characteristics differs across types of employers and employees’ types of diseases.Methods:Register data on disability assessments and employment status of N=84 394 long-term sick-listed employees with residual work capacity were obtained from the Dutch Employee Insurance Agency between 2010 and 2017. The dependent variable was continued employment four months after the assessment. We linked employees to their (former) employer to measure sector, firm size, and workforce composition. The average employment outcome of all employees assessed in the same firm and year served as a proxy measure for the extent of implemented disability-related policies and practices. Using multilevel multiple regression analysis, we compared the relative contribution of employer characteristics with employees’ characteristics.Results:Employer characteristics accounted for 10% of the variability in employment outcomes. In comparison, employees’ socio-demographic and disease characteristics accounted for 13% of the variability. The prevalence of continued employment was lowest in smaller firms and construction and low-wage service-orientated sectors. Furthermore, there were sizeable differences in employment outcomes between similar employers in terms of size, sector and workforce-composition, particularly between larger firms and among employees with mental or musculoskeletal disorders compared to other diseases.Conclusions:This study shows substantial differences between employers in facilitating continued employment of employees with residual work capacity. Encouraging firms to invest more in disability-related policies and practices may result in better employment opportunities for these employees.     

Additive anticonvulsant effects of agmatine and lithium chloride on pentylenetetrazole-induced clonic seizure in mice: involvement of α₂-adrenoceptor

After 60 years, lithium is still the mainstay in the treatment of mood disorders and widely used in clinic. In addition to its mood stabilizer effects, lithium also shows some anticonvulsant properties. Similar to lithium, agmatine also plays a protective role in the CNS against seizures and has been reported to enhance the effect of different antiepileptic agents. Moreover, both agmatine and lithium have modulatory effects on α(2)-adrenoceptors. So, we designed this study: 1) to investigate whether agmatine and lithium show an additive effect against clonic seizures induced by pentylenetetrazole; 2) to assess whether this additive effect is mediated through the α(2)-adrenoceptor or not. In our study, acute administration of a single effective dose of lithium chloride (30 mg/kg, i.p.) increased the seizure threshold. Pre-treatment with low and, per se, non-effective doses of agmatine (1 and 3mg/kg) potentiated a sub-effective dose of lithium (10mg/kg). Interestingly, the anticonvulsant effects of these effective combinations of lithium and agmatine were prevented by pre-treatment with low and non-effective doses of yohimbine [α(2)-adrenoceptor antagonist] (0.1 and 0.5mg/kg). On the other hand, clonidine [α(2)-adrenoceptor agonist] augmented the anticonvulsant effect of a sub-effective combination of lithium (5mg/kg i.p.) and agmatine (1mg/kg) at relatively low doses (0.1 and 0.25mg/kg). In summary, our findings demonstrate that agmatine and lithium chloride exhibit additive anticonvulsant properties which seem to be mediated through α(2)-adrenoceptor.     

The role of 5-HT(3) receptors in the additive anticonvulsant effects of citalopram and morphine on pentylenetetrazole-induced clonic seizures in mice

Citalopram, a selective serotonin reuptake inhibitor (SSRI), is frequently used in the treatment of major depressive disorders. In addition to its antidepressant features, citalopram shows some anticonvulsive properties at lower doses, whereas higher doses, ingested in cases of suicide, have been associated with seizures. Moreover, some reports support the enhancing effect of morphine on different responses of SSRIs such as analgesic and anticonvulsant properties. Although the exact mechanisms of these additive effects are not yet fully understood, 5-HT(3) receptor has recently been shown to play an important role in the central effects of SSRIs and morphine. In this regard, we used a model of clonic seizures induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether morphine and citalopram exhibit additive anticonvulsant effects and, if so, whether this effect is mediated through modulation of 5-HT(3) receptors. In our study, citalopram at lower doses (0.5 and 1 mg/kg, ip) significantly increased the seizure threshold (P<0.01) and at a higher dose (50 mg/kg) had proconvulsive effects. Moreover, morphine at low and noneffective doses had additive effects on the anticonvulsive properties of citalopram. This additive effect was prevented by pretreatment with low and noneffective doses of tropisetron (a 5-HT(3) receptor antagonist) and augmented by 1-(m-chlorophenyl)-biguanide (mCPBG, a 5-HT(3) receptor agonist). Moreover, low doses of morphine (0.1 and 0.5 mg/kg) alone or in combination with potent doses of 5-HT(3) receptor agonist or antagonist could not alter the proconvulsive properties of citalopram at higher dose (50 mg/kg), ruling out the contribution of 5-HT(3) to this effect. In summary, our findings demonstrate that 5-HT(3) receptor mediates the additive anticonvulsant properties of morphine and low-dose citalopram. This could constitute a new approach to augmenting the efficacy and curtailing the adverse effects of citalopram.     

Pulmonary squamous cell carcinoma associated with repaired congenital tracheoesophageal fistula and esophageal atresia

We report a 19‐year‐old man with pulmonary squamous cell carcinoma (SCC) who had a history of vertebral, anal, cardiac, tracheal, esophageal, renal, and radial limb defects (VACTERL) association and tracheoesophageal fistula (TEF) + esophageal atresia (EA) repair as an infant. Children that undergo TEF + EA repair may have an increased risk for developing cancer as they reach adulthood. Pediatr Pulmonol. 2010; 45:202–204. © 2010 Wiley‐Liss, Inc.     

Brainstem stroke following uncomplicated cervical epidural steroid injection

BACKGROUND: Cervical epidural steroid injection treatment of radicular pain has become a common procedure. OBJECTIVES: To describe the clinical, radiologic, and autopsy findings of a 41-year-old patient treated with methylprednisolone acetate cervical epidural steroid injection, who developed a fatal hemorrhagic brainstem infarction and to discuss the possible mechanisms involved. DESIGN: Case report. SETTING: Pain management center and tertiary care hospital. RESULTS: Immediately following a seemingly uncomplicated epidural steroid injection at C5-6, the patient developed progressive symptoms of extensive brainstem and thalamic infarction (documented by magnetic resonance imaging and autopsy) with hemorrhagic conversion and hydrocephalus. Hemorrhage within the adventitia of the left vertebral artery, but no dissection, was found at the C5 vertebral level at necropsy. CONCLUSIONS: This case report shows the possibility of serious intracranial pathology resulting from cervical epidural steroid injection despite use of fluoroscopic guidance. Vascular spasm distant to the site of injection is a possible mechanism.