CSF-1, RANKL and OPG regulate osteoclastogenesis during murine tooth eruption

During tooth eruption, osteoclast-mediated bone resorption predominates in alveolar bone along the occlusal surface rather than in bone basal to the tooth. CSF-1, RANKL and OPG, regulatory molecules essential for osteoclastogenesis, are expressed during eruption. However, it is unclear if these cytokines exhibit an expression pattern that correlates with sites of osteoclastogenesis in vivo. To address this issue, mouse mandibles, isolated from 1 to 14 days postnatal, were analysed for osteoclast activity using tartrate-resistant acid phosphatase (TRAP) staining as well as colony-stimulating factor-1 (CSF-1), receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG) mRNA expression using in situ hybridisation. Results showed that CSF-1, RANKL and OPG are expressed in a distinct temporal and spatial manner. In the occlusal region, osteoclast activity was maximal at day 5 and correlated with a relative high expression of CSF-1 and RANKL compared to OPG. In basal bone at this time point, osteoclast activity decreased despite persistent CSF-1 expression and was associated with increased expression of OPG compared to RANKL. By day 8, osteoclastogenesis declined and correlated with upregulation of OPG at the occlusal and basal regions, with this effect continuing throughout eruption. These findings suggest that the spatiotemporal pattern and relative abundance of CSF-1, RANKL and OPG during eruption are key determinants of site-specific osteoclast activity in bone surrounding the tooth. Targeting these cytokines to specific regions in alveolar bone may provide a mechanism for regulating osteoclastogenesis in dental disorders associated with altered tooth eruption.     

Patients with epilepsy: a high-risk population prone to severe burns as a consequence of seizures while showering

We document the severe burns sustained by three patients with epilepsy who suffered seizures while showering. On the basis of the circumstances of these accidents, we suggest preventative measures to help other patients with epilepsy avoid similar burn injuries. Patient data collected from January 1987 to May 2004 by the Burn Unit of the Department of Plastic Surgery, University of Aachen, Germany, were reviewed. Three patients with epileptic disorders were found who suffered severe burn injuries caused by seizures that occurred while showering. Scald location and depth was assessed. Three patients (two women, one man) sustained extensive scald injuries after epileptic seizures while showering. Burn extent ranged from 20% to 35% TBSA. Scalds primarily affected the trunk, legs, arms, and buttocks. Two of the three patients used showers with levers for controlling water temperature. Safety devices for limiting water temperature were absent. All patients used shower cubicles. Patients with epilepsy may sustain serious burns, typically affecting the trunk, legs, arms, and buttocks, when a seizure occurs while showering. We suggest that individuals with epilepsy use showers designed with pirouetting taps, rather than levers, to regulate water temperature. Pirouetting taps are less likely to be shifted out of position during a seizure. We also recommend that epileptic patients have safety devices installed in their water heaters that limit maximum water temperature. Such safety devices prevent scald injury. And, finally, we suggest that people with comparable disorders generally avoid using shower cubicles. Instead, showers with curtains should be used, which may allow occupants to escape from dangerously hot shower water more easily.     

Sudden-onset Severe Acute Asthma: Clinical Features and Response to Therapy

Abstract. Objectives : To characterize patients with sudden onset of severe acute asthma (SAA) and to examine whether this presentation is associated with rapid recovery. Methods : Retrospective cohort study of ED visits to a teaching hospital. Subjects were aged 18–64 years, with SAA ( n = 225), denned as initial peak expiratory flow rate (PEFR) ≤40% of predicted. Visits for sudden-onset SAA (≤3 hours of symptoms) were characterized and multivariate logistic regression was used to examine the association between sudden onset and rapid recovery. Results : Patient visits for sudden-onset SAA had different triggers as compared with those for the slower-onset group (p = 0.006). The sudden-onset patients were less likely to report an upper-respiratory-tract infection (17% vs 40%) and more likely to have an unidentifiable trigger (40% vs 19%). In the multivariate logistic regression model, sudden onset was a strong independent predictor of rapid response [odds ratio (OR) 4.3, 95% confidence interval (CI) 1.6–11.6]. Sudden-onset visits were less likely to lead to admission (23% vs 43%, p = 0.03). Conclusions : These data suggest that different triggers may be involved in sudden-onset SAA and that sudden onset of symptoms is independently associated with rapid recovery. In their rapid deterioration and rapid response, these subjects share certain characteristics with "sudden asphyxic asthmatics" and may constitute a population suitable for further study of factors contributing to that condition. While these visits led to admission less frequently, prospective studies are necessary to provide information on duration of response and risk for relapse.     

Robotically Assisted Revision of Bariatric Surgeries Is Safe and Effective to Achieve Further Weight Loss

Background

As more bariatric operations are being performed in the USA every year, the number of revisions has increased. These operations are challenging and have a higher morbidity than the initial operation. We have reviewed our series of robotically assisted revisions.

Methods

At the University of Texas Medical School at Houston, we reviewed robotic revision cases from 2004 through 2011 and found 99 bariatric revisions using robotic assistance. Selected endpoints included body mass index (BMI) at follow-up, percent excess weight loss (%EWL), complications, intubation time, operative time, and length of hospital stay.

Results

The average BMI at the time of revision was 44.8 kg/m² and fell to 29 kg/m² after 3 years. BMI was significantly lower at all time intervals (3, 12, 24, and 36 months) compared to initial BMI (p < 0.001). The %EWL was also significant at 1, 3, 12, 24, and 36 months post-revision (p < 0.001). There was a 24 % (13/55) 90-day readmission rate. The overall complication rate was 17 %, with each individual complication rate between 2 and 4 %. There were no deaths. The average operative time was 204 min, and the average length of hospital stay was 2.3 days.

Conclusions

Revising previous bariatric operations to gastric bypass is difficult and time consuming. Although robotically assisted revision can be done safely and can result in effective further weight loss, the high postoperative complication rate is an issue that warrants further attention.     

Defining the directionality and quality of influenza virus-specific CD8+ T cell cross-reactivity in individuals infected with hepatitis C virus

Cross-reactivity of murine and recently human CD8(+) T cells between different viral peptides, i.e., heterologous immunity, has been well characterized. However, the directionality and quality of these cross-reactions is critical in determining their biological importance. Herein we analyzed the response of human CD8(+) T cells that recognize both a hepatitis C virus peptide (HCV-NS3) and a peptide derived from the influenza neuraminidase protein (Flu-NA). To detect the cross-reactive CD8(+) T cells, we used peptide-MHC class I complexes (pMHCs) containing a new mutant form of MHC class I able to bind CD8 more strongly than normal MHC class I complexes. T cell responses against HCV-NS3 and Flu-NA peptide were undetectable in normal donors. In contrast, some responses against the Flu-NA peptide were identified in HCV(+) donors who showed strong HCV-NS3-specific reactivity. The Flu-NA peptide was a weak agonist for CD8(+) T cells in HCV(+) individuals on the basis of novel pMHCs and functional assays. These data support the idea of cross-reactivity between the 2 peptides, but indicate that reactivity toward the Flu-NA peptide is highly CD8-dependent and occurs predominantly after priming during HCV infection. Our findings indicate the utility of the novel pMHCs in dissecting cross-reactivity and suggest that cross-reactivity between HCV and influenza is relatively weak. Further studies are needed to relate affinity and functionality of cross-reactive T cells.     

Meox2Cre-mediated disruption of CSF-1 leads to osteopetrosis and osteocyte defects

CSF-1, a key regulator of mononuclear phagocyte production, is highly expressed in the skeleton by osteoblasts/osteocytes and in a number of nonskeletal tissues such as uterus, kidney and brain. The spontaneous mutant op/op mouse has been the conventional model of CSF-1 deficiency and exhibits a pleiotropic phenotype characterized by osteopetrosis, and defects in hematopoiesis, fertility and neural function. Studies to further delineate the biologic effect of CSF-1 within various tissues have been hampered by the lack of suitable models. To address this issue, we generated CSF-1 floxed/floxed mice and demonstrate that Cre-mediated recombination using Meox2Cre, a Cre line expressed in epiblast during early embryogenesis, results in mice with ubiquitous CSF-1 deficiency (CSF-1KO). Homozygous CSF-1KO mice lacked CSF-1 in all tissues and displayed, in part, a similar phenotype to op/op mice that included: failure of tooth eruption, osteopetrosis, reduced macrophage densities in reproductive and other organs and altered hematopoiesis with decreased marrow cellularity, circulating monocytes and B cell lymphopoiesis. In contrast to op/op mice, CSF-1KO mice showed elevated circulating and splenic T cells. A striking feature in CSF-1KO mice was defective osteocyte maturation, bone mineralization and osteocyte-lacunar system that was associated with reduced dentin matrix protein 1 (DMP1) expression in osteocytes. CSF-1KO mice also showed a dramatic reduction in osteomacs along the endosteal surface that may have contributed to the hematopoietic and cortical bone defects. Thus, our findings show that ubiquitous CSF-1 gene deletion using a Cre-based system recapitulates the expected osteopetrotic phenotype. Moreover, results point to a novel link between CSF-1 and osteocyte survival/function that is essential for maintaining bone mass and strength during skeletal development.