The Validity of the Neale and Kendler Model-Fitting Approach in Examining the Etiology of Comorbidity

Given that knowledge regarding the etiology of comorbidity between disorders can have a significant impact on research regarding the classification, treatment, and etiology of the disorders, the ability to reject incorrect hypotheses regarding the causes of comorbidity is very important. A simulation study was conducted to assess the validity of the Neale and Kendler (1995) model-fitting approach in examining the etiology of comorbidity between two disorders. First, data were simulated under the assumptions of the 13 alternative comorbidity models described by Neale and Kendler. Second, model-fitting analyses testing the comorbidity models were conducted on the simulated datasets. Thirteen sets of data with varying model parameters were simulated to test Neale and Kendler's assertion that their model-fitting approach is appropriate across a range of potential prevalences and degrees of familiality. The validity of the model-fitting approach in examining unselected twin data and a combination of selected family data and unselected family data was explored. The model-fitting approach successfully discriminated several classes of comorbidity models, although discrimination between models within classes of related models was less accurate. Results suggest that the model-fitting approach can be a useful tool in examining the etiology of the comorbidity between disorders if the caveats of the present study's results are considered carefully. As predicted by Neale and Kendler, variations in the disorder prevalences and familial correlations did not affect the validity of their model-fitting approach, but affected the power to discriminate the correct model. As suggested by Neale and Kendler, the model-fitting approach can be applied to both unselected and selected data and to both twin and family data.     

Sebaceous carcinoma ex-pleomorphic adenoma: a rare phenotypic occurrence

Primary sebaceous carcinoma of salivary glands is a rare entity with approximately 22 de novo documented cases. Similar tumor arising in a benign mixed tumor has only been reported once. We report a second case of sebaceous carcinoma in a pleomorphic adenoma and discuss the clinicopathologic features, histogenesis, and the differential diagnosis of this unusual tumor.     

Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins

Lymphatic vessels are essential for immune surveillance, tissue fluid homeostasis and fat absorption. Defects in lymphatic vessel formation or function cause lymphedema. Here we show that the vascular endothelial growth factor C (VEGF-C) is required for the initial steps in lymphatic development. In Vegfc-/- mice, endothelial cells commit to the lymphatic lineage but do not sprout to form lymph vessels. Sprouting was rescued by VEGF-C and VEGF-D but not by VEGF, indicating VEGF receptor 3 specificity. The lack of lymphatic vessels resulted in prenatal death due to fluid accumulation in tissues, and Vegfc+/- mice developed cutaneous lymphatic hypoplasia and lymphedema. Our results indicate that VEGF-C is the paracrine factor essential for lymphangiogenesis, and show that both Vegfc alleles are required for normal lymphatic development.     

The SLC26 gene family of multifunctional anion exchangers

The ten-member SLC26 gene family encodes anion exchangers capable of transporting a wide variety of monovalent and divalent anions. The physiological role(s) of individual paralogs is evidently due to variation in both anion specificity and expression pattern. Three members of the gene family are involved in genetic disease; SLC26A2 in chondrodysplasias, SLC26A3 in chloride-losing diarrhea, and SLC26A4 in Pendred syndrome and hereditary deafness (DFNB4). The analysis of Slc26a4-null mice has significantly enhanced the understanding of the roles of this gene in both health and disease. Targeted deletion of Slc26a5 has in turn revealed that this paralog is essential for electromotor activity of cochlear outer hair cells and thus for cochlear amplification. Anions transported by the SLC26 family, with variable specificity, include the chloride, sulfate, bicarbonate, formate, oxalate and hydroxyl ions. The functional versatility of SLC26A6 identifies it as the primary candidate for the apical Cl(-)-formate/oxalate and Cl(-)-base exchanger of brush border membranes in the renal proximal tubule, with a central role in the reabsorption of Na(+)-Cl(-) from the glomerular ultrafiltrate. At least three of the SLC26 exchangers mediate electrogenic Cl(-)-HCO(3)(-) and Cl(-)-OH(-) exchange; the stoichiometry of Cl(-)-HCO(3)(-) exchange appears to differ between SLC26 paralogs, such that SLC26A3 transports >/=2 Cl(-) ions per HCO(3)(-) ion, whereas SLC26A6 transports >/=2 HCO(3)(-) ions per Cl(-) ion. SLC26 Cl(-)-HCO(3)(-) and Cl(-)-OH(-) exchange is activated by the cystic fibrosis transmembrane regulator (CFTR), implicating defective regulation of these exchangers in the reduced HCO(3)(-) transport seen in cystic fibrosis and related disorders; CFTR-independent activation of these exchangers is thus an important and novel goal for the future therapy of cystic fibrosis.     

Evolution of Vertebroplasty: A Biomechanical Perspective

This paper is a collection of computational, finite element studies on vertebroplasty performed in our laboratory, which attempts to provide new biomechanical evidence and a fresh perspective into how the procedure can be implemented more effectively toward the goal of preventing osteoporosis-related fractures. The percutaneous application of a bone cement to vertebral defects associated with osteoporotic vertebral compression fracture has proven clinical successful in alleviating back pain. When the biomechanical efficacy of the procedure was examined, however, vertebroplasty was found to be limited in its ability to provide sufficient augmentation to prevent further fractures without risking complications arising from cement extravasations. The procedure may instead be more efficient biomechanically as a prophylactic treatment, to mechanically reinforce osteoporotic vertebrae at risk for fracture. Patient selection for such intervention may be reliably achieved with the more accurate fracture risk assessments based on vertebral strength, predicted using geometrically detailed, specimen-specific finite element models, rather than on bone density alone. Optimal cement volume, placement, and material properties were also recommended. The future of vertebroplasty involving biodegradable augmentation material laced with osteogenic agents that upon release will stimulate new bone growth and increase bone mass was proposed.     

Anti-HLA class I antibody-mediated activation of the PI3K/Akt signaling pathway and induction of Bcl-2 and Bcl-xL expression in endothelial cells

Anti-human leukocyte antigen (HLA) antibodies (Ab) have long been implicated in the process of acute and chronic allograft rejection, yet their mechanism(s) of action is not well understood. The aim of this study was to determine whether ligation of HLA class I molecules by anti-HLA Ab on the surface of human endothelial cells (EC) activates the PI3 Kinase (PI3K)/Akt signaling pathway and downstream target proteins of the cell death apparatus. We report that Ab ligation of major histocompatibility complex (MHC) class I molecules on the surface of EC triggers phosphorylation of Akt, PI3K, and recruitment of PI3K and Akt into a signaling unit with focal adhesion kinase. Signaling through class I also stimulated phosphorylation of Bad and upregulated expression of Bcl-2 and Bcl-xL. Pretreatment of EC with the PI3K inhibitor wortmannin blocked class I-mediated expression of Bcl-2, but not Bcl-xL, suggesting a role for the PI3K/Akt signaling pathway in regulation of class I-induced Bcl-2 expression. The intracellular events initiated by class I ligation were influenced by the concentration of the anti-HLA Ab with the lowest tested concentrations of Ab stimulating the highest level of Akt phosphorylation, Bcl-xL and Bcl-2 expression. Consistent with the in vitro experiments, analysis of biopsy samples from heart transplant recipients with evidence of Ab-mediated rejection exhibited increased Bcl-2 expression on the vascular endothelium. These results suggest that exposure of the graft endothelium to low concentrations of anti-HLA Ab may promote cell survival by transducing signals resulting in upregulation of cell survival genes.     

Protein expression of MMP-13, uPA, and PAI-1 in pseudocapsular and interface tissue around implants of loose artificial hip joints and in osteoarthritis

Matrix metalloproteinase 13 (MMP-13), urokinase type plasminogen activator (uPA), and plasminogen activator inhibitor type-1 (PAI-1) have been reported to be involved in aseptic loosening of artificial hip joints. This study for the first time presents the protein levels of all of these factors in synovial-like interfaces between bone and prosthesis and in pseudocapsular tissues surrounding the artificial joint in patients with aseptic loosening (n=17) measured by ELISA. No differences were observed in the antigen expression of MMP-13, uPA, and PAI-1, comparing interface and pseudocapsular tissue. Also, no significant correlation between the protein expression of these factors and years from arthroplasty to revision or to type of fixation (cemented vs. cementless) was observed. As control, MMP-13, uPA, and PAI-1 antigen levels were also determined in the synovium of patients with osteoarthritis (n=10). Yet, the antigen levels of MMP-13, uPA, and PAI-1 in tissue specimens from patients with aseptic loosening of artificial hip joints were significantly higher compared to their expression in synovial capsular tissues obtained from patients with osteoarthritis. In conclusion, this study shows that elevated protein levels of uPA, PAI-1, and MMP-13 in periprosthetic pseudocapsular and interface tissues from patients after total hip replacement due to aseptic loosening seem not to be associated with the patient outcome.     

Rapid diagnosis of pharyngitis caused by group A streptococci

Although commercial rapid antigen detection tests (RADTs) are more expensive than blood agar plate (BAP) cultures, the advantage they offer is the speed with which they provide results. Rapid identification and consequent prompt treatment of patients with pharyngitis due to group A beta-hemolytic streptococci (GABHS) can reduce the risk of spread of GABHS, can allow patients to return to school or work sooner, and may reduce the acute morbidity of this illness. In most studies, RADTs have been compared with BAP cultures as the criterion standard. However, these comparisons are complicated by the fact that there is no universally accepted procedure for performing a BAP culture. The great majority of the RADTs that are currently available have a high specificity (i.e., 95% or greater) and a sensitivity of between 70 and 90% compared with BAP cultures. Few published studies have compared the performance of various RADTs to each other or examined the performance of various RADTs in the office setting. There is also relatively little published information about how physicians in practice actually use RADTs, but the available information suggests that many physicians do not follow recommended guidelines. While the development of easy-to-perform RADTs for the diagnosis of GABHS pharyngitis has altered clinical practice substantially, only limited data about cost-effectiveness are currently available.     

Expression microdissection: operator-independent retrieval of cells for molecular profiling.

Tissue microdissection is an important method for the study of disease states. However, it is difficult to perform high-throughput molecular analysis with current techniques. We describe here a prototype version of a novel technique (expression microdissection) that allows for the procurement of desired cells via molecular targeting. Expression microdissection (xMD) offers significant advantages over available methods, including an increase in dissection speed of several orders of magnitude. xMD may become a valuable tool for investigators studying cancer or other disease states in patient specimens and animal models.     

Motor conversion symptoms and pseudoseizures: a comparison of clinical characteristics

The authors prospectively studied consecutive neurological inpatients with either motor conversion symptoms or pseudoseizures of recent onset. Patients were administered a structured psychiatric diagnostic interview, a measure of perceived parental care, and a life events inventory. They found that patients with pseudoseizures (N=20, mean age=27 years): 1) were younger than patients with motor conversion symptoms (N=30, mean age=39 years), 2) were more likely to have a borderline personality disorder), 3) were more likely to have a lower perception of parental care and to report incest, and 4) reported more life events in the 12 months before symptom onset. These differences in their characteristics and associated factors raised the question of whether it is helpful to group patients with pseudoseizures and motor conversion symptoms in a single diagnostic category of conversion disorder. An alternative view, that gives primacy to the symptoms rather than a disorder, may enable more precise research questions to be posed.