γ-Catenin-Dependent Signals Maintain BCR-ABL1+ B Cell Acute Lymphoblastic Leukemia

1. Download high-res image (135KB)
2. Download full-size image

     

Epithelial barrier and oral bacterial infection

The oral epithelial barrier separates the host from the environment and provides the first line of defense against pathogens, exogenous substances and mechanical stress. It consists of underlying connective tissue and a stratified keratinized epithelium with a basement membrane, whose cells undergo terminal differentiation resulting in the formation of a mechanically resistant surface. Gingival keratinocytes are connected by various transmembrane proteins, such as tight junctions, adherens junctions and gap junctions, each of which has a specialized structure and specific functions. Periodontal pathogens are able to induce inflammatory responses that lead to attachment loss and periodontal destruction. A number of studies have demonstrated that the characteristics of pathogenic oral bacteria influence the expression and structural integrity of different cell–cell junctions. Tissue destruction can be mediated by host cells following stimulation with cytokines and bacterial products. Keratinocytes, the main cell type in gingival epithelial tissues, express a variety of proinflammatory cytokines and chemokines, including interleukin‐1alpha, interleukin‐1beta, interleukin‐6, interleukin‐8 and tumor necrosis factor‐alpha. Furthermore, the inflammatory mediators that may be secreted by oral keratinocytes are vascular endothelial growth factor, prostaglandin E₂, interleukin‐1 receptor antagonist and chemokine (C‐C motif) ligand 2. The protein family of matrix metalloproteinases is able to degrade all types of extracellular matrix protein, and can process a number of bioactive molecules. Matrix metalloproteinase activities under inflammatory conditions are mostly deregulated and often increased, and those mainly relevant in periodontal disease are matrix metalloproteinases 1, 2, 3, 8, 9, 13 and 24. Viral infection may also influence the epithelial barrier. Studies show that the expression of HIV proteins in the mucosal epithelium is correlated with the disruption of epithelial tight junctions, suggesting a possible enhancement of human papilloma virus infection by HIV‐associated disruption of tight junctions. Altered expression of matrix metalloproteinases was demonstrated in keratinocytes transformed with human papilloma virus‐16 or papilloma virus‐18,. To summarize, the oral epithelium is able to react to a variety of exogenous, possibly noxious influences.     

Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme replacement therapy (agalsidase). However, recent studies suggest an endogenous inhibition of agalsidase in patients with FD, as reported for other lysosomal storage diseases. To assess the clinical consequences of serum-mediated agalsidase inhibition in affected patients, we determined the agalsidase inhibition status of 168 patients (68 male) with FD and compared outcomes of inhibition-positive patients with those of inhibition-negative patients. The assessment included clinical events during time on agalsidase, determination of renal and cardiac function, and evaluation of FD-related symptoms. The frequency of serum-mediated agalsidase inhibition was 40% in agalsidase-treated males. Inhibition did not depend on the compound initially used (agalsidase-α or -β). Agalsidase inhibition was associated with higher lyso-globotriaosylceramide levels and worse disease severity scores in patients. Compared with agalsidase inhibition-negative men, agalsidase inhibition-positive men showed greater left ventricular mass (P=0.02) and substantially lower renal function (difference in eGFR of about –30 ml/min per 1.73 m²; P=0.04), which was confirmed by a longitudinal 5-year retrospective analysis. Additionally, affected patients presented more often with FD-typical symptoms, such as diarrhea, fatigue, and neuropathic pain, among others. Therefore, patients with poor clinical outcome on agalsidase should be tested for agalsidase inhibition. Future studies are warranted to determine if affected patients with FD benefit from acute reduction of anti-agalsidase antibodies or long-term immune modulation therapies to suppress agalsidase inhibition and to identify mechanisms that minimize antibody generation against agalsidase.     

Dissociative Process and the Depressed Patient

This article postulates a connection between the clinical phenomena of depression and dissociation. In cases of patients presenting with recurrent bouts of depression without apparent causes, rather than positing a purely biological origin of the depressed states, I suggest the presence of an underlying dissociative process triggered by intense shame. Analyzing such shame as a phenomenon of severe self-judgment fueled by hidden, grandiose self-expectations, we can detect the powerful eliminatory force of dissociative process at work. For a self-identity precariously based on inflated standards, ordinary experiences of negative evaluation can become traumatic humiliations. The radical dissociation of such injury produces a state of mind devoid of significant memories, a pervasive sense of meaningless emptiness, and an impoverished sense of self. The treatment of such depressions is based on the recognition that the depression itself is a secondary phenomenon. Retrieving the primary, intolerable not-me experience of shamed humiliation will allow the patient to mourn the loss of great expectations.     

A novel TMEM16A splice variant lacking the dimerization domain contributes to calcium‐activated chloride secretion in human sweat gland epithelial cells

Sweating is an important physiological process to regulate body temperature in humans, and various disorders are associated with dysregulated sweat formation. Primary sweat secretion in human eccrine sweat glands involves Ca²⁺‐activated Cl^? channels (CaCC). Recently, members of the TMEM16 family were identified as CaCCs in various secretory epithelia; however, their molecular identity in sweat glands remained elusive. Here, we investigated the function of TMEM16A in sweat glands. Gene expression analysis revealed that TMEM16A is expressed in human NCL‐SG3 sweat gland cells as well as in isolated human eccrine sweat gland biopsy samples. Sweat gland cells express several previously described TMEM16A splice variants, as well as one novel splice variant, TMEM16A(acΔe3) lacking the TMEM16A‐dimerization domain. Chloride flux assays using halide‐sensitive YFP revealed that TMEM16A is functionally involved in Ca²⁺‐dependent Cl^? secretion in NCL‐SG3 cells. Recombinant expression in NCL‐SG3 cells showed that TMEM16A(acΔe3) is forming a functional CaCC, with basal and Ca²⁺‐activated Cl^? permeability distinct from canonical TMEM16A(ac). Our results suggest that various TMEM16A isoforms contribute to sweat gland‐specific Cl^? secretion providing opportunities to develop sweat gland‐specific therapeutics for treatment of sweating disorders.     

Optimizing implantable cardioverter-defibrillator treatment of rapid ventricular tachycardia: Antitachycardia pacing therapy during charging

BACKGROUND: Previous studies in implantable cardioverter-defibrillator (ICD) patients demonstrated the efficacy and safety of antitachycardia pacing (ATP) for rapid ventricular tachycardias (VT). To prevent shock delay in case of ATP failure, a new feature (ATP during charging) was developed to deliver ATP for rapid VT while charging for shock. OBJECTIVE: The purpose of this study was to determine the efficacy and safety of this new feature. METHODS: In a prospective, nonrandomized trial, patients with standard ICD indication received an EnTrust ICD. VT and ventricular fibrillation (VF) episodes were reviewed for appropriate detection, ATP success, rhythm acceleration, and related symptoms. RESULTS: In 421 implanted patients, 116 VF episodes occurred in 37 patients. Eighty-four (72%) episodes received ATP during or before charging. ATP prevented a shock in 58 (69%) of 84 episodes in 15 patients. ATP stopped significantly more monomorphic (77%) than polymorphic VTs (44%, P = .05). Five (6%) episodes accelerated after ATP but were terminated by the backup shock(s). No symptoms were related to ATP during charging. In four patients, 38 charges were saved by delivering ATP before charging. Of 98 induced VF episodes, 28% were successfully terminated by ATP versus 69% for spontaneous episodes (P <.01). CONCLUSION: Most VTs detected in the VF zone can be painlessly terminated by ATP delivered during charging, with a low risk of acceleration or symptoms. ATP before charging allows delivery of two ATP attempts before shock in the same time that would otherwise be required to deliver only one ATP plus a shock. It also offers potential battery energy savings.     

Host-derived amino acids support the proliferation of symbiotic bacteria

Animals are typically colonized by diverse bacterial symbionts, many of which are commensal and, in numerous cases, even essential for their host’s proper development and growth. In exchange, the host must supply a sufficient array and quantity of nutrients to support the proliferation and persistence of its microbial community. In this investigation, we have examined such a nutritional environment by determining the symbiotic competence of auxotrophic mutants of the bioluminescent bacterium Vibrio fischeri, and have demonstrated that the host squid Euprymna scolopes provides at least 9 aa to the growing culture of symbiotic V. fischeri present in its light-emitting organ. We also collected and analyzed the extracellular fluid from this organ, in which the symbionts reside, and confirmed that it contained significant amounts of amino acids. The combined results suggested that host-derived free amino acids, as well as peptides or proteins, are a source of the amino acids that support the growth of the symbionts. This work describes a technique to sample the symbionts and their surrounding environment without contamination by host tissue components and, in combination with molecular genetic studies, allows the characterization of the nutritional conditions that support a cooperative animal–bacterial symbiosis.     

Hypertension exacerbates the effect of hypercholesterolemia on the myocardial microvasculature

OBJECTIVE: Hypercholesterolemia (HC) and hypertension (HT) are both major risk factors for the development and progression of atherosclerotic heart disease, and their co-existence has been associated with an increased incidence of cardiac events in clinical studies. HC and HT are individually associated with abnormal myocardial vascular function, but whether HT exacerbates the HC-induced myocardial vascular dysfunction remains unclear. METHODS: We studied in pigs the effect of renovascular HT superimposed on diet-induced HC (HC+HT) on myocardial perfusion and microvascular permeability in vivo (using electron-beam computed tomography) in response to cardiac challenge (i.v. adenosine and dobutamine). The involvement of systemic and myocardial tissue oxidative stress in vitro was assessed by oxidizability of LDL, levels of endogenous antioxidants, and tissue activities of radical-scavenger systems. RESULTS: While in normal animals myocardial perfusion increased in response to i.v. adenosine (+36+/-13%, P<0.05), in HC and HT alone the increase was blunted. In HC+HT myocardial perfusion response was further attenuated and significantly lower than normal, and myocardial vascular resistance failed to decrease (+7.6+/-8.8 vs. -21.0+/-5.8%, P=0.02 versus normal). HC+HT also showed blunted response to dobutamine, and augmented increases in microvascular permeability in vivo. These functional abnormalities were associated with increased systemic and myocardial tissue oxidative stress compared to HC or HT alone, and a synergistic decrease in endogenous antioxidant defenses in myocardial tissue. Furthermore, chronic antioxidant vitamin supplementation in combined HC and HT improved myocardial vascular responses. CONCLUSION: HT amplifies the HC-induced myocardial microvascular dysfunction in vivo and increased oxidative stress in vitro. These alterations may potentially play a role in the increased incidence of cardiac events observed when HC and HT co-exist.     

Relationship between angiographic late loss and target lesion revascularization after coronary stent implantation: analysis from the TAXUS-IV trial

OBJECTIVES: We sought to evaluate the relationship between angiographic late loss and clinical outcomes in the drug-eluting stent era. BACKGROUND: The interrelationship between angiographic late loss, binary restenosis, and clinical recurrence (target lesion revascularization [TLR]) after coronary stent implantation has been incompletely evaluated. METHODS: Using the angiographic substudy of the TAXUS-IV trial, in which 1,314 patients with de novo coronary lesions were randomized to either the paclitaxel-eluting TAXUS stent or to its bare-metal equivalent, we defined the relationship between in-stent and analysis segment late loss, the shape of the late loss histogram (variance and skewedness), and nine-month TLR. RESULTS: Late loss by several measures was closely related to TLR (area under the receiver-operator curve >0.90). For individual vessels of the size in this study (2.8 +/- 0.5 mm), the likelihood of TLR did not exceed 5% until analysis segment late loss was >0.5 mm, and did not exceed 10% until late loss was >0.65 mm. At greater late losses, the late loss TLR relationship was steep and nearly linear. For the overall patient cohort, the rate of TLR was related, however, not only to median late loss, but also to measures of its statistical distribution (TLR increased with lack of homogeneous biologic response [greater variance and greater right skewedness]). Similar relationships held for late loss measured within the confines of the stent itself. CONCLUSIONS: Coronary stents result in large lumens with "room" to accommodate up to approximately 0.5 to 0.65 mm of tissue (angiographic analysis segment late loss) before the likelihood of clinical restenosis (TLR) exceeds 5% to 10%. These data have important implications toward understanding the absolute and relative efficacy of drug-eluting stents.