Endothelial dysfunction may play a key role in keloid and hypertrophic scar pathogenesis – Keloids and hypertrophic scars may be vascular disorders

Keloids and hypertrophic scars are fibroproliferative disorders (FPDs) of the skin that result from abnormal healing of injured or irritated skin. They can be called pathological or inflammatory scars. Common causes are trauma, burn, surgery, vaccination, skin piercing, folliculitis, acne, and herpes zoster infection. The pathogenesis of these scars clearly involves local conditions such as delayed wound healing, wound depth, and the tension of the skin around the scars. Scar severity is also shaped by interactions between these local factors and genetic and systemic factors such as hypertension and sex hormones. Notably, to evaluate scar severity, the Japan Scar Workshop (JSW) has established the JSW Scar Scale.Our studies show that tension on the skin around the wound results in prolonged and/or repeated bouts of inflammation in the reticular layer of the dermis and that this inflammation generates abnormal numbers of blood vessels (as well as collagen and nerve fibers) in the dermal reticular layer. We hypothesize that local factors, such as the mechanobiology of the dermis and blood vessels, along with genetic and systemic factors promote pathological scar development by inducing endothelial dysfunction (i.e., vascular hyperpermeability) during the inflammatory stage of wound healing. The continued presence of these factors prolongs the influx of inflammatory cells and factors, thereby leading to fibroblast dysfunction.Evidence for this hypothesis includes the fact that all effective treatments of keloids, namely, radiotherapy, compression therapy, steroid administration, and long-pulsed Nd:YAG laser therapy, act, at least partly, by suppressing blood vessels.At present, keloids are classified as strongly inflammatory scars, while hypertrophic scars are considered to be mildly inflammatory scars. However, we propose that keloids and hypertrophic scars are simply manifestations of the same skin FPD and differ only in the degree of endothelial dysfunction and therefore inflammation. We therefore suggest that these pathological scars should be classified on the basis of the factor that causes the endothelial dysfunction. Thus, primary scars are caused by congenital endothelial dysfunction (e.g., a mutation prevents endothelial gaps from closing smoothly) while secondary scars are caused by endothelial dysfunction that results from aging, arterial sclerosis, and/or repeated/very strong local mechanical forces. We expect that primary keloids develop at younger ages and tend to become severe, while secondary keloids are seen in all ages and can vary in clinical severity.Thus, abnormal blood vessel regulation may underlie keloid and hypertrophic scar pathogenesis, which suggests that inhibiting abnormal angiogenesis and vascular hyperpermeability may be an important therapeutic approach.     

Food protein–induced allergic proctocolitis may have distinct phenotypes

BackgroundFood protein–induced allergic proctocolitis (FPIAP) is a non–immunoglobulin E (IgE)-mediated food allergy, which presents with bloody mucoid stool in infants. Although IgE-mediated allergy and sensitizations to offending foods have been described in other non–IgE-mediated food allergies, it has not been investigated in FPIAP.ObjectiveTo investigate IgE-mediated allergy and sensitization to offending foods in FPIAP.MethodsPatients (n = 204) were retrospectively recruited and grouped as FPIAP (n = 180; FPIAP with or without the symptoms of IgE-mediated food hypersensitivity to offending and nonoffending foods at initial consultation), FPIAP-IgE sensitization to offending foods (n = 17), and FPIAP-transition to IgE-mediated allergy to offending foods (n = 7). The study was performed in accordance with the protocol approved by the local ethical committee of the Hacettepe University.ResultsThe median age of onset of symptoms and the development of tolerance was 2 months (interquartile range [IQR], 1.0-3.0) and 12 months (IQR, 10.0-14.0), respectively, and of the patients with skin prick test or serum specific IgE tests (n = 196), 38 (19.4%) had evidence of IgE sensitization to offending foods at the initial consultation or during follow-up; 17 (8.6%) had IgE sensitization, 7 (3.6%) indicated a transition to IgE-mediated allergy to FPIAP-induced foods. The median age of tolerance development of the FPIAP-transition group (19 months, IQR, 18.0-29.0) was significantly later than that of the FPIAP group (11 months, IQR, 10.0-14.0; P < .001) and the FPIAP-IgE sensitization group (11.0 months, IQR, 9.5-12.0; P < .001). Tolerance was observed within the study period in almost all the patients.ConclusionChildren with FPIAP may have sensitization or develop IgE-mediated allergy over time to offending foods. In addition, IgE sensitization in FPIAP does not have an unfavorable effect on tolerance development; however, the transition to an IgE-mediated phenotype may delay tolerance for a brief time.     

Statins may potentiate bisphosphonates anticancer properties: a new pharmacological approach?

Both statins and bisphosphonates may inhibit cancer proliferation by two main different mechanisms: inducing apoptosis along cholesterol synthesis pathway and by antiangiogenic properties. Moreover, also an immunomediated mechanism could be involved in anticancer properties of these molecules. The association of these two drugs could represent an interesting pharmacological approach in anticancer treatment. The available data offer the rationale for future in vitro studies aimed at evaluating proapoptotic and antiangiogenic action of this association. If the results of vitro studies should confirm the hypothesis that statins potentiate the action of bisphosphonates, further clinical investigations could be mandatory to evaluate the efficacy of this new pharmacological approach in anticancer therapy.     

EPAC–STX interaction may play a role in neurodevelopment/neurogenesis

During embryonic life a group of cells become proliferated, migrated and differentiated to develop central nervous system. Migration has been suggested to be due to accumulation of polysialic acid (PSA), a negatively-charged glycoside, on the outer cell membrane. The same event happens to PSA in a tumor mass as well. Polysialylation is the product of polysialyl transfrase isozymes; STX (ST8SIA2), the embryonic active isoform, and PST (ST8SIA4), expressed in adults CNS. Additionally, cAMP concludes to activation of PKA and EPAC resulting to the initiation of gene expressions which are highly required during development. EPAC, the latter known target of cAMP in mammalian nervous system, has proliferative properties in the developing CNS. We propose for the proper action of EPAC, namely CNS development, the presence of STX and its elevation after EPAC activation is mandatory. This hypothesis is put forward after observing, in a preliminary experiment, a relationship between EPAC activation and STX mRNA expression levels in rat hippocampus. The interaction between EPAC and STX may be suggested to be through EPAC-induced gene expression of the latter. From the above assumptions one may suggest the use of EPAC activators as neurogenesis inducers and its inhibitors as tumor modulators.     

The Tego™ needleless connector for hemodialysis catheters may protect against catheter colonization

Catheter connectors used in hemodialysis patients are those with open caps to manage high blood flows. However, current guidelines for the prevention of catheter infections recommend closed connectors. Tego? is a closed connector designed to enable high blood flows. We used an in vitro model to compare the efficacy of Tego? against contamination with that of standard caps in a real-life practice scenario. The model consisted of 200 blood culture bottles (BCB) with an inserted cannula closed either with Tego? (100) or with open caps (100). BCB were manipulated using two different methods: under aseptic conditions and with gloves contaminated with a 0.05 McFarland Staphylococcus aureus solution. The BCB were incubated at 37 °C under continuous shaking for up to 7 days or until positive. When a BCB turned positive, 100 μL of the fluid was cultured. The positivity rate and time to positivity of the BCB in each method were compared. Overall, 4.0 % of BCB with Tego? and 52.0 % of BCB with open caps were positive in the sterile model (p?<?0.001), whereas all BCB in the contamination model were positive. We did not find differences regarding the median time (hours) to positivity between Tego? and the standard cap in the contamination model (19.04 vs. 17.87, p?=?0.465). In our model, Tego? proved to be better than the standard cap for the prevention of contamination when the device was handled under optimal conditions. Moreover, it was as efficient as the standard catheter cap in the contamination model.     

The TNF-�� -308 polymorphism may affect the severity of Crohn's disease

OBJECTIVE:

The goal of this project was to analyze the association between Crohn''s disease, its clinical features, and the tumor necrosis factor alpha (TNF-α) -308 polymorphism.

METHODS:

This is a case-control and cross-sectional study that enrolled 91 patients with Crohn''s disease and 91 controls. Patients with Crohn''s disease were characterized according to the Montreal Classification, along with their clinical and surgical treatment history. Analysis of the TNF-α -308 polymorphism was performed using a commercial kit. A stratified analysis was applied using an OR (odds ratio) with a 95% confidence interval. The chi-square and Fisher''s exact tests were utilized for analysis of the association between the polymorphism and the clinical features of Crohn''s disease.

RESULTS:

The low producer predicted phenotype was present in 76.9% of Crohn''s disease cases and 75.8% of controls (OR 0.94 [0.45-1.97]). The TNF2 allele and the high producer predicted phenotype were more frequent among patients with Crohn''s disease penetrating behavior (p = 0.004). The TNF2 allele and the high producer predicted phenotype were also associated with a history of colectomy (p = 0.02), and the TNF2 allele was associated with small bowel resection (p = 0.03).

CONCLUSIONS:

The TNF-α -308 polymorphism appears to affect the severity of the disease. However, TNF-α -308 polymorphism does not appear to be important for the susceptibility in the development of Crohn''s disease.     

What should we do with donated embryos that may be genetically affected?

The ethical and legal issues arising from genetic screening in embryo donation are discussed in relation to two recent cases where embryos with uncertain genetic health were offered for donation.     

Mechanisms of AD neurodegeneration may be independent of Aβ and its derivatives

Alzheimer's disease (AD) is the most common cause of dementia in the aged population. Most cases are sporadic although a small percent are familial (FAD) linked to genetic mutations. AD is caused by severe neurodegeneration in the hippocampus and neocortical regions of the brain but the cause of this neuronal loss is unclear. A widely discussed theory posits that amyloid depositions of Aβ peptides or their soluble forms are the causative agents of AD. Extensive research in the last 20 years however, failed to produce convincing evidence that brain amyloid is the main cause of AD neurodegeneration. Moreover, a number of observations, including absence of correlations between amyloid deposits and cognition, detection in normal individuals of amyloid loads similar to AD, and animal models with behavioral abnormalities independent of amyloid, are inconsistent with this theory. Other theories propose soluble Aβ peptides or their oligomers as agents that promote AD. These peptides, however, are normal components of human CSF and serum and there is little evidence of disease-associated increases in soluble Aβ and oligomers. That mutants of amyloid precursor protein (APP) and presenilin (PS) promote FAD suggests these proteins play crucial roles in neuronal function and survival. Accordingly, PS regulates production of signaling peptides and cell survival pathways while APP functions in cell death and may promote endosomal abnormalities. Evidence that FAD mutations inhibit the biological functions of PS combined with absence of haploinsufficiency mutants, support a model of allelic interference where inactive FAD mutant alleles promote autosomal dominant neurodegeneration by also inhibiting the functions of wild type alleles.     

Tombusvirus genome may encode the sixth small protein near its 3′ terminus

A short open reading frame (ORF), ORF6, potentially encoding a polypeptide (pX) of 32–69 amino acids, was revealed upon computer translation of the 3 terminal regions of tomato bushy stunt, cymbidium ringspot, cucumber necrosis, and artichoke mottled crinkle tombusviruses. ORF6 has an initiating AUG codon in a favorable context and is evaluated as expressible, judging the distribution of guanosine residues within the codons. Inspection of the alignment of the four putative products encoded by ORF6 shows statistically significant sequence conservation over 11 SD above the random expectation. Secondary structure predictions based on the Garnier method demonstrate strict conservation of a loop between two -strands, thus suggesting functional conservation of pXs. It is suggested that pX is not involved in tombusvirus genome replication and encapsidation incis.     

Diabetic foot cellular hypoxia may be due to capillary shunting – A novel hypothesis

Diabetic foot is traditionally attributed to a triad of neuropathy, ischemia and infection. Cellular hypoxia in diabetic foot can neither be attributed to an occlusive large artery disease (which are mostly patent) nor to the so called diabetic small vessel disease (where such occlusion was never proved). The physiological findings that accompany cellular hypoxia are confusing: elevated local blood flow and high oxygen saturation in both the tissue and its collecting veins. It is well known that some tissues (e.g. skin) are wired with two types of capillaries: True capillaries – also known as exchange capillaries, where nutrients and gases exchange takes place, and metarteriole thoroughfare channels – also known as shunting capillaries. We hypothesize that in the diabetic foot tissue blood flow is rerouted through the metarteriole thoroughfare channel, bypassing the exchange capillaries. Hence, nutrient and gas exchange is disabled and tissue cells became hypoxic regardless of the tissue blood flow. As a result of the shunt, arterial oxygen is not consumed and the oxygen saturation in the collecting veins remains high. The hereby hypothesis suggests that mal-perfusion rather than hypo-perfusion is the underlying cause of cellular hypoxia in diabetic foot. This hypothesis complies with the findings of patent arteries proximal to the affected site, normal to elevated tissue blood flow and high oxygen saturation in the affected tissue and its collecting veins.     

Cardiorespiratory fitness effect may be under-estimated in ‘fat but fit’ hypothesis studies

Background: Both cardiorespiratory fitness and body fat have been independently related to metabolic syndrome in adolescents; however, the strength of these relationships seems to be dependent on the outcome composition.

Aim: To analyse the relationship between cardiorespiratory fitness and body fat combined with different indicators of metabolic risk in adolescents.

Subjects and methods: The sample was composed of 957 adolescents (58.7% girls). Cardiorespiratory fitness was obtained using the 20-metre shuttle run test and skinfold thickness was collected for body fat estimation. Metabolic risk score was calculated from waist circumference, systolic and diastolic blood pressure, glucose, HDL cholesterol and triglycerides measurements and an alternative outcome without the central obesity indicator was adopted. Chronological age and somatic maturity were used as covariates.

Results: Higher metabolic risk was observed in the highest fat/lowest fit adolescents (p?Conclusion: These findings suggest that body fat is strongly related to cardiovascular risk, but, when the outcome is calculated without the central obesity indicator, cardiorespiratory fitness becomes more related to metabolic risk.     

“Dark” (compacted) neurons may not die through the necrotic pathway

Dark neurons were produced in the cortex of the rat brain by hypoglycemic convulsions. In the somatodendritic domain of each affected neuron, the ultrastructural elements, except for disturbed mitochondria, were remarkably preserved during the acute stage, but the distances between them were reduced dramatically (ultrastructural compaction). Following a 1-min convulsion period, only a few neurons were involved and their environment appeared undamaged. In contrast, 1-h convulsions affected many neurons and caused swelling of astrocytic processes and neuronal dendrites (excitotoxic neuropil). A proportion of dark neurons recovered the normal structure in 2 days. The non-recovering dark neurons were removed from the brain cortex through two entirely different pathways. In the case of 1-h convulsions, their organelles swelled, then disintegrated and finally dispersed into the neuropil through large gaps in the plasma membrane (necrotic-like removal). Following a 1-min convulsion period, the non-recovering dark neurons fell apart into membrane-bound fragments that retained the compacted interior even after being engulfed by astrocytes or microglial cells (apoptotic-like removal). Consequently, in contrast to what is generally accepted, the dark neurons produced by 1-min hypoglycemic convulsions do not die as a consequence of necrosis. As regards the case of 1-h convulsions, it is assumed that a necrotic-like removal process is imposed, by an excitotoxic environment, on dark neurons that previously died through a non-necrotic pathway. Apoptotic neurons were produced in the hippocampal dentate gyrus by intraventricularly administered colchicine. After the biochemical processes had been completed and the chromatin condensation in the nucleus had reached an advanced phase, the ultrastructural elements in the somatodendritic cytoplasm of the affected cells became compacted. If present in an apparently undamaged environment such apoptotic neurons were removed from the dentate gyrus through the apoptotic sequence of morphological changes, whereas those present in an impaired environment were removed through a necrotic-like sequence of morphological changes. This suggests that the removal pathway may depend on the environment and not on the death pathway, as also assumed in the case of the dark neurons produced by hypoglycemic convulsions.     

Distinct cytokine patterns may regulate the severity of neonatal asphyxia—an observational study

Background

Neuroinflammation and a systemic inflammatory reaction are important features of perinatal asphyxia. Neuroinflammation may have dual aspects being a hindrance, but also a significant help in the recovery of the CNS. We aimed to assess intracellular cytokine levels of T-lymphocytes and plasma cytokine levels in moderate and severe asphyxia in order to identify players of the inflammatory response that may influence patient outcome.

Methods

We analyzed the data of 28 term neonates requiring moderate systemic hypothermia in a single-center observational study. Blood samples were collected between 3 and 6 h of life, at 24 h, 72 h, 1 week, and 1 month of life. Neonates were divided into a moderate (n?=?17) and a severe (n?=?11) group based on neuroradiological and amplitude-integrated EEG characteristics. Peripheral blood mononuclear cells were assessed with flow cytometry. Cytokine plasma levels were measured using Bioplex immunoassays. Components of the kynurenine pathway were assessed by high-performance liquid chromatography.

Results

The prevalence and extravasation of IL-1b + CD4 cells were higher in severe than in moderate asphyxia at 6 h. Based on Receiver operator curve analysis, the assessment of the prevalence of CD4+ IL-1β+ and CD4+ IL-1β+ CD49d+ cells at 6 h appears to be able to predict the severity of the insult at an early stage in asphyxia. Intracellular levels of TNF-α in CD4 cells were increased at all time points compared to 6 h in both groups. At 1 month, intracellular levels of TNF-α were higher in the severe group. Plasma IL-6 levels were higher at 1 week in the severe group and decreased by 1 month in the moderate group. Intracellular levels of IL-6 peaked at 24 h in both groups. Intracellular TGF-β levels were increased from 24 h onwards in the moderate group.

Conclusions

IL-1β and IL-6 appear to play a key role in the early events of the inflammatory response, while TNF-α seems to be responsible for prolonged neuroinflammation, potentially contributing to a worse outcome. The assessment of the prevalence of CD4+ IL-1β+ and CD4+ IL-1β+ CD49d+ cells at 6 h appears to be able to predict the severity of the insult at an early stage in asphyxia.

     

Inhibiting Eph kinase activity may not be “Eph”ective for cancer treatment

Abstract

Several Eph receptor tyrosine kinases (RTKs) are commonly over-expressed in epithelial and mesenchymal cancers and are recognized as promising therapeutic targets. Although normal interaction between Eph receptors and their ephrin ligands stimulates kinase activity and is generally tumor suppressive, significant Eph over-expression allows activation of ligand- and/or kinase-independent signaling pathways that promote oncogenesis. Single-agent kinase inhibitors are widely used to target RTK-driven tumors but acquired and de novo resistance to such agents is a major limitation to effective clinical use. Accumulating evidence suggests that Ephs can be inhibited by “leaky” or low-specificity kinase inhibitors targeted at other RTKs. Such off-target effects may therefore inadvertently promote ligand- and/or kinase-independent oncogenic Eph signaling, thereby providing a new mechanism by which resistance to the RTK inhibitors can emerge. We propose that combining specific, non-leaky kinase inhibitors with tumor-suppressive stimulators of Eph signaling may provide more effective treatment options for overcoming treatment-induced resistance and clinical failure.