Ceramide-Activated Phosphatase Mediates Fatty Acid–Induced Endothelial VEGF Resistance and Impaired Angiogenesis

Endothelial dysfunction, including endothelial hyporesponsiveness to prototypical angiogenic growth factors and eNOS agonists, underlies vascular pathology in many dysmetabolic states. We investigated effects of a saturated free fatty acid, palmitic acid (PA), on endothelial cell responses to VEGF. PA-pretreated endothelial cells had markedly diminished Akt, eNOS, and ERK activation responses to VEGF, despite normal VEGFR2 phosphorylation. PA inhibited VEGF-induced angiogenic cord formation in Matrigel, and PA-treated endothelial cells accumulated early species (C16) ceramide. The serine palmitoyltransferase inhibitor myriocin reversed these defects. Protein phosphatase 2A (PP2A) became more eNOS-associated in PA-treated cells; the PP2A inhibitor okadaic acid reversed PA-induced signaling defects. Mice fed a diet high in saturated fat for 2 to 3 weeks had impaired i) aortic Akt and eNOS phosphorylation to infused VEGF, ii) ear angiogenic responses to intradermal adenoviral-VEGF injection, and iii) vascular flow recovery to hindlimb ischemia as indicated by laser Doppler and α_Vβ₃ SPECT imaging. High-fat feeding did not impair VEGF-induced signaling or angiogenic responses in mice with reduced serine palmitoyltransferase expression. Thus, de novo ceramide synthesis is required for these detrimental PA effects. The findings demonstrate an endothelial VEGF resistance mechanism conferred by PA, which comprises ceramide-induced, PP2A-mediated dephosphorylation of critical activation sites on enzymes central to vascular homeostasis and angiogenesis. This study defines potential molecular targets for preservation of endothelial function in metabolic syndrome.Endothelial dysfunction is the inability of the endothelium to promote vasodilation in a stimulus-dependent fashion, primarily as a consequence of impaired nitric oxide (NO) production. Individuals with risk factors for vascular disease, including metabolic syndrome and dysplipidemia,¹ exhibit varying degrees of endothelial dysfunction, which is an early feature of vascular pathology with prognostic significance.² Elevation of circulating free fatty acids (FFAs), experimentally or as seen in obese insulin-resistant individuals and in type 2 diabetes, results in 40% to 50% lower endothelium-dependent vasodilation.^3,4 The elevation of circulating FFA in obesity, metabolic syndrome, and type 2 diabetes is associated with impaired endothelium-dependent vasodilation, suggesting a link between FFA and endothelial dysfunction. We investigated such a link by assessing the effect of FFA on NO-producing growth factor signaling in the endothelium.Similar to hyperinsulinemia in insulin resistance, elevated systemic VEGF levels have been detected in individuals with visceral obesity, type 2 diabetes, and atherosclerosis.^5,6 VEGF levels are also elevated in chronically ischemic coronary and peripheral artery disease states,⁶ as well as in essential hypertension.⁷ In the present study, we evaluated the effects of palmitic acid (PA) on endothelial signaling responses to VEGF. PA profoundly impaired VEGF-dependent eNOS activation and angiogenic responses in vitro and in two independent in vivo murine models. The effects of PA were dependent on de novo synthesis of ceramide, which increased association of protein phosphatase 2A (PP2A) with eNOS. Here, we discuss this VEGF resistance as a possible central feature of the widespread vascular pathology seen in numerous dysmetabolic states.     

Experimental study on cross‐reactivity of α‐arbutin toward p‐phenylenediamine and hydroquinone in guinea pigs

Hydroquinone (HQ) has been used as a skin‐lightening cosmetic ingredient, while it has been known that HQ shows sensitizing potential and cross‐reactivity toward a strong sensitizer, p‐phenylenediamine (PPD). α‐Arbutin, a glycoside of HQ (4‐hydroxyphenyl α‐D‐glucopyranoside), is used worldwide as a skin‐lightening agent. The aim of this study was to evaluate the cross‐reactivity of α‐arbutin toward PPD and HQ. All tests were performed using the guinea pig maximization test. In experiments on the cross‐reactivity of α‐arbutin or HQ to PPD, six animals in each group were induced with PPD at 0.1% by i.d. injection and at 1.0% by topical application. The animals were challenged with α‐arbutin, HQ or PPD (as a positive control) at concentrations of 0.01%, 0.05% and 0.1%. In experiments on the cross‐reactivity of α‐arbutin to HQ, four animals in each group were induced with HQ at 2% by i.d. injection and at 1% by topical application. The animals were challenged with α‐arbutin or HQ (as a positive control) at concentrations of 0.2%, 2% and 20%. The cross‐reactivity toward PPD was observed with HQ (4/6) only at 0.1% challenge. However, α‐arbutin showed no apparent cross‐reactivity to either PPD or HQ even at their highest challenge concentrations. Potent sensitization was observed with PPD (6/6) even at 0.01% challenge and with HQ (3/4) at 0.2%. In conclusion, glycosylation of HQ remarkably reduced the sensitization potency of HQ and the cross‐reactivity of HQ to PPD.     

Cytokine gene polymorphisms and sudden infant death syndrome

Aim: Several studies indicate that the mucosal immune system is stimulated in cases of sudden infant death syndrome (SIDS), and our hypothesis is that this immune reaction is because of an unfavourable combination of functional polymorphisms in the cytokine genes. Methods: Thus, in this study, single nucleotide polymorphisms (SNPs) in the genes encoding IL‐6, IL‐8, IL‐12, IL‐13, IL‐16, IL‐18 and IFNγ were investigated in 148 SIDS cases, 56 borderline SIDS cases, 41 cases of infectious death and 131 controls. Results: Regarding genotype distribution, no differences between the investigated groups were found. However, in the SIDS group, the genotypes IL‐8 ?251AA/AT and IL‐8 ?781CT/TT were significantly more frequent in the SIDS cases found dead in a prone sleeping position, compared with SIDS cases found dead in other sleeping positions. In addition, there was an association between fever prior to death and the genotype IL‐13 +4464GG in the cases of infectious death. Conclusion: This study indicates that specific interleukin genotypes are a part of a genetic make up that make infants sleeping prone at risk for SIDS.     

Interferons increase cell resistance to Staphylococcal alpha-toxin

Many bacterial pathogens, including Staphylococcus aureus, use a variety of pore-forming toxins as important virulence factors. Staphylococcal alpha-toxin, a prototype β-barrel pore-forming toxin, triggers the release of proinflammatory mediators and induces primarily necrotic death in susceptible cells. However, whether host factors released in response to staphylococcal infections may increase cell resistance to alpha-toxin is not known. Here we show that prior exposure to interferons (IFNs) prevents alpha-toxin-induced membrane permeabilization, the depletion of ATP, and cell death. Moreover, pretreatment with IFN-α decreases alpha-toxin-induced secretion of interleukin 1β (IL-1β). IFN-α, IFN-β, and IFN-γ specifically protect cells from alpha-toxin, whereas tumor necrosis factor alpha (TNF-α), IL-6, and IL-4 have no effects. Furthermore, we show that IFN-α-induced protection from alpha-toxin is not dependent on caspase-1 or mitogen-activated protein kinases, but requires protein synthesis and fatty acid synthase activity. Our results demonstrate that IFNs may increase cell resistance to staphylococcal alpha-toxin via the regulation of lipid metabolism and suggest that interferons play a protective role during staphylococcal infections.     

Validation of Embletta portable diagnostic system for identifying patients with suspected obstructive sleep apnoea syndrome (OSAS)

Background and objectives: This study aimed to evaluate the diagnostic accuracy of Embletta portable diagnostic system (PDS, Medcare, Reykjavik, Iceland) for the screening of sleep apnoea in clinical practice. Methods: The Embletta PDS is a digital three‐channel recording device that measures airflow through a nasal cannula connected to a pressure transducer, oxygen saturation plus both respiratory and abdominal movements via built‐in effort and body position sensors. An AHI is determined based on recording time. Nocturnal polysomnography (Alice 4, Healthdyne, Atlanta, USA), with airflow measured by a nasal pressure transducer (PTAF2, Pro‐Tech, Woodinville, WA, USA)) and Embletta PDS recordings, was performed simultaneously in consecutive patients with suspected OSA syndrome. The PSG recordings were analysed manually by a blinded investigator. Results: Ninety subjects were recruited and 10 failed Embletta PDS studies due to measurement failure. Among the remaining 80 subjects, 63 were males. The mean age (SD) was 51.4 (11.9) years old, BMI 27.1(4.2) kg/m², neck circumference 38.6 (3.6) cm and Epworth Sleepiness Score 9.7 (5.3). The AHI obtained by the Embletta PDS correlated closely with that obtained by PSG (Pearson correlation, r = 0.979, P < 0.001). Comparison of AHI based on the Embletta PDS against the PSG demonstrated high sensitivity at AHI ≥ 5/h (sensitivity 0.924 and specificity 0.857) and high specificity at AHI ≥ 20/h (sensitivity 0.853 and specificity 0.957). Conclusions: The Embletta PDS is a highly sensitive and specific screening device in quantifying AHI when compared against PSG in patients with suspected OSA syndrome.     

Complex Immune Cell Interplay in the Gamma Interferon Response during Toxoplasma gondii Infection

Toxoplasma gondii is an obligate intracellular parasite of clinical importance, especially in immunocompromised patients. Investigations into the immune response to the parasite found that T cells are the primary effector cells regulating gamma interferon (IFN-γ)-mediated host resistance. However, recent studies have revealed a critical role for the innate immune system in mediating host defense independently of the T cell responses to the parasite. This body of knowledge is put into perspective by the unifying theme that immunity to the protozoan parasite requires a strong IFN-γ host response. In the following review, we discuss the role of IFN-γ-producing cells and the signals that regulate IFN-γ production during T. gondii infection.     

Primary and secondary histiocytic lymphoma of the brain: CT features

The authors examined 19 patients with diffuse histiocytic lymphoma of the brain, including 8 with primary disease and 11 with secondary disease. Both primary disease and secondary disease involving the brainstem and deep nuclei exhibited the characteristic CT appearance, consisting of a large, solid, homogeneously enhanced mass with varying amounts of edema. However, most secondary lymphomas outside the brainstem and basal ganglia contained large areas of low attenuation consistent with necrosis. Multifocal lesions were seen only in patients with secondary lymphoma. Systemic chemotherapy for extracranial lymphoma had no effect on the CT appearance of intracranial lesions. The authors suggest that these "unusual" CT patterns are actually typical of a distinct subset of histiocytic lymphomas.     

Counseling interventions delivered in women with breast cancer to improve health-related quality of life: a systematic review

Background

Higher survival rates for breast cancer patients have led to concerns in dealing with short- and long-term side effects. The most common complications are impairment of shoulder functions, pain, lymphedema, and dysesthesia of the injured arm; psychological consequences concern: emotional distress, anxiety, and depression, thereby, deeply impacting/affecting daily living activity, and health-related quality of life.

Objective

To perform a systematic review for assessing the efficacy or effectiveness of interventions aiming at improving health-related quality of life, return to daily activity, and correct lifestyles among breast cancer patients.

Methods

A literature search was conducted in December 2016 using the databases PubMed and Scopus. Search terms included: (counseling) AND (breast cancer) AND (quality of life). Articles on counseling interventions to improve quality of life, physical and psychological outcomes were included.

Results

Thirty-five articles met the inclusion criteria. The interventions were grouped in five main areas: concerning lifestyle counseling interventions, related to combined interventions (physical activity and nutritional counseling), physical therapy, peer counseling, multidisciplinary approach, included psychological, psycho-educational interventions, and cognitive-behavior therapy (CBT). Exercise counseling as well as physical therapy are effective to improve shoulder mobility, healing wounds, and limb strength. Psychological therapies such as psychoeducation and CBT may help to realize a social and psychological rehabilitation.

Conclusion

A multidisciplinary approach can help in sustaining and restoring impaired physical, psychosocial, and occupational outcomes of breast cancer patients.

     

盆腔外子宫内膜异位症19例临床分析

目的 探讨盆腔外子宫内膜异位症的临床特征。方法收集本院1990年1月至2000年12月收治的19例盆腔外子宫内膜异位症患者的临床资料,分析其发病情况、临床表现、诊断、治疗及预后。结果 18例患者为育龄期妇女,1例为围绝经期妇女,平均年龄36.2岁。病变部位8例位于手术切口、宫颈及阴道穹隆6例、胃肠道2例、泌尿系统3例及其他部位1例。主要症状:8例有皮下结节伴经期疼痛、2例月经期血尿及排便痛等,5例无典型症状。术前诊断率较低(52.6％)。治疗以局部病灶切除为主,术后辅以药物治疗。结论盆腔外子宫内膜异位症原因较复杂,因临床表现不典型,术前诊断率不高,应注意原发症状与月经周期的关系,提高对本病的认识。治疗应以切除病灶、缓解症状、恢复功能为主。