Nursing grand rounds: multiple sclerosis.

Multiple sclerosis (MS) is a highly variable, unpredictable disease and one of the most life-altering diagnoses a person can receive. Because it usually strikes in the prime of life, frequently progresses to disability, and has no cure, MS can make a strong emotional impact--not only on those who suffer from it, but also the healthcare team. Because MS is such a complex, multifaceted disorder, nurses who care for people with MS are faced with numerous clinical challenges. Many of the challenges are unique to MS, demanding, and time-consuming. Well-informed nurses are positioned to evaluate and explain the disease process, assist in the alleviation of symptoms, educate partners and families, and help improve quality of life. A case example can help nurses understand the real-life concerns of a person with MS.     

Trehalose dimycolate enhances resistance to infection in neutropenic animals.

Bacterial infections are lethal complications of neutropenia, and antibiotics alone are inadequate therapy for these infections. Irradiated mice become severely neutropenic and remain susceptible to infection for 2 to 3 weeks, depending on the dose and quality of radiation. Some bacterial cell wall derivatives stimulate nonspecific host defense mechanisms against a variety of microbes which might cause postirradiation infection. In this study we determined if the cell wall glycolipid trehalose dimycolate (TDM), derived from Mycobacterium phlei, or a synthetic preparation of TDM was able to (i) enhance survival in mice when given before or after lethal doses of 60Co radiation and (ii) increase nonspecific resistance to postirradiation infection. Treatment with TDM oil-in-water emulsions and with synthetic TDM significantly enhanced survival before and after lethal doses of 60Co irradiation. This result correlated with the ability of TDM to reduce the translocation of intestinal bacteria and to stimulate hematopoiesis. With respect to nonspecific resistance to infection, TDM injected 1 h after sublethal irradiation increased resistance to a lethal Klebsiella pneumoniae challenge (10 50% lethal doses of K. pneumoniae in 30 days [LD50/30]) 4 or 14 days later. Increasing the dose of K. pneumoniae to 5,000 LD50/30 on day 4 overwhelmed the ability of TDM-treated mice to overcome infection. However, TDM treatment 1 h postirradiation combined with ceftriaxone antibiotic therapy (days 5 through 14) enhanced survival, even when the higher dose of bacteria (5,000 LD50/30) was used. These results indicate that in irradiated mice, TDM can be used to enhance survival and, as a potent stimulant of nonspecific resistance to infection in neutropenic mice, can act synergistically with antibiotic therapy to reduce sepsis and mortality.     

Analysis of IFN-kappa expression in pathologic skin conditions: downregulation in psoriasis and atopic dermatitis.

Interferon-kappa (IFN-kappa) is a type I IFN expressed by keratinocytes, monocytes and dendritic cells (DCs). In human keratinocytes, it is produced in response to double-stranded RNA (dsRNA) and other IFNs and protects from viral infections. In monocytes and DCs, IFN-kappa induces tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) and inhibits lipopolysaccharide (LPS)-induced IL-12. In this study, we evaluated IFN-kappa expression in skin lesions of patients with common immune-mediated inflammatory disorders using immunohistochemical techniques. IFN-kappa was not detectable in healthy skin but was strongly expressed in allergic contact dermatitis and lichen planus-affected skin. IFN-kappa was localized mainly in basal and suprabasal keratinocytes and in some leukocytes infiltrating the dermis. In contrast, IFN-kappa expression in psoriatic or atopic dermatitis (AD) pidermis was weak and detectable in only 2 of 5 patients examined. Consistently, cultured keratinocytes and monocytes obtained from psoriatic and AD patients expressed null or low levels of IFN-kappa in response to IFN-gamma, which strongly upregulates IFN-kappa in normal keratinocytes. IFN-kappa accumulated in keratinocyte cytoplasm and plasma membrane, and only limited amounts were released extracellularly. Soluble IFN-kappa did not influence keratinocyte proliferation or chemokine and membrane molecule expression, and only its membrane-associated form activated IFN-stimulated response element (ISRE) signaling. Given the difference in IFN-kappa expression levels in the skin disorders examined, IFN-kappa presence or deficiency might have different pathogenetic consequences depending also on other disease-specific intrinsic alterations.     

Asistencia al niño y adolescente con diabetes. Unidades de referencia en diabetes pediátrica

Intensive treatment of type 1 diabetes mellitus (DM1) delays and slows down the progression of chronic diabetes complications (DCCT 1993).This type of treatment in children and adolescents with DM1 has a different complexity to other stages of life and therefore, needs specialized care units. Various documents and declarations of diabetic patient's rights are evaluated, and the need for an adequate health care is emphasized.In the last decade, several projects have been developed in Europe to create a benchmark treatment of pediatric diabetes, with the aim of establishing hospitals with highly qualified healthcare to control it.The Diabetes Working Group of the Spanish Society for Pediatric Endocrinology (SEEP) has prepared this document in order to obtain a national consensus for the care of children and adolescents with type 1 diabetes in specialist Pediatric Diabetes Units, and at the same time advise Health Care Administrators to establish a national healthcare network for children and adolescents with diabetes mellitus, and organize comprehensive pediatric diabetes care units in hospitals with a reference level in quality of care.     

Reduced concentrations of the B cell cytokine interleukin 38 are associated with cardiovascular disease risk in overweight subjects

The IL-1 family member IL-38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL-38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL-38 correlated negatively with age (p = 0.02) and was stable in 48 subjects for 1 year. In comparison with primary keratinocytes, IL1F10 expression in CD19⁺ B cells from PBMC was lower, whereas cell-associated IL-38 expression was comparable. In vitro, IL-38 is released from CD19⁺ B cells after stimulation with rituximab. Intravenous LPS in humans failed to induce circulating IL-38, compared to 100-fold induction of IL-6 and IL-1 receptor antagonist. In a cohort of 296 subjects with body mass index > 27 at high risk for cardiovascular disease, IL-38 plasma concentrations were significantly lower than in healthy subjects (p < 0.0001), and lowest in those with metabolic syndrome (p < 0.05). IL-38 also correlated inversely with high sensitivity C-reactive protein (p < 0.01), IL-6, IL-1Ra, and leptin (p < 0.05). We conclude that a relative deficiency of the B cell product IL-38 is associated with increased systemic inflammation in aging, cardiovascular and metabolic disease, and is consistent with IL-38 as an anti-inflammatory cytokine.     

Quality-Control Culture System Restores Diabetic Endothelial Progenitor Cell Vasculogenesis and Accelerates Wound Closure

Delayed diabetic wound healing is, in part, the result of inadequate endothelial progenitor cell (EPC) proliferation, mobilization, and trafficking. Recently, we developed a serum-free functional culture system called the quality and quantity culture (QQc) system that enhances the number and vasculogenic potential of EPCs. We hypothesize that QQc restoration of diabetic EPC function will improve wound closure. To test this hypothesis, we measured diabetic c-kit⁺Sca-1⁺lin⁻ (KSL) cell activity in vitro as well as the effect of KSL cell–adoptive transfer on the rate of euglycemic wound closure before and after QQc. KSL cells were magnetically sorted from control and streptozotocin-induced type I diabetic C57BL6J bone marrow. Freshly isolated control and diabetic KSL cells were cultured in QQc for 7 days and pre-QQc and post-QQc KSL function testing. The number of KSL cells significantly increased after QQc for both diabetic subjects and controls, and diabetic KSL increased vasculogenic potential above the fresh control KSL level. Similarly, fresh diabetic cells form fewer tubules, but QQc increases diabetic tubule formation to levels greater than that of fresh control cells (P < 0.05). Adoptive transfer of post-QQc diabetic KSL cells significantly enhances wound closure compared with fresh diabetic KSL cells and equaled wound closure of post-QQc control KSL cells. Post-QQc diabetic KSL enhancement of wound closure is mediated, in part, via a vasculogenic mechanism. This study demonstrates that QQc can reverse diabetic EPC dysfunction and achieve control levels of EPC function. Finally, post-QQc diabetic EPC therapy effectively improved euglycemic wound closure and may improve diabetic wound healing.Although blood supply is essential for tissue viability, new blood vessel formation is critical for tissue recovery, regeneration, and repair. Postnatal new blood vessel formation was long thought to be restricted to angiogenesis, the sprouting of new blood vessels from existing vascular structures. However, in 1997, we demonstrated that the de novo formation of new blood vessel derived from bone marrow (BM)-derived cells (i.e., vasculogenesis) is an important part of postnatal healing (1–3). The BM-derived endothelial progenitor cells (EPCs) are precursors of endothelial cells (ECs) and are characterized by their surface expression of KDR, CD133, and CD34 for humans and of lineage-negative c-kit⁺Sca-1⁺ (KSL) cells for murine BM cells (4–6).After injury, locally derived circulating factors mobilize EPCs from their endosteal BM niche. Circulating BM-derived EPCs traffic to the site of injury, experience diapedesis, cluster, tubulize, and canalize to form nascent vessels that inosculate with the existing vasculature (7,8). EPCs have been shown to revascularize numerous ischemic tissues, including myocardium (i.e., myocardial infarction), brain (i.e., cerebral infarction), and skin (i.e., cutaneous wounding) (9,10). Whereas BM-derived EPCs contribute to only 25% of newly formed endothelium in healing tissues, when EPC function is impaired there are marked deficits in tissue repair mechanisms (11,12).Compared with nondiabetic patients, diabetic EPCs have impaired proliferation, adhesion, migration, and differentiation (13–15). Although the pathogenesis of impaired diabetic wound healing is multifactorial, EPC dysfunction plays a central role (16,17). These intrinsic diabetic EPC vasculogenic impairments may result in >83,000 amputations each year and a postamputation 3-year mortality rate of 75.9% (18). In preclinical studies, the administration of exogenous EPCs has improved ventricular function after myocardial ischemia (19,20), enhanced neuronal recovery after cerebral vascular occlusion, and accelerated restoration of blood flow to ischemic limbs (13,16,17,21–23). Based on these exciting results, we have conducted a phase 3 clinical trial of autologous granulocyte colony-stimulating factor–mobilized peripheral blood EPC therapy for nonhealing diabetic foot patients (24). The results demonstrated that more successful therapeutic results were seen in patients receiving high-vasculogenic EPCs. From these results, we hypothesize that successful autologous diabetic EPC therapy relies on the vasculogenic function of transplanted EPCs and speculate that the intrinsic diabetic EPC dysfunction will limit the efficacy of the therapeutic strategy (25,26).Recently, our group established a serum-free quality and quantity culture (QQc) system (containing stem cell factor, thrombopoietin, vascular endothelial growth factor, interleukin-6, and Flt-3 ligand) that enhances the vasculogenic potential of EPCs (27). We hypothesize that QQc can reverse the detrimental effects of diabeties-induced EPC dysfunction and can supply a sufficient number of functional EPCs for adoptive autologous cell–based therapy for diabetic patients. In the current study, we tested this hypothesis.     

Segmental diastolic compression of circumflex coronary artery secondary to pericardial constriction: an uncommon cause of angina pectoris

Diastolic segmental compression of a native coronary artery is an uncommon cause of chest pain. Here we describe a 24-year-old woman with constrictive pericarditis who had retrosternal chest pain, progressive dyspnea, tachycardia, and bilateral leg edema. She was diagnosed with compression of the first and second obtuse marginal branches of left circumflex coronary artery secondary to constrictive pericarditis. She underwent pericardiectomy and her symptoms were relieved following surgery.     

Endoglin and activin receptor-like kinase 1 heterozygous mice have a distinct pulmonary and hepatic angiogenic profile and response to anti-VEGF treatment

Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia associated with dysregulated angiogenesis and arteriovascular malformations. The disease is caused by mutations in endoglin (ENG; HHT1) or activin receptor-like kinase 1 (ALK1; HHT2) genes, coding for transforming growth factor β (TGF-β) superfamily receptors. Vascular endothelial growth factor (VEGF) has been implicated in HHT and beneficial effects of anti-VEGF treatment were recently reported in HHT patients. To investigate the systemic angiogenic phenotype of Endoglin and Alk1 mutant mice and their response to anti-VEGF therapy, we assessed microvessel density (MVD) in multiple organs after treatment with an antibody to mouse VEGF or vehicle. Lungs were the only organ showing an angiogenic defect, with reduced peripheral MVD and secondary right ventricular hypertrophy (RVH), yet distinctly associated with a fourfold increase in thrombospondin-1 (TSP-1) in Eng ^+/? versus a rise in angiopoietin-2 (Ang-2) in Alk1 ^+/? mice. Anti-VEGF treatment did reduce lung VEGF levels but interestingly, led to an increase in peripheral pulmonary MVD and attenuation of RVH; it also normalized TSP-1 and Ang-2 expression. Hepatic MVD, unaffected in mutant mice, was reduced by anti-VEGF therapy in heterozygous and wild type mice, indicating a liver-specific effect of treatment. Contrast-enhanced micro-ultrasound demonstrated a reduction in hepatic microvascular perfusion after anti-VEGF treatment only in Eng ^+/? mice. Our findings indicate that the mechanisms responsible for the angiogenic imbalance and the response to anti-VEGF therapy differ between Eng and Alk1 heterozygous mice and raise the need for systemic monitoring of anti-angiogenic therapy effects in HHT patients.