Interferon alpha promotes caspase-8 dependent ultraviolet light-mediated keratinocyte apoptosis via interferon regulatory factor 1.

Introduction: Ultraviolet (UV) light is a known trigger of both cutaneous and systemic disease manifestations in lupus patients. Lupus skin has elevated expression of type I interferons (IFNs) that promote increased keratinocyte (KC) death after UV exposure. The mechanisms by which KC cell death is increased by type I IFNs are unknown. Methods: Here, we examine the specific cell death pathways that are activated in KCs by type I IFN priming and UVB exposure using a variety of pharmacological and genetic approaches. Mice that overexpress Ifnk in the epidermis were exposed to UVB light and cell death was measured. RNA-sequencing from IFN-treated KCs was analyzed to identify candidate genes for further analysis that could drive enhanced cell death responses after UVB exposure. Results: We identify enhanced activation of caspase-8 dependent apoptosis, but not other cell death pathways, in type I IFN and UVB-exposed KCs. In vivo, overexpression of epidermal Ifnk resulted in increased apoptosis in murine skin after UVB treatment. This increase in KC apoptosis was not dependent on known death ligands but rather dependent on type I IFN-upregulation of interferon regulatory factor 1 (IRF1). Discussion: These data suggest that enhanced sensitivity to UV light exhibited by lupus patients results from type I IFN priming of KCs that drives IRF1 expression resulting in caspase-8 activation and increased apoptosis after minimal exposures to UVB.

Retrograde jejunogastric intussusception presenting as haematemesis in a patient following pancreaticoduodenectomy.

Intussusception is defined as the invagination of one part of the gastrointestinal tract into another. Jejunogastric intussusception is a rare phenomenon following major upper abdominal surgery, where its aetiology is not well understood. We describe a 68-year-old woman who presented with abdominal pain and haematemesis on the background of a previous pancreaticoduodenectomy (Whipple procedure) for pancreatic cancer. Gastroscopy demonstrated retrograde jejunogastric intussusception, where part of the efferent jejunal limb had prolapsed into the remnant stomach. As a consequence, this intussuscepted segment had become oedematous and ischaemic. The patient subsequently underwent a laparotomy, where the original gastrojejunostomy was resected, which showed the intussuscepted jejunum. The non-viable portion was removed and a Roux-en-Y anastomosis was created. This case highlights the need to 'think outside the box' with respect to differential diagnoses when a patient presents with abdominal pain on the background of previous complex abdominal surgery.

Angioleiomyoma presenting as a lateral neck lump: a diagnostic dilemma.

Angioleiomyomas are defined as benign dermal or subcutaneous tumours consisting of smooth muscle cells arranged around vascular channels. Head and neck angioleiomyomas are rarely encountered as they usually occur in the extremities. We report a case of a 71-year-old male, who presented with a 3-month history of a painless lateral neck lump. Ultrasound and computed tomography scans localised the suspicious hypervascular tumour to the right supraclavicular fossa between the two heads of sternocleidomastoid muscle. He subsequently underwent an excisional biopsy, where histological analysis determined that the lateral neck mass was a venous subtype angioleiomyoma. To the best of our knowledge, this is only the third reported case of an angioleiomyoma in the supraclavicular fossa. Although supraclavicular masses are typically synonymous with malignancy, this case report highlights that angioleiomyoma should be considered as a differential diagnosis when investigating patients with a lateral neck lump.

Arteriovenous Buttonhole Access Cannulation in Pediatric Patients on Hemodialysis.

The arteriovenous fistula (AVF) is the recommended hemodialysis access for pediatric patients who weight more than 20 kg and who are not expected to receive a kidney transplant for one year or longer. Whereas buttonhole cannulation of the AVF has been discouraged in adults because of the associated risk of infection, the published pediatric experience with this technique is extremely limited. A retrospective chart review of all buttonhole cannulated AVFs in a single pediatric hemodialysis unit was performed. Approximately 5,600 cannulations were performed over 215.5 patient months with no infections of the AVF or adjacent skin in 13 of 14 (93%) patients. Results from this experience provide evidence that the buttonhole cannulation technique can be successfully performed in pediatric patients on hemodialysis without an associated increased risk of infection.

Ultraviolet light induces increased T cell activation in lupus-prone mice via type I IFN-dependent inhibition of T regulatory cells.

Ultraviolet (UV) light is a known trigger of skin and possibly systemic inflammation in systemic lupus erythematosus (SLE) patients. Although type I interferons (IFN) are upregulated in SLE skin after UV exposure, the mechanisms to explain increased UVB-induced inflammation remain unclear. This paper compares the role of type I IFNs in regulating immune cell activation between wild-type and lupus-prone mice following UVB exposure. 10-week old female lupus-prone (NZM2328), wild-type (BALB/c) and iNZM mice (lack a functional type I IFN receptor on NZM2328 background) were treated on their dorsal skin with 100 mJ/cm2 of UVB for 5 consecutive days. Following UVB treatment, draining lymph node cell populations were characterized via flow cytometry and suppression assays; treated skin was examined for changes in expression of type I IFN genes. Only NZM2328 mice showed an increase in T cell numbers and activation 2 weeks post UVB exposure. This was preceded by a significant increase in UVB-induced type I IFN expression in NZM2328 mice compared to BALB/c mice. Following UVB exposure, both BALB/c and iNZM mice demonstrated an increase in functional T regulatory (TReg) cells; however, this was not seen in NZM2328 mice. These data suggest a skewed UVB-mediated T cell response in lupus-prone mice where activation of T cells is enhanced secondary to a type I IFN-dependent suppression of TReg cells. Thus, we propose type I IFNs are important for UVB-induced inflammation in lupus-prone mice and may be an effective target for prevention of UVB-mediated flares.

A Potential Link between the C5a Receptor 1 and the ß1-Adrenoreceptor in the Mouse Heart.

PURPOSE: Inflammation may contribute to the pathogenesis of specific cardiovascular diseases, but it is uncertain if mediators released during the inflammatory process will affect the continued efficacy of drugs used to treat clinical signs of the cardiac disease. We investigated the role of the complement 5a receptor 1 (C5aR1/CD88) in the cardiac response to inflammation or atenolol, and the effect of C5aR1 deletion in control of baseline heart rate in an anesthetized mouse model. METHODS: An initial study showed that PMX53, an antagonist of C5aR1 in normal C57BL6/J (wild type, WT) mice reduced heart rate (HR) and appeared to have a protective effect on the heart following induced sepsis. C5aR1 knockout (CD88-/-) mice had a lower HR than wild type mice, even during sham surgery. A model to assess heart rate variability (HRV) in anesthetized mice was developed to assess the effects of inhibiting the ß1-adrenoreceptor (ß1-AR) in a randomized crossover study design. RESULTS: HR and LF Norm were constitutively lower and SDNN and HF Norm constitutively higher in the CD88-/- compared with WT mice (P< 0.001 for all outcomes). Administration of atenolol (2.5 mg/kg) reduced the HR and increased HRV (P< 0.05, respectively) in the wild type but not in the CD88-/- mice. There was no shift of the sympathovagal balance post-atenolol in either strains of mice (P> 0.05), except for the reduced LF/HF (Lower frequency/High frequency) ratio (P< 0.05) at 60 min post-atenolol, suggesting increased parasympathetic tone of the heart due to the effect of atenolol administration. The HR of the WT mice were lower post atenolol compared to the CD88-/- mice (P = 0.001) but the HRV of CD88-/- mice were significantly increased (P< 0.05), compared with WT mice. CONCLUSION: Knockout of the C5aR1 attenuated the effect of ß1-AR in the heart, suggesting an association between the ß1-AR and C5aR1, although further investigation is required to determine if this is a direct or causal association.

mHealth Clinic Appointment PC Tablet: Implementation, Challenges and Solutions.

BACKGROUND: Patients requiring daily intravenous (IV) home parenteral nutrition (HPN) would benefit from in-home professional observation to improve self-care, to assess, detect and prevent serious complications. AIMS: The study aims are to assess the viability and utility of conducting mobile healthcare (mHealth) videoconference assessments with patients managing lifelong daily 12-hour IV nutrition infusions in their homes. The challenges and solutions to implementing mobile personal computer (PC) tablet based clinic appointments are described. METHODS: A wireless Apple iPad Mini™ mobile touch-screen tablet computer with 5 mega-pixel camera was loaned to patients. Each tablet had Polycom RealPresence software and a fourth generation (4G) mobile telecommunications data plan. These supported audio-visual mobile videoconferencing encrypted connections between health professionals in their offices and HPN patients and their family members in their homes. Patients' and professionals' evaluations of their mHealth clinic experiences are collected. RESULTS: Patients (mean age = 41.9, SD = 2.8 years) had been prescribed 12-hour home parenteral nutrition (HPN) infusions daily due short bowel disorders. Patients had been on HPN from 1 to 10 years (M=4, SD=3.6). Evaluation of clinic appointments revealed that 100% of the patients (n=45) and the professionals (n=6) indicated that they can clearly hear and easily see one another. The mHealth audio-visual interactions were highly rated by patients and family members. Professionals highly rated their ability to obtain a medical history and visual inspection of patients. Several challenges were identified and recommendations for resolutions are described. DISCUSSION: All patients and professionals highly rated the iPad mHealth clinic appointments for convenience and ease of communicating between homes and offices. An important challenge for all mHealth visits is the clinical professional's ability to make clinically accurate judgments about what they observed and heard from the patients. Following our solutions for obtaining clear visuals with the iPad can improve ability to make clinical assessments.

Intestinal ischemia-reperfusion injury leads to inflammatory changes in the brain.

Intestinal ischemia-reperfusion (I/R) injury is a well-established animal model of systemic inflammation and can lead to multiple organ failure as well as severe and lasting morbidity and even death. It can occur in humans as a result of vascular surgery or as secondary sequelae to many common conditions including low blood pressure, myocardial infarction, and necrotizing enterocolitis. Systemic inflammation induced through kidney I/R injury has been shown previously to lead to encephalopathic adverse effects, and it was theorized that intestinal injury would also cause secondary central nervous system effects. This study presents evidence that over a 6-h time frame, mouse intestinal I/R injury does not cause neuronal cell death in the brain in vivo. However, at the genetic level, certain inflammatory mediators such as endothelial nitric oxide synthase, intercellular adhesion molecule 1, P selectin, TNF-α, and IL-6 are significantly upregulated. There was a significant increase in brain edema observed in sham-operated animals as well as in fasted and nonfasted I/R groups, but neurons were not apoptotic, in the 6-h time period. Conversely, Iba1-expressing activated microglia cells and glial fibrillary acidic protein-expressing astrocytes were found to be markedly increased in fasted and nonfasted I/R mice compared with controls and sham-operated animals. These data demonstrate that intestinal I/R injury induces inflammatory changes in the brain.

Plumbagin, a novel Nrf2/ARE activator, protects against cerebral ischemia.

Many phytochemicals function as noxious agents that protect plants against insects and other damaging organisms. However, at subtoxic doses, the same phytochemicals may activate adaptive cellular stress response pathways that can protect cells against a variety of adverse conditions. We screened a panel of botanical pesticides using cultured human and rodent neuronal cell models, and identified plumbagin as a novel potent activator of the nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. In vitro, plumbagin increases nuclear localization and transcriptional activity of Nrf2, and induces the expression of the Nrf2/ARE-dependent genes, such as heme oxygenase 1 in human neuroblastoma cells. Plumbagin specifically activates the Nrf2/ARE pathway in primary mixed cultures from ARE-human placental alkaline phosphatase reporter mice. Exposure of neuroblastoma cells and primary cortical neurons to plumbagin provides protection against subsequent oxidative and metabolic insults. The neuroprotective effects of plumbagin are abolished by RNA interference-mediated knockdown of Nrf2 expression. In vivo, administration of plumbagin significantly reduces the amount of brain damage and ameliorates-associated neurological deficits in a mouse model of focal ischemic stroke. Our findings establish precedence for the identification and characterization of neuroprotective phytochemicals based upon their ability to activate adaptive cellular stress response pathways.

Complement factors C3a and C5a have distinct hemodynamic effects in the rat.

In the rat, C5a infusion mediates well-defined effects including hypotension and neutropenia. Conversely, the comparative effect of C3a in the rat is not yet defined. In the current study, we have investigated C3a receptor (C3aR) activation in the rat, using recombinant human C3a, the C3aR agonist WWGKKYRASKLGLAR, which is a C-terminal analogue of C3a, and a nonpeptide C3aR antagonist SB-290157, as pharmacological tools. In vitro, C3a and WWGKKYRASKLGLAR selectively bound to C3aRs and induced degranulation of C3aR-transfected RBL-2H3 cells. C3a or WWGKKYRASKLGLAR-induced degranulation was dose-dependently antagonized in a surmountable fashion by the nonpeptide C3aR antagonist. Intravenous infusion of C3a and WWGKKYRASKLGLAR to rats induced a rapid, transient and concentration-dependent hypertensive response, which was mediated by C3aR-induced prostanoid release. C3a and WWGKKYRASKLGLAR caused a small drop in circulating neutrophils, but a rise in circulating neutrophils was evident after 90-120 min. In contrast to C3a, C5a infusion resulted in hypotension, and rapid and transient neutropenia. These results demonstrate that C3a and C5a mediate distinct effects on blood pressure and circulating polymorphonuclear leukocytes in the rat.