Silicone allergy mimicking shunt infection.

PURPOSE: The purpose of this case report is to highlight silicone allergy as a rare cause of ventriculo-peritoneal shunt complication, often mimicking infection. MATERIALS AND METHODS: Information regarding the patient presented was obtained by review of their medical notes, both paper and electronically. A literature review was performed by searching Pubmed using the following terms; silicone allergy and shunt allergy, to identify similar publications. RESULTS: Nine publications between 1994 and 2019 formed the basis of the literature review. The primary aim was to identify clinical presentations that may help to identify silicone allergy as the cause of shunt complication. CONCLUSION: Silicone allergy is a rare cause of ventriculo-peritoneal (V-P) shunt failure and can mimic infection. This diagnosis should be consideredwith a predominantly lymphocytic CSF leucocytosis and no bacteriological evidence of a responsible organism, a peripheral eosinophilia and an intense fibrosis around a recently placed V-P shunt, as described in this case report.

Radiological investigations in non-aneurysmal subarachnoid haemorrhage: A 5-year review.

•All patients with a Fisher grade 2 bleed and a negative CT angiogram had catheter angiography negative for any abnormality.•Neuroradiologists identified vascular abnormalities not reported by district general hospitals.•Follow-up MRI may be a useful adjunct in subarachnoid haemorrhage.

Treatment of acute aneurysmal subarachnoid haemorrhage with primary flow diversion: 5-year single-centre experience.

AIM: To evaluate the safety and efficacy of treatment of patients presenting with acute aneurysmal subarachnoid haemorrhage (SAH) with primary flow-diverting stents (FDS; with or without adjuncts), with comparison to the published literature. MATERIALS AND METHODS: A retrospective single-centre review was undertaken of prospectively obtained data on patients treated for SAH over a 60-month period. Of 354 patients treated for SAH during that time period, 24 patients with a total of 25 aneurysms were identified. Baseline patient demographics were recorded and clinical and imaging outcomes assessed. RESULTS: Eighty-eight per cent (22/25) of the aneurysms were completely occluded (Raymond-Roy 1) at mean 12-month follow-up. The minor complication rate was 12.5% (3/24) without permanent morbidity. Mortality rate was 4% (1/25) after one patient died following aneurysmal rebleed on day 7 post-procedure. Forty-two per cent (10/24) of patients had a high-pressure shunt placed prior to endovascular treatment, no haemorrhagic complications of neurosurgical intervention were observed. CONCLUSION: The necessity of dual antiplatelet therapy (DAPT) therapy when deploying FDS will rightly continue to limit their use in the acutely ruptured setting to a case-by-case basis whereby other treatment options are deemed unsafe. Methods employed to minimise subsequent haemorrhagic risks from DAPT in these patients may be worthy of further investigation.

Cerebral Nocardiosis: A Rare Cause of Hemiplegia in the Acute Medicine Unit.

Nocardiosis, a rare infection occurring mostly in immunosuppressed patients can present with neurological complications including cerebral abscess formation, and is associated with high morbidity and mortality. We describe the case of a 54-year-old immunocompetent man with cerebral nocardiosis, who presented with sudden onset hemiparesis in an acute medicine unit. He required three craniotomies with excision, following failure to respond to antimicrobial therapy, with subsequent clinical improvement and radiological resolution of multiple cerebral abscesses. Challenges in diagnosis and management of hemiparesis in the acute medical unit are discussed. Successful management of cerebral nocardiosis require early communication with a neurosurgical unit, neuropathology and microbiology services to optimise management with targeted antimicrobial therapy.

Neurosurgical management of multiple intracranial Nocardia and Enterococcus abscesses in an immunocompetent patient.

Nocardia farcinica and Enterococcus faecium are both rare causes of cerebral abscess. The former is associated with high morbidity and mortality. We describe a neurosurgical approach to the management of multiple intracranial abscesses of dual microbial pathology in an immunocompetent patient to achieve a good outcome.

Diffuse large B-cell lymphoma: a rare complication of an abdominal CSF pseudocyst.

Abdominal CSF pseudocysts are an uncommon complication of ventriculo-peritoneal shunting. We report the case of a 35 year old man with a myelomenigocele, associated Chiari 2 malformation, and VP shunt developing a Diffuse Large B-Cell Lymphoma within the lining of an abdominal CSF pseuodcyst. This diagnosis should be considered in those with recurrent pseudocysts, or those associated with a swinging pyrexia and high C-Reactive protein, in the absence of infection.

The importance of autonomic symptoms in trigeminal neuralgia. Clinical article.

OBJECT: Autonomic symptoms can occur in association with the facial pain of trigeminal neuralgia (TN). The distinction between first division (V1) TN and trigeminal autonomic cephalgias, particularly short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), can be difficult. The goal in this study was to investigate the frequency of autonomic symptoms with TN and to determine their effect on surgical outcome. METHODS: The authors sent questionnaires and reviewed the records of 92 patients who underwent surgical procedures for TN to obtain visual analog scale scores for pain before and after surgery and to determine the location of the pain and the presence of autonomic symptoms. RESULTS: Sixty-seven percent of patients had at least 1 autonomic symptom, and 14% had 4 or more autonomic symptoms associated with their pain. With V1 pain, the most common autonomic symptoms were conjunctival injection, ptosis, and excessive tearing. With pain involving the second division (V2), facial swelling was the most common autonomic symptom. Excessive salivation occurred most often when the pain involved the third division (V3). In patients who underwent microvascular decompression (MVD), visual analog scores for pain showed significantly greater improvement postoperatively in those who had no preoperative autonomic symptoms than in those who reported autonomic symptoms. There was also a significantly greater number of patients who were pain free postoperatively in the group without autonomic symptoms. There were 3 patients with V1 facial pain associated with conjunctival injection and tearing who, in retrospect, fulfilled all the current diagnostic criteria for SUNCT. These patients underwent MVD, during which a vessel was found to compress the trigeminal nerve. Postoperatively, the 3 patients experienced complete and long-lasting pain relief. CONCLUSIONS: The presence of autonomic symptoms in TN correlated with a worse prognosis for pain relief after MVD. First division TN with autonomic symptoms can present identically to SUNCT but can respond to MVD if there is a compressive vessel. Neurosurgeons should be aware of SUNCT, especially in patients with V1 TN and autonomic symptoms, to ensure that all potential medical therapies have been tried prior to surgical treatment.

Sexual behaviour, condom use and rates of sexually transmitted infections in HIV clinic attendees in South East London.

The aim of this study was to examine sexual behaviour, condom use and rates of sexually transmitted infections (STIs) among attendees at a dedicated on-site STI clinic at a South London HIV centre. Data were prospectively collected by using a nurse-completed questionnaire. Ninety-eight percent of women reported one or no sexual partners in the preceding three months, whereas 57% of men who have sex with men (MSM) reported two or more partners. Only 28% of women, 53% of heterosexual men and 29% of MSM always used a condom for vaginal or anal intercourse. Positive STI diagnoses were found in 17.5% of women, 20% of heterosexual men and 49% of MSM. Twenty percent of patients who reported always using a condom and 38% of MSM reporting no sexual activity in the preceding three months had an STI. These results highlight the need for safe sex promotion and STI screening in HIV-infected patients regardless of self-reported sexual activity.

Vasoactive hormone adrenomedullin and its binding protein: anti-inflammatory effects by up-regulating peroxisome proliferator-activated receptor-gamma.

Sepsis is a critical inflammatory condition from which numerous patients die due to multiple organ failure and septic shock. The vasoactive hormone adrenomedullin (AM) and its binding protein (AMBP-1) are beneficial in sepsis by abrogating the progression to irreversible shock and decreasing proinflammatory cytokine release. To investigate the anti-inflammatory mechanism, we studied to determine the effect of the AM/AMBP-1 complex on peroxisome proliferator-activated receptor-gamma (PPAR-gamma) expression and activation by using RAW264.7 cells and a rat endotoxemia model. LPS treatment significantly decreased PPAR-gamma expression in vivo and in vitro and was associated with increased TNF-alpha production. Treatment with AM/AMBP-1 for 4 h completely restored PPAR-gamma levels in both models, resulting in TNF-alpha suppression. In a knockdown model using small interfering RNA in RAW264.7 macrophages, AM/AMBP-1 failed to suppress TNF-alpha production in the absence of PPAR-gamma. LPS caused the suppression of intracellular cyclic AMP (cAMP), which was prevented by simultaneous AM/AMBP-1 treatment. Although incubation with dibutyryl cAMP significantly decreased LPS-induced TauNuF-alpha release, it did not alter PPAR-gamma expression. Through inhibition studies using genistein and PD98059 we found that the Pyk-2 tyrosine kinase-ERK1/2 pathway is in part responsible for the AM/AMBP-1-mediated induction of PPAR-gamma and the anti-inflammatory effect. We conclude that AM/AMBP-1 is protective in sepsis due to its vasoactive properties and direct anti-inflammatory effects mediated through both the cAMP-dependent pathway and Pyk-2-ERK1/2-dependent induction of PPAR-gamma.

Ghrelin down-regulates proinflammatory cytokines in sepsis through activation of the vagus nerve.

OBJECTIVE: To test the hypothesis that administration of ghrelin attenuates inflammatory responses in sepsis through vagal nerve stimulation. SUMMARY BACKGROUND DATA: Ghrelin has been demonstrated to possess multiple functions, including stimulation of the vagus nerve. Our recent study has shown that plasma levels of ghrelin were significantly reduced in sepsis; and ghrelin administration improved organ perfusion and function. However, it remained unknown whether ghrelin also decreases proinflammatory cytokines in sepsis and, if so, whether the down-regulatory effect of ghrelin is mediated by activation of the vagus nerve. METHODS: Male rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 hours after CLP, a bolus intravenous injection of 2 nmol ghrelin was followed by a continuous infusion of 12 nmol ghrelin via a primed 200-microL Alzet mini-pump for 15 hours. At 20 hours after CLP, plasma and peritoneal fluid levels of TNF-alpha and IL-6 were determined. The direct effect of ghrelin on cytokine production was studied using cultured normal rat Kupffer cells or peritoneal macrophages stimulated by lipopolysaccharide (LPS). In additional animals, vagotomy or sham vagotomy was performed in sham and septic animals immediately prior to ghrelin administration and cytokine levels were then measured. RESULTS: Ghrelin significantly reduced TNF-alpha and IL-6 levels in sepsis. In contrast, ghrelin did not inhibit TNF-alpha and IL-6 release from LPS-stimulated Kupffer cells or peritoneal macrophages. However, vagotomy, but not sham vagotomy, prevented ghrelin's down-regulatory effect on TNF-alpha and IL-6 production. CONCLUSIONS: Ghrelin down-regulates proinflammatory cytokines in sepsis through activation of the vagus nerve. Pharmacologic stimulation of the vagus nerve may offer a novel approach of anti-sepsis therapy.

Adrenomedullin and adrenomedullin-binding protein-1 downregulate inflammatory cytokines and attenuate tissue injury after gut ischemia-reperfusion.

BACKGROUND: Recent studies have shown that adrenomedullin (AM) and AM-binding protein-1 (AMBP-1) possess anti-inflammatory properties in sepsis. We hypothesized that administration of AM/AMBP-1 after gut ischemia-reperfusion (I/R) downregulates inflammatory cytokines and attenuates tissue injury. METHODS: Male Sprague-Dawley rats (275-325 g) were used. Gut ischemia was induced by placing a microvascular clip across the superior mesenteric artery (SMA) for 90 minutes. Upon release of the SMA clamp, the animals were treated by AM (12 microg per kilogram of body weight) and AMBP-1 (40 microg per kilogram of body weight) in combination, or vehicle (1 mL 0.9% NaCl) over 30 minutes via a femoral vein catheter. The animals undergoing sham operation or ischemia for 90 minutes only, did not receive AM/AMBP-1 treatment. At 60 minutes after the completion of the treatment (ie, 90 minutes after reperfusion), blood samples were collected. Plasma AM and AMBP-1 were measured by radioimmunoassay and Western blot analysis, respectively. Serum levels of TNF-alpha, interleukin (IL)-1beta, IL-6, IL-10, transaminases (ie, alanine aminotransaminase, aspartate aminotransaminase), lactate, and creatinine were determined with the use of enzyme-linked immunosorbent assay and other standard methods. In additional groups of animals, the 10-day survival rate was recorded after gut I/R. RESULTS: Ischemia alone was sufficient to downregulate both AM and AMBP-1. Unlike AMBP-1 that remained decreased, AM levels increased significantly after reperfusion. I/R but not ischemia alone significantly increased serum levels of inflammatory cytokines. Moreover, I/R-induced tissue injury was evidenced by increased levels of transaminases, lactate, and creatinine. Administration of AM/AMBP-1 after ischemia, however, markedly reduced cytokine levels, attenuated tissue injury, and improved survival. CONCLUSIONS: AM/AMBP-1 may be a novel treatment to attenuate the reperfusion injury after gut ischemia.

Adrenomedullin and adrenomedullin binding protein-1 prevent metabolic acidosis after uncontrolled hemorrhage in rats.

OBJECTIVE: Management of trauma victims with uncontrolled hemorrhage remains a major problem in combat casualty care at the far-forward battlefield setting. The neuroendocrine response to hemorrhage is to maintain perfusion to the heart and brain, often at the expense of other organ systems. Decreased organ perfusion after hemorrhagic shock is associated with metabolic acidosis, in which the up-regulated endothelin-1 plays an important role. We have recently shown that vascular responsiveness to adrenomedullin (AM), a newly discovered vasodilator peptide, is depressed after hemorrhage and resuscitation. Down-regulation of AM binding protein (AMBP-1) appears to be responsible for this hyporesponsiveness. We therefore hypothesized that administration of AM/AMBP-1 would prevent metabolic acidosis after uncontrolled hemorrhage via down-regulation of endothelin-1. DESIGN: Prospective, controlled, and randomized animal study. SETTING: A research institute laboratory. SUBJECTS: Male Sprague-Dawley rats (275-325 g). INTERVENTIONS: A rat model of uncontrolled hemorrhage with an extremely low volume of fluid resuscitation was used to mimic the combat situation. MEASUREMENTS AND MAIN RESULTS: Both lumbar veins of male adult rats were isolated and severed at the junction to the vena cava. The abdomen was kept open but covered with a saline wet gauze for 45 mins and then closed in layers. The animals received 1 mL of normal saline (vehicle) with or without AM (12 microg/kg of body weight) and AMBP-1 (40 microg/kg of body weight) over 45 mins. Various variables were measured at 4 hrs after resuscitation. The bleed-out volumes in the vehicle group and the AM/ AMBP-1 treatment group were 6.78 +/- 0.19 and 6.81 +/- 0.25 mL/rat, respectively. The results indicate that AM/AMBP-1 administration prevented metabolic acidosis, mitigated organ injury, down-regulated preproendothelin-1 gene expression, and decreased plasma levels of endothelin-1 after hemorrhage. CONCLUSIONS: AM/AMBP-1 may provide a novel approach for the treatment of uncontrolled hemorrhage. The beneficial effect of AM/AMBP-1 is associated with down-regulation of endothelin-1.

Suppression of hepatocyte CYP1A2 expression by Kupffer cells via AhR pathway: the central role of proinflammatory cytokines.

The hepatic cytochrome P-450 (CYP) enzyme system provides a major aspect of liver function, yet alterations of CYP in sepsis remain largely unknown. Although we have recently shown that CYP1A2, one of the major isoforms of CYP in rats, is downregulated in sepsis, the underlying mechanism and possible therapeutic approaches warrant further investigation. The aim of this study was to determine whether Kupffer cells (KCs) play any role in suppressing CYP1A2 in the hepatocytes (HCs) and if so, how to modulate CYP1A2 expression in sepsis. To study this, primary KCs and HCs were cultured separately or together with or without transwells. Cells and supernatant samples were collected after various stimulations. Additionally, polymicrobial sepsis was induced in rats by cecal ligation and puncture (CLP) with or without curcumin pretreatment. Liver samples were harvested 20 h post-CLP. The results show that lipopolysaccharide (LPS) did not suppress CYP1A2 in HC or HC/KC coculture with transwells. However, LPS downregulated CYP1A2, aryl hydrocarbon receptor (AhR, a nuclear receptor) and AhR nuclear translocator (Arnt) in coculture without transwells. Anti-TNF-alpha and anti-IL-1beta antibodies attenuated this downregulation. Moreover, elevated hepatic levels of TNF-alpha and IL-1beta post-CLP were decreased by curcumin pre-treatment. This reduction was associated with increased expression of AhR and CYP1A2. These results indicate that KCs-derived proinflammatory cytokines may play an important role in downregulating CYP1A2 in sepsis. The reduction of AhR/Arnt may be the underlying mechanism for such downregulation. Inhibition of proinflammatory cytokines by curcumin may provide a novel approach to modulate the hepatic CYP function in sepsis.

The anti-inflammatory effect of curcumin in an experimental model of sepsis is mediated by up-regulation of peroxisome proliferator-activated receptor-gamma.

OBJECTIVE: Although phytochemical curcumin has been shown to possess anti-inflammatory properties, it remains unknown whether this agent has any beneficial effects in sepsis. The purpose of this study was to demonstrate whether curcumin protects septic animals and, if so, whether activation of peroxisome proliferator-activated receptor (PPAR)-gamma, an anti-inflammatory nuclear receptor, plays any role. DESIGN: Prospective, controlled, and randomized animal study. SETTING: A research institute laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: A bolus injection of 0.2 micromol of curcumin was given intravenously to male adult rats, followed by continuous infusion of curcumin (0.24 micromol/day) for 3 days via a primed 2-mL mini-pump. The rats were then subjected to sepsis by cecal ligation and puncture (CLP). MEASUREMENTS AND MAIN RESULTS: Serum levels of liver enzymes (alanine aminotransferase and aspartate aminotransferase), lactate, albumin, and tumor necrosis factor (TNF)-alpha were measured at 20 hrs after CLP (i.e., late stage of sepsis). In addition, a 10-day survival curve was conducted following CLP and cecal excision with or without curcumin treatment. Furthermore, macrophages cell line RAW 264.7 cells were treated with curcumin followed by stimulation with endotoxin. TNF-alpha and PPAR-gamma expression were then measured. The results indicate that intravenous administration of curcumin before the onset of sepsis attenuated tissue injury, reduced mortality, and decreased the expression of TNF-alpha in septic animals. Similar results were also found when curcumin was administered after the onset of sepsis. Moreover, the down-regulated PPAR-gamma in the liver at 20 hrs after CLP was significantly improved by curcumin treatment. Concurrent administration of curcumin and GW9662, a specific PPAR-gamma antagonist, completely abolished the beneficial effects of curcumin under such conditions. In cultured RAW 264.7 cells, curcumin inhibited endotoxin-induced increases in TNF-alpha expression and markedly up-regulated PPAR-gamma expression without affecting cell viability. Curcumin also prevented morphologic alterations in macrophages induced by endotoxin. CONCLUSIONS: The protective effect of curcumin makes it or its analogues strong candidates as a novel therapy for sepsis. The beneficial effect of curcumin appears to be mediated by up-regulation of nuclear receptor PPAR-gamma.

Herpes zoster of the trigeminal nerve following microvascular decompression.

A patient developed herpes zoster of the maxillary division of the trigeminal nerve after microvascular decompression. Varicella zoster virus lies dormant in the Gasserian ganglion until reactivation and can cause herpes zoster ophthalmicus. This can result in serious ocular complications including blindness. Antiviral agents are effective if commenced promptly.

Proapoptotic effect of curcumin on human neutrophils: activation of the p38 mitogen-activated protein kinase pathway.

OBJECTIVE: Despite advances in the management of sepsis and acute respiratory distress syndrome, the mortality rate remains high. Delayed apoptosis of neutrophils is associated with multiple organ failure under those conditions. Thus, development of nontoxic neutrophil apoptosis regulating molecules may provide a novel therapeutic strategy. Curcumin is a promising dietary supplement for cancer prevention. However, the effect of curcumin on human neutrophil apoptosis remains unknown. We therefore hypothesized that curcumin would produce a proapoptotic effect on neutrophils. DESIGN: Prospective, controlled, and randomized in vitro study. SETTING: Research institute laboratory. SUBJECTS: Human peripheral neutrophils obtained from normal subjects. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In the presence or absence of curcumin, both spontaneous neutrophil apoptosis and apoptosis of neutrophils following transmigration across a human lung endothelium-epithelium bilayer were studied by morphology and terminal dUTP nucleotide end labeling analyses, respectively. Myeloperoxidase activity and migration assays were performed to determine the impact of curcumin on neutrophil function. To elucidate the potential mechanism, the p38 mitogen-activated protein kinase pathway and caspase-3 activity were examined by Western blotting and enzymatic analyses. The data demonstrate that curcumin increased constitutive neutrophil apoptosis and abrogated the transbilayer migration-induced delay in neutrophil apoptosis. Neutrophil activation was reduced by curcumin treatment as evidenced by a decrease in migration and myeloperoxidase release. A marked increase in p38 phosphorylation and caspase-3 activity was observed following curcumin exposure. In addition, inhibition of p38 mitogen-activated protein kinase with SB203580 suppressed apoptosis and caspase-3 activation induced by curcumin. Thus, activation of p38 mitogen-activated protein kinase or an increase in caspase-3 activity appears to contribute to the proapoptotic effect of human neutrophil apoptosis by curcumin. CONCLUSION: The characteristics of curcumin, including its proapoptotic effect and antidegranulation effect, make it a potential candidate for the therapy of neutrophil-induced lung injury and sepsis.

Ghrelin improves tissue perfusion in severe sepsis via downregulation of endothelin-1.

OBJECTIVES: Severe sepsis is associated with increased total peripheral resistance (TPR) and decreased organ blood flow, in which endothelin-1 (ET-1) plays an important role. Plasma levels of ghrelin, a newly-identified endogenous ligand for growth hormone secretagogue receptor and a potent vasodilatory peptide, are significantly reduced in sepsis. Ghrelin downregulation heralds the hypodynamic response in severe sepsis. Therefore, we hypothesized that the administration of exogenous ghrelin improves organ blood flow by downregulation of ET-1 under such conditions. METHODS: Male adult Sprague-Dawley rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 h post-CLP, a bolus intravenous injection of 2 nmol ghrelin was followed by a continuous infusion of 12 nmol ghrelin via a primed mini-pump over 15 h. At 20 h post-CLP (i.e., severe sepsis), cardiac output (CO), stroke volume (SV), TPR, and organ blood flow were measured using (141)Ce-microspheres. Plasma ET-1 levels and preproET-1 gene expression in the liver, small intestine, and kidneys were measured by ELISA and RT-PCR, respectively. The direct effect of ghrelin on ET-1 production was studied using cultured human umbilical vein endothelial cells (HUVECs) treated with tumor necrosis factor-alpha (TNF-alpha). RESULTS: Ghrelin administration reduced TPR, increased CO, SV, and organ blood flow, downregulated preproET-1 gene expression, and decreased plasma levels of ET-1 in sepsis. Ghrelin inhibited TNF-alpha-induced ET-1 release from HUVECs in a dose-dependent manner. Moreover, ghrelin inhibited TNF-alpha-induced activation of nuclear factor-kappaB (NF-kappaB) in HUVECs. CONCLUSIONS: The improvement of tissue perfusion by ghrelin in severe sepsis appears to be mediated by downregulation of ET-1 involving a NF-kappaB-dependent pathway.

Divergent roles of murine neutrophil chemokines in hemorrhage induced priming for acute lung injury.

Neutrophil associated lung injury is identified with a variety of local and systemic priming insults. In vitro studies have shown that TNF-alpha mediated suppression of neutrophil apoptosis is due to the secretion of interleukin-8 (IL-8), a human chemokine shown to alter neutrophil chemotaxis. Our initial in vitro antibody neutralization studies with neutrophil chemotactic proteins, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein-2alpha (MIP-2alpha), mouse IL-8 homologues, indicate that MIP-2alpha but not KC appears to mediate TNF-alpha suppression of mouse neutrophil apoptosis. Therefore, we hypothesized that in vivo neutralization of KC or MIP-2alpha during an initial priming insult would produce differential effects on the extent of lung injury by restoring normal neutrophil apoptotic function. To assess this, mice were hemorrhaged followed with septic challenge at 24 h. Antibody against KC or MIP-2alpha or a nonspecific IgG was given during resuscitation immediately following hemorrhage. Anti-MIP-2alpha treatment resulted in a significant reduction in lung tissue IL-6 and myeloperoxidase levels. Percentage of neutrophil apoptosis increased significantly in the anti-KC group. Tissue and plasma KC and MIP-2alpha were reduced in their respective treatment groups. These data suggest that KC and MIP-2alpha differ in their mediation of neutrophil function (apoptosis and chemotaxis) and contribution to the pathogenesis of lung injury following hemorrhage subsequent to sepsis.

Gut-derived norepinephrine plays an important role in up-regulating IL-1beta and IL-10.

Previous studies have shown that the gut is a major source of norepinephrine (NE) released in early sepsis and that gut-derived NE plays an important role in up-regulating TNF-alpha expression in Kupffer cells (KC) via an alpha(2)-adrenoceptor (alpha(2)-AR) pathway. However, it remains unknown whether NE affects the release of other inflammatory cytokines such as IL-1beta and IL-10 and, if so, whether alpha(2)-AR is also involved in such a process. To study this, a branch of the portal vein in normal adult male rats was cannulated under anesthesia. NE (20 muM in ascorbate saline), NE plus yohimbine (YHB, a specific alpha(2)-AR antagonist, 1 mM) or vehicle (0.1% ascorbate saline) was infused at a rate of 13 mul/min for 2 h. The above rate of NE infusion was used to increase the portal level of NE to approximately 20 nM, similar to that observed in sepsis. Blood samples were then collected and serum levels of IL-1beta and IL-10 were measured. In addition, the KC was isolated from normal rats and stimulated with either NE (20 nM) or NE plus YHB (1 muM). The gene expression of IL-1beta and IL-10 in KC and their supernatant levels were assessed. The results indicate that serum levels of IL-1beta and IL-10 increased significantly after the intraportal infusion of NE. Co-administration of NE and YHB, however, significantly attenuated IL-1beta and IL-10 production. Similarly, IL-1beta and IL-10 gene expression and release from KC were up-regulated by NE stimulation, whereas YHB attenuated both cytokines. Thus, gut-derived NE up-regulates IL-1beta and IL-10 expression and release in the liver through an alpha(2)-AR pathway. Since adenylate cyclase activator forskolin prevents the increase in NE-induced IL-1beta and IL-10, the up-regulatory effect of NE on those cytokines appears to be mediated, at least in part, by inhibition of adenylate cyclase and reduction in intracellular cyclic AMP levels.