A right-to-left or bidirectional ductal shunt in preterm neonates: grave implication?

We delineate the natural history of a right-to-left or bidirectional (RL/BD) patent ductus arteriosus (PDA) in preterm infants and compare outcomes of an RL/BD and a left-to-right (LR) ductal shunt. We performed a retrospective chart review of preterm infants (< 32 weeks), who, between 2 and 30 days of age, had an RL/BD PDA > 1.5 mm (study group; N = 74) or an LR PDA (N = 87) on echocardiogram (ECHO). In the study group, 27% of infants who were of significantly lower gestational age and birth weight had a "prolonged" RL/BD PDA on two or more ECHOs. Infants with RL/BD PDA required significantly greater surfactant (98.6% versus 94.2%) and less PDA therapy (27% versus 92%) and had higher mortality (48.6% versus 21.8%) compared with those with LR PDA. On regression analysis, lower gestation (odds ratio [OR] 1.45; 95% confidence interval [CI]: 1.15 to 1.83) and RL/BD PDA (OR 4.74; 95% CI: 2.18 to 10.3) were significantly associated with mortality. The independent association between an RL/BD PDA shunt and mortality warrants further investigation. Insights into the etiology of pulmonary hypertension may optimize outcomes in this population.     

Phage typing in dermatitis cruris pustulosa et atrophicans: does staphylococcal carrier status have a role?

Background Dermatitis cruris pustulosa et atrophicans (DCPA) is a form of chronic folliculitis of the legs with a multifactorial etiopathogenesis, seen primarily in tropical countries. Staphylococcus aureus has been isolated from the pustules in earlier studies, although the organisms isolated have not been further characterized. Materials and methods Patients with DCPA, who attended the Dermatology outpatient clinic at JIPMER, Pondicherry, India, during the study period (December 2006–June 2008) were included. Pus from the lesions as well as swabs from carrier sites (nares, axillae, and gluteal fold) were cultured. Staphylococcus aureus isolates were subjected to phage typing at the National Staphylococcal Phage Typing Center, Department of Microbiology, Maulana Azad Medical College, New Delhi, India. Results Thirty‐seven patients were included in the study. Pus from the folliculitic lesions grew S. aureus in 32 (86.49%) patients. Based on the comparison of antibiotic sensitivity patterns, isolates from pus and carrier sites were found to be similar in 15 patients. Phage typing established the organism to be identical in five of these patients. Conclusions Characterization of S. aureus in DCPA shows that there is no specific phage type that is uniformly responsible for the lesions in most patients. However, in view of the unclear etiology of this condition, the pathogenicity of a staphylococcal carrier state in individual patients needs to be addressed.     

IAP inhibitors enhance co-stimulation to promote tumor immunity

The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor κB (NF-κB) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of several novel small molecule IAP antagonists. In addition to roles in cancer, increasing evidence suggests that IAPs have an important function in immunity; however, the impact of IAP antagonists on antitumor immune responses is unknown. In this study, we examine the consequences of IAP antagonism on T cell function in vitro and in the context of a tumor vaccine in vivo. We find that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli. The activity of IAP antagonists depends on the activation of NF-κB2 signaling, a mechanism paralleling that responsible for the cytotoxic activity in cancer cells. We further show that IAP antagonists can augment both prophylactic and therapeutic antitumor vaccines in vivo. These findings indicate an important role for the IAPs in regulating T cell–dependent responses and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer.The inhibitor of apoptosis proteins (IAPs) were initially identified as caspase inhibitors capable of blocking both extrinsic and intrinsic apoptotic signals. Recent work has established diverse roles for the IAP family, in which they have been shown to regulate apoptosis through the modulation of NF-κB signaling downstream of several TNF family receptors and to play an essential role in the modulation of FAS-induced cell death (Hu et al., 2006; Leulier et al., 2006; Rigaud et al., 2006; Gaither et al., 2007; Lu et al., 2007; Petersen et al., 2007; Varfolomeev et al., 2007, 2008; Vince et al., 2007, 2008; Xu et al., 2007; Bertrand et al., 2008; Mahoney et al., 2008; Matsuzawa et al., 2008; Srinivasula and Ashwell, 2008; Wang et al., 2008; Csomos et al., 2009; Jost et al., 2009). All IAPs contain baculovirus inhibitory repeat domains that mediate protein binding, and several, including cellular IAP-1 (cIAP-1) and cIAP-2, X-linked IAP (XIAP), and melanoma-IAP/Livin, contain RING finger E3 ubiquitin ligase domains, which can cause autoubiquitination as a means of regulating apoptosis (Schile et al., 2008; Srinivasula and Ashwell, 2008). IAPs are regulated endogenously by second mitochondrial-derived activator of caspases (SMAC), which interacts with IAP baculovirus inhibitory repeat domains via a tetrapeptide motif. Several pharmacologic SMAC mimetics have been developed that induce tumor death through binding to the RING domain containing IAPs and leading to ubiquitin-mediated destruction (Gaither et al., 2007; Petersen et al., 2007; Varfolomeev et al., 2007; Vince et al., 2007; Wang et al., 2008). These pharmacologic SMAC mimetics act as broad antagonists of the RING domain containing IAPs and are actively being investigated as a potential novel class of cancer chemotherapeutics.In addition to roles in tumor biology, several studies suggest important functions for the IAPs in immunoregulation. XIAP-deficient humans develop X-linked lymphoproliferative disease and were initially reported to lack NKT cells, although the specificity of this finding has recently been challenged (Rigaud et al., 2006; Marsh et al., 2009). XIAP-deficient mice have difficulty controlling Listeria monocytogenes infections and are more susceptible to infection with MHV-68 (mouse herpes virus 68); however, the mechanism for this immunodeficiency is unknown and is not associated with decreased NKT cell function (Bauler et al., 2008; Rumble et al., 2009). cIAP-2 is involved in a recurrent translocation in mucosal-associated lymphoid tissue lymphoma and has been reported to function as an E3 ligase for BCL10 in lymphocytes, although the physiological importance of this activity is unknown (Hu et al., 2006). More recently, the cIAPs were shown to be critical for c-Jun N-terminal kinase activation downstream of CD40 and to negatively regulate alternative NF-κB activation by the BAFF (B cell activation factor of the TNF family) receptor (Matsuzawa et al., 2008; Vallabhapurapu et al., 2008; Zarnegar et al., 2008). These findings position the cIAPs as potentially key regulators of B cell homeostasis, although how the cIAPs regulate B cell–dependent immune responses has, at present, been incompletely explored. In addition to roles in adaptive immunity, the cIAPs and XIAP have been shown to be required for NOD-1 and -2 (nucleotide biding and oligomerization domain 1 and 2) signaling and downstream cytokine production after exposure to muramyl dipeptide (Bertrand et al., 2009; Krieg et al., 2009). Furthermore, cIAP-2–deficient mice show altered responses to lipopolysaccharide that may indicate a role for cIAP-2 in inflammatory cytokine-induced apoptosis in macrophages (Conte et al., 2006). Moreover, neuronal apoptosis inhibitor protein (NAIP), a member of both the NOD-like receptor and IAP families, is a component of the inflammasome and is required for control of Legionella pneumophila infections (Diez et al., 2003; Rigaud et al., 2006).Although evidence now links the IAP family to regulation of both tumor cell survival and immune function, the impact of IAP inhibitors on antitumor immune responses is unknown. In particular, the consequences of IAP antagonism in the key effector cells responsible for antitumor immunity such as CD4⁺ and CD8⁺ T cells, NKT cells, and NK cells has not been explored. Given the potential for IAP antagonists to simultaneously induce tumor cell death and modulate immunity, understanding how IAP antagonism might alter nascent antitumor responses and responses to other forms of tumor immunotherapy may have implications for the use of these agents to treat cancer.In this study, we examine the consequences of IAP antagonism on T cell function both in vitro and in the context of a tumor vaccine in vivo. Unexpectedly, we find that IAPs function as negative co-stimulators during T cell stimulation and that small molecule IAP antagonists can augment both human and mouse T cell responses to physiologically relevant stimuli, including tumor antigens, without producing responses in unstimulated cells.     

Pulmonary hypertension in children: the twenty-first century

Pulmonary hypertension is an elevation in pulmonary artery pressure that is associated with a spectrum of diseases and causes. Its clinical severity and presentation are widely varied. The field of study has changed immensely over the past several years. Significant knowledge has been gained in the pathophysiology, genetics, and vascular biology associated with pulmonary hypertension. These discoveries have contributed to medical interventions that have improved outcomes associated with pulmonary hypertension. This article reviews pulmonary hypertension in children, focusing on idiopathic pulmonary hypertension. Because most information is associated with children who have this form of the disease, formerly classified as primary pulmonary hypertension, medical therapy is discussed with a focus on this patient group. Additional therapeutic concepts relevant to other causes of pulmonary hypertension are highlighted.     

The analgesic effects of preemptive gabapentin in patients undergoing surgery for brachial plexus injury--a preliminary study

There are reports indicating that gabapentin may have place in the treatment of postoperative pain. No study has evaluated the effects of gabapentin on acute, postoperative pain in patients undergoing surgery for brachial plexus injuries. In this preliminary study, we evaluated gabapentin as preemptive analgesic for intraoperative period and during the acute postoperative period at rest and during movement. Twenty consecutive adult patients undergoing surgery for brachial plexus injury were enrolled for the study. Patients randomly received either oral gabapentin 800 mg or placebo capsules 2 hours before surgery. General anesthesia was induced and maintained with propofol, at bispectral index value between 40 and 60. Intraoperative fentanyl and propofol requirements were noted. Postoperatively, all patients were alert and pain was assessed using visual analog scale (VAS) for 24 hours, both during rest and movement. Whenever VAS score was more than 50 or on patients' demand, ketorolac 30 mg was given as rescue analgesic. The demographics, duration of surgery, and propofol consumption in both groups were comparable. Intraoperative and postoperative heart rate and mean blood pressure were also comparable. Significant difference was noted in intraoperative fentanyl consumption (P=0.03), total dose of rescue analgesic (P=0.004), and VAS score at rest and movement, between the 2 groups; less in gabapentin group as compared with placebo group (P=0.01 and 0.04, at rest and movement, respectively). A single oral dose of gabapentin 800 mg, as preemptive analgesic in patients undergoing surgery for brachial plexus injury is found to be an effective adjunct to intraoperative and postoperative pain. Pain is reduced not only at rest but also during movement.     

Intensive care management of patients with acute intermittent porphyria: Clinical report of four cases and review of literature

Acute intermittent porphyria (AIP), the most common and the most severe form of acute hepatic porphyria, is an autosomal dominant condition. It results from lower-than-normal levels (less than 50%) of porphobilinogen (PBG) deaminase. Patients may present commonly with gastrointestinal complaints and neuropsychiatric manifestations. Diagnosis may be confirmed with the presence of intermediary metabolites of haem synthesis, amino levulinic acid (ALA) and PBG in urine or with specific enzyme assays. Abdominal pain is the most common symptom (90%). Peripheral polyneuropathy, primarily motor with flaccid paresis of proximal musculature, with or without autonomic involvement, is characteristic. Respiratory failure necessitates ventilator and intensive care support. Avoidance of precipitating factors and the use of haem preparations and intravenous dextrose form the basis of management. Gabapentin and propofol, rather than the conventional antiepileptics appear to be the appropriate choice for seizure control. Here, we present intensive care management of four cases of AIP with varying clinical presentation.     

Effect of Punarnavine,an Alkaloid from Boerhaavia diffusa,on Cell-Mediated Immune Responses and TIMP-1 in B16F-10 Metastatic Melanoma-Bearing Mice

Effect of Punarnavine on the cell-mediated immune (CMI) response in metastatic condition was studied using C57BL/6 mice model. Administration of Punarnavine enhanced Natural Killer (NK) cell activity, antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent complement mediated cytotoxicity (ACC) and the activity was observed in treated group much earlier compared to the metastatic tumor-bearing control. Production of cytokines such as IL-2 and IFN-γ were significantly enhanced by the administration of Punarnavine compared to the untreated metastatic tumor-bearing control. Peaks of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α were significantly lowered by Punarnavine administration compared to metastatic control. The level and expression of TIMP-1 was also enhanced by the administration of Punarnavine compared to metastatic tumor bearing control. These results indicate Punarnavine could enhance the immune response against metastatic progression of B16F-10 melanoma cells in mice.