Rare complications after second hematopoietic stem cell transplantation for thalassemia major.

We describe an 11-year-old girl with thalassemia major who underwent a second hematopoietic stem cell transplantation from a matched related donor and who subsequently developed posttransplant lymphoproliferative disorder complicated by severe ascending paralysis resembling Guillian-Barré syndrome. Six months later she developed a massive pericardial effusion. She received a multimodal treatment for these complications and currently, 18 months after transplantation, she is in a good clinical condition, is transfusion independent, with no evidence of graft-versus-host disease and off all treatment. This case highlights the dilemma surrounding second hematopoietic stem cell transplantations in hemoglobinopathies and the need for a careful, well informed, and collaborative decision-making process by patients, families, and medical professionals.

TMEM70 mutations are a common cause of nuclear encoded ATP synthase assembly defect: further delineation of a new syndrome.

BACKGROUND: The TMEM70 gene defect was recently identified as a novel cause of autosomal recessive ATP synthase deficiency. Most of the 28 patients with TMEM70 disorder reported to date display a distinctive phenotype characterised by neonatal onset of severe muscular hypotonia hypertrophic cardiomyopathy, facial dysmorphism, profound lactic acidosis, and 3-methylglutaconic aciduria. Almost all share a common Roma descent and are homozygous for a single founder splice site mutation. METHODS: Six new patients from four separate families, with clinical and biochemical diagnosis of ATP synthase deficiency, were studied. TMEM70 sequence analysis of the three exons and their flanking splice junction consensus sequences was performed in all patients. In addition their clinical phenotype and disease course was strictly studied. RESULTS: Four novel deleterious homozygous TMEM70 mutations were identified. The previously described clinical spectrum was expanded to include infantile onset cataract, early onset gastrointestinal dysfunction and congenital hypertonia with multiple contractures resembling arthrogryposis. The first characterisation of fetal presentation of the syndrome is also provided, featuring significant intrauterine growth retardation, severe oligohydramnios, fetal hypotonia, and myocardial wall thickening. CONCLUSIONS: The current report corroborates the previously described unique phenotype of TMEM70 deficiency. The study identifies TMEM70 gene defect as a pan-ethnic disorder and further redefines it as the most common cause of nuclear-origin ATP synthase deficiency.

Increased extent of and risk factors for pandemic (H1N1) 2009 and seasonal influenza among children, Israel.

During the pandemic (H1N1) 2009 outbreak in Israel, incidence rates among children were 2× higher than that of the previous 4 influenza seasons; hospitalization rates were 5× higher. Children hospitalized for pandemic (H1N1) 2009 were older and had more underlying chronic diseases than those hospitalized for seasonal influenza.

Serum transaminases as a prognostic factor in children post cardiac surgery.

BACKGROUND: Elevated serum transaminases that are often observed in critically ill children are frequently attributed to liver injury. Indeed, hypoperfused or hypoxemic livers will produce sudden and marked elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The aim of this study was to determine the frequency and consequences of elevated serum transaminases in children following cardiac surgery. METHODS: Charts of all children admitted to the Pediatric Intensive Care Unit following cardiac surgery over a 10-year period were retrospectively analyzed. RESULTS: Of the 384 children studied, 46 (11.9%) had elevated transaminases. Extreme ALT and AST levels (≥20-fold elevations over the upper limit of normal) were found in 3.4% and 4.7% of the children, respectively. Tetralogy of Fallot and double outlet right ventricle were significantly more common (P < 0.001) among the elevated transaminases group (26% and 13% vs 17% and 2.5%, respectively). A significant difference (P < 0.001) was noted between overall mortality among 384 patients studied: 15.8%, versus a mortality of 43.4% among children who manifested elevated transaminases levels following cardiac surgery. AST, ALT and lactate dehydrogenase peak levels were significantly higher in the group of children who died in comparison to the survivors (P < 0.05). Kaplan-Meier survival analysis demonstrated lower survival among the patients who had extreme ALT elevations (P < 0.05). CONCLUSIONS: Elevation of transaminases following cardiac surgery occurs more frequently than previously reported, particularly in the setting of right-sided heart failure. Extreme elevation of ALT, AST and lactate dehydrogenase correlated with decreased postoperative survival and places these children in a high-risk category, requiring closer, more stringent monitoring.

Differential neuroprotective properties of endogenous and exogenous erythropoietin in a mouse model of traumatic brain injury.

Both heat acclimation (HA) and post-injury treatment with recombinant human erythropoietin (Epo, rhEpo, exogenous Epo) are neuroprotective against traumatic brain injury (TBI). Our previous data demonstrated that HA-induced neuroprotection includes improved functional recovery and reduced cerebral edema formation. Additionally, in earlier Western-blot analyses, we found that HA mice display increased expression of the specific erythropoietin receptor (EpoR) and of hypoxia-inducible factor-1 alpha (HIF-1 alpha), the inducible subunit of the transcription factor, which regulates Epo gene expression, but not of Epo itself. In light of this, the aim of the current study was threefold: (1) to assess Epo expression in the trauma area and hippocampus following HA, rhEpo administration, or combined HA-rhEpo treatment, using immunohistochemical methods that offer enhanced anatomical resolution; (2) to examine the effects of endogenous and exogenous Epo on edema formation in normothermic (NT) mice; and (3) to evaluate the effects of exogenous Epo administration on neuroprotective outcome measures in HA animals. HA induced enhanced expression of endogenous Epo in the trauma area and the hippocampus. Treatment with anti-Epo antibody given to NT mice increased edema formation, whereas rhEpo induced no beneficial effect. Cognitive performance testing and immunohistochemical findings reinforced HA and rhEpo as separate protective interventions but showed no advantage to combining the two strategies. We therefore suggest that HA-induced neuroprotection is shaped by pre-existing mediators but cannot be modified by post-injury treatment aimed at increasing the levels of neuroprotective agents.

The Ras inhibitor S-trans, trans-farnesylthiosalicylic acid exerts long-lasting neuroprotection in a mouse closed head injury model.

Traumatic brain injury activates N-methyl-d-aspartate receptors (NMDAR) inducing activation of the Ras protein (a key regulator of cell growth, survival, and death) and its effectors. Thus, trauma-induced increase in active Ras-GTP might contribute to traumatic brain injury pathology. Based on this hypothesis, a new concept of neuroprotection is proposed, examined here by investigating the effect of the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS) in a mouse model of closed head injury (CHI). Mice subjected to CHI were treated systemically 1 h later with FTS (5 mg/kg) or vehicle. After 1 h, Ras-GTP in the contused hemisphere showed a significant (3.8-fold) increase, which was strongly inhibited by FTS (82% inhibition) or by the NMDA-receptor antagonist MK-801 (53%). Both drugs also decreased active (phosphorylated) extracellular signal-regulated kinase. FTS prevented the CHI-induced reduction in NMDAR binding in cortical, striatal, and hippocampal regions, measured by [3H]-MK-801 autoradiography, and decreased lesion size by 50%. It also reduced CHI-induced neurologic deficits, indicated by the highly significant (P < 0.0001) 60% increase in extent of recovery. Thus, FTS provided long-term neuroprotection after CHI, rescuing NMDAR binding in the contused hemisphere and profoundly reducing neurologic deficits. These findings suggest that nontoxic Ras inhibitors such as FTS may qualify as neuroprotective drugs.

Elevated intracranial IL-18 in humans and mice after traumatic brain injury and evidence of neuroprotective effects of IL-18-binding protein after experimental closed head injury.

Proinflammatory cytokines are important mediators of neuroinflammation after traumatic brain injury. The role of interleukin (IL)-18, a new member of the IL-1 family, in brain trauma has not been reported to date. The authors investigated the posttraumatic release of IL-18 in murine brains following experimental closed head injury (CHI) and in CSF of CHI patients. In the mouse model, intracerebral IL-18 was induced within 24 hours by ether anesthesia and sham operation. Significantly elevated levels of IL-18 were detected at 7 days after CHI and in human CSF up to 10 days after trauma. Published data imply that IL-18 may play a pathophysiological role in inflammatory CNS diseases; therefore its inhibition may ameliorate outcome after CHI. To evaluate the functional aspects of IL-18 in the injured brain, mice were injected systemically with IL-18-binding protein (IL-18BP), a specific inhibitor of IL-18, 1 hour after trauma. IL-18BP-treated mice showed a significantly improved neurological recovery by 7 days, accompanied by attenuated intracerebral IL-18 levels. This demonstrates that inhibition of IL-18 is associated with improved recovery. However, brain edema at 24 hours was not influenced by IL-18BP, suggesting that inflammatory mediators other than IL-18 induce the early detrimental effects of intracerebral inflammation.

Tumor necrosis factor-mediated inhibition of interleukin-18 in the brain: a clinical and experimental study in head-injured patients and in a murine model of closed head injury.

Tumor necrosis factor (TNF) and interleukin-(IL)-18 are important mediators of neuroinflammation after closed head injury (CHI). Both mediators have been previously found to be significantly elevated in the intracranial compartment after brain injury, both in patients as well as in experimental model systems. However, the interrelation and regulation of these crucial cytokines within the injured brain has not yet been investigated. The present study was designed to assess a potential regulation of intracranial IL-18 levels by TNF based on a clinical study in head-injured patients and an experimental model in mice. In the first part, we investigated the interrelationship between the daily TNF and IL-18 cerebrospinal fluid levels in 10 patients with severe CHI for up to 14 days after trauma. In the second part of the study, the potential TNF-dependent regulation of intracerebral IL-18 levels was further characterized in an experimental set-up in mice: (1) in a standardized model of CHI in TNF/lymphotoxin-alpha gene-deficient mice and wild-type (WT) littermates, and (2) by intracerebro-ventricular injection of mouse recombinant TNF in WT C57BL/6 mice. The results demonstrate an inverse correlation of intrathecal TNF and IL-18 levels in head-injured patients and a TNF-dependent inhibition of IL-18 after intracerebral injection in mice. These findings imply a potential new anti-inflammatory mechanism of TNF by attenuation of IL-18, thus confirming the proposed "dual" function of this cytokine in the pathophysiology of traumatic brain injury.

Improved recovery and delayed cytokine induction after closed head injury in mice with central overexpression of the secreted isoform of the interleukin-1 receptor antagonist.

The acute inflammatory response following traumatic brain injury (TBI) has been shown to play an important role in the development of secondary tissue damage. The proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNFalpha), are induced early after brain injury and have been implicated in the delayed damage. The IL-1 receptor antagonist (IL-1ra) has been shown to modulate the proinflammatory cytokine cascade by blocking the binding of IL-1 to its signaling receptor. In this study, we investigated the effect of transgenic overexpression of IL-1ra on the cytokine expression and neurological damage in a closed head injury (CHI) model of TBI. The neurological recovery, as analyzed by neurological severity score (NSS), was significantly higher in transgenic mice overexpressing the human secreted form of IL-1ra in astrocytes, directed by the murine glial fibrillary acidic protein promoter, as compared to wild-type mice. Analysis of tissue levels of cytokines by ELISA showed increased levels of TNFalpha in the cerebral cortex from the wild type mice 1 h after injury. After 4 h significant increases in the levels of IL-1beta and IL-6 were observed in the wild type mice. In the transgenic mice, on the other hand, no effect on TNFalpha levels was observed and no significant increases in IL-1beta and IL-6 levels could be detected until 6 h after injury. Thus, it can be concluded that blockage of IL-1 signaling by elevated levels of IL-1ra has a neuroprotective effect, in agreement with previous reports, and that central overexpression of IL-1ra results in delayed proinflammatory cytokine induction and improved neurological recovery after traumatic brain injury.

A multidisciplinary team approach for management of a giant congenital cervical teratoma.

Congenital cervical teratomas are associated with a high rate of perinatal mortality due to airway obstruction. We describe a multidisciplinary management of a neonate with prenatal diagnosis of giant cervical teratoma. An 'operation on placenta support' (OOPS) technique was carried out during delivery, and intubation was successfully performed with no perinatal anoxic damage. Postnatal computed tomography and angiography showed a huge teratoma covering both sides of the neck with agenesis of the big blood vessels on the left side. A rapidly developing third space phenomenon and deterioration in the general status of the neonate, required early surgical intervention. During surgical excision, the left carotid artery and internal jugular vein, the left lobe of the thyroid gland and the left recurrent laryngeal nerve were not detected. The left vagus, accessory and hypoglossal nerves were positioned between the skin and the tumor, at a distance from their normal anatomical location. Pathologic examination confirmed the diagnosis indicating immature teratoma with no signs of malignancy. The postoperative period was complicated by neurological deterioration, pharyngo-cutaneous fistula and paresis of the left hypoglossal nerve. However, all the symptoms resolved spontaneously. Tracheotomy was performed when the baby was 6 weeks old due to paralysis of the left vocal cord and to severe laryngo-tracheomalacia. She was decannulated when she was 3 years old. Today, she is suffering only from dysphonia. This report confirms the efficacy of a multidisciplinary team-approach and the usefulness of the OOPS technique in prenatally diagnosed cervical masses. It emphasizes the extraordinary characteristics of this case, mainly the development of a third space phenomenon and the unusual surgical findings.

An outbreak of adenovirus type 7 in a residential facility for severely disabled children.

BACKGROUND: Adenoviruses cause a variety of clinical symptoms, involving the respiratory, gastrointestinal, urogenital, and neurologic systems. Only a few of the 55 known serotypes of adenovirus that affect humans can cause outbreaks of respiratory tract infection. AIM: To describe the characteristics and clinical manifestations of severe respiratory disease contracted by 8 physically and cognitively disabled children during a very short outbreak of adenovirus serotype 7 infection in a residential facility. METHODS: The clinical, imaging, and laboratory findings of the patients who were hospitalized with severe respiratory symptoms were retrospectively reviewed. Molecular typing of the adenovirus was performed. RESULTS: During 10 days in February 2010, 8 severely disabled children, 9 months to 5 years of age (median 22.5 months), from the same residential facility, were hospitalized due to severe acute respiratory disease with hypoxemia. Four of them (50%) needed mechanical ventilation for 2 to 8 days and one developed multisystem failure, including acute renal failure. Adenovirus serotype 7 was detected in the respiratory specimens of all 8 children. Two patients were treated with intravenous cidofovir. All 8 patients survived and were discharged after hospitalization of 6 to 15 (median: 11.5) days. The epidemiologic investigation revealed that all the 8 affected children shared a playroom and a caregiver worked with them while suffering fever, sore throat, and conjunctivitis before the onset of the outbreak. CONCLUSIONS: Adenovirus type 7 may cause short outbreaks of infection in institutions, causing children to develop life-threatening disease. Early detection of pathogens causing respiratory infections in institutions, isolation, and other preventive precautions are advocated. Moreover, vaccination of health care providers in institutions with the currently available live, oral adenovirus vaccine for types 4 and 7 should be considered.

Intradural lumbar varix resembling a tumor: case report of a magnetic resonance imaging-based diagnosis.

STUDY DESIGN: Review the presentation and diagnosis of a lumbar intradural varix. OBJECTIVE: To report an innovative magnetic resonance imaging (MRI) technique that enabled radiographic diagnosis in a rare case of symptomatic lumbar intradural varix. SUMMARY OF BACKGROUND DATA: Lumbar variceal veins rarely occur intradurally, and may radiographically mimic nerve-sheath tumors. These lesions are typically diagnosed at surgery performed due to suspicion of tumor. METHODS: A 55-year-old man presented with radicular lower back pain and normal neurologic examination. MRI revealed an ellipsoid intradural enhancing mass at the L2 level. The patient refused to undergo the surgical procedure that was recommended. Over 2-year follow-up, symptoms resolved together with weight reduction. Repeat MRI revealed an unchanged lumbar lesion in addition to engorged epidural and intradural veins, thought to be related to outflow obstruction secondary to past right nephrectomy and obliterated inferior vena cava. Breath-holding and Valsalva maneuvers during MRI caused a change in the shape of the intradural lesion. RESULTS: The patient's refusal to undergo surgery led to noninvasive assessment of his lumbar spinal pathology. Diagnosis of nonthrombosed intradural varix was established on MRI-based detection of a change in the shape of the lesion following breath-hold and Valsalva maneuvers. CONCLUSION: We diagnosed a nonthrombosed intradural varix by demonstrating a change in the lesion's shape on MRI, following breath-hold and Valsalva maneuvers. This is the first report of nonpathologic, purely radiologic diagnosis of such a lesion. This is a relatively simple, noninvasive method of evaluating these patients.

Congenital chylothorax: clinical course and prognostic significance.

OBJECTIVE: To determine the underlying etiology, associated malformations, clinical course, and prognostic significance of congenital chylothorax. STUDY DESIGN: A retrospective analysis of 11 neonates admitted to our neonatal intensive care unit with congenital chylothorax between January 2000 and June 2008. The post-discharge clinical and developmental course was evaluated by a telephone survey performed in July 2008. RESULTS: Antenatal diagnosis was established in 9 out of 11 infants by ultrasound examination; 5 had intrauterine pleural drainage. Eight infants had either structural or chromosomal abnormalities. The postnatal treatment included mechanical ventilation, drainage of pleural fluid and feeding with enriched medium chain triglyceride formula. Somatostatin was administered in one case. Six patients developed nosocomial infections. Two patients died after resolution of the chylothorax from deteriorating renal failure. Seven patients were traced for follow up and six of them achieved age appropriate developmental milestones. CONCLUSION: The recovery from chylothorax and future prognosis were dependent on the underlying etiology. Chylothorax was often a secondary event, with apparently favorable clinical and developmental prognosis when the underlying or/and associated condition was treatable.

Comparison of N-terminal pro-B-type natriuretic peptide levels in critically ill children with sepsis versus acute left ventricular dysfunction.

OBJECTIVE: N-terminal pro-B-type natriuretic peptide has been shown to be a marker for cardiac dysfunction. The peptide level is also elevated in patients with sepsis. The purpose of this study was to assess whether N-terminal pro-B-type natriuretic peptide levels can differentiate pediatric patients with sepsis from patients with acute left ventricular dysfunction. PATIENTS AND METHODS: Pediatric patients admitted to an ICU with sepsis or acute left ventricular dysfunction were evaluated clinically, and the grade of systemic inflammatory-response syndrome was determined. Echocardiography was performed, and their levels of N-terminal pro-B-type natriuretic peptide were measured. The N-terminal pro-B-type natriuretic peptide level was also measured in patients with simple febrile illness. RESULTS: There were 10 patients with sepsis and 10 with acute left ventricular dysfunction. The age of the patients was similar, and systemic inflammatory-response syndrome grading was not different (sepsis: 2.8 +/- 0.4; acute left ventricular dysfunction: 2.6 +/- 0.7). N-terminal pro-B-type natriuretic peptide levels were elevated in patients with sepsis (median: 6064 pg/mL; range: 495-60,417 pg/mL) but were significantly higher in patients with acute left ventricular dysfunction (median: 65,630 pg/mL; range: 15,125-288,000). The area under the receiver operating characteristics curve for the diagnosis of acute left ventricular dysfunction was 0.9. N-terminal pro-B-type natriuretic peptide levels of patients with sepsis and impaired systolic function were not different from those of patients with sepsis and normal systolic function. The N-terminal pro-B-type natriuretic peptide levels of 20 patients with simple febrile illness were significantly lower. CONCLUSIONS: N-terminal pro-B-type natriuretic peptide levels are elevated in pediatric patients with sepsis but are higher in some, but not all, patients with acute left ventricular dysfunction. The overlap between N-terminal pro-B-type natriuretic peptide levels in sepsis and acute left ventricular dysfunction precludes the use of the peptide's level as a sole means to differentiate between these conditions. Excessive elevation in N-terminal pro-B-type natriuretic peptide levels, however, suggests cardiac etiology for acute hemodynamic deterioration in infants and children.

Brain trauma induces X-box protein 1 processing indicative of activation of the endoplasmic reticulum unfolded protein response.

Brain trauma was induced in mice using a closed head injury (CHI) model. At 1, 6 or 24 h after trauma, brains were dissected into the cortex, striatum and hippocampus. Changes in levels of processed X-box protein 1 (xbp1), glucose-regulated protein 78 (grp78), growth arrest and DNA damage-inducible gene 153 (gadd153) and heat-shock protein 70 (hsp70) mRNA, indicating impaired endoplasmic reticulum (ER) and cytoplasmic functioning, were evaluated by quantitative PCR. In the cortex, processed xbp1 mRNA levels rose to 2000% of control 1 h after CHI, and stayed high throughout the experiments. In the hippocampus and striatum, processed xbp1 mRNA levels rose in a delayed fashion, peaking at 6 h (1000% of control) and 24 h after CHI (1500% of control) respectively. Levels of grp78 mRNA were only slightly increased in the cortex 24 h after CHI (150% of control), and were unchanged or transiently decreased in the hippocampus and striatum. Levels of gadd153 mRNA did not change significantly after trauma. A transient rise in hsp70 mRNA levels was observed only in the cortex, peaking at 1 h after CHI (600% of control). Processing of xbp1 mRNA is a sign of activation of the unfolded protein response indicative of ER dysfunction. The results suggest that brain trauma induces ER dysfunction, which spreads from the ipsilateral cortex to the hippocampus and striatum. These observations may have clinical implications and should therefore be considered for future investigations on therapeutic intervention of brain injury caused by contusion-induced neurotrauma.