808 nm wavelength light induces a dose-dependent alteration in microglial polarization and resultant microglial induced neurite growth.

BACKGROUND AND OBJECTIVE: Despite the success of using photobiomodulation (PBM), also known as low level light therapy, in promoting recovery after central nervous system (CNS) injury, the effect of PBM on microglia, the primary mediators of immune and inflammatory response in the CNS, remains unclear. Microglia exhibit a spectrum of responses to injury, with partial or full polarization into pro- and anti-inflammatory phenotypes. Pro-inflammatory (M1 or classically activated) microglia contribute to chronic inflammation and neuronal toxicity, while anti-inflammatory (M2 or alternatively activated) microglia play a role in wound healing and tissue repair; microglia can fall anywhere along this spectrum in response to stimulation. MATERIALS AND METHODS: The effect of PBM on microglial polarization therefore was investigated using colorimetric assays, immunocytochemistry, proteomic profiling and RT-PCR in vitro after exposure of primary microglia or BV2 microglial cell line to PBM of differing energy densities (0.2, 4, 10, and 30 J/cm(2) , 808 nm wavelength, 50 mW output power). RESULTS: PBM has a dose-dependent effect on the spectrum of microglial M1 and M2 polarization. Specifically, PBM with energy densities between 4 and 30 J/cm(2) induced expression of M1 markers in microglia. Markers of the M2 phenotype, including CD206 and TIMP1, were observed at lower energy densities of 0.2-10 J/cm(2) . In addition, co-culture of PBM or control-treated microglia with primary neuronal cultures demonstrated a dose-dependent effect of PBM on microglial-induced neuronal growth and neurite extension. CONCLUSION: These data suggest that the Arndt-Schulz law as applied to PBM for a specific bioassay does not hold true in cells with a spectrum of responses, and that PBM can alter microglial phenotype across this spectrum in a dose-dependent manner. These data are therefore of important relevance to not only therapies in the CNS but also to understanding of PBM effects and mechanisms.

Limitations of Chromogranin A in clinical practice.

CONTEXT: Usefulness of circulating Chromogranin A (CgA) for the diagnosis of neuroendocrine tumors (NEN) is controversial. The aim of the present study was to assess the actual role of this marker as diagnostic tool. METHODS: Serum blood samples were obtained from 42 subjects affected with NEN, 120 subjects affected with non-endocrine neoplasias (non-NEN) and 100 non-neoplastic subjects affected with benign nodular goitre (NNG). Determination of CgA was performed by means of immunoradiometric assay. RESULTS: The CgA levels among NEN-patients were not significantly different from NNG and non-NEN subjects. The Receiver operating characteristic (ROC) curves analysis failed to identify a feasible cut-off value for the differential diagnosis between NEN and the other conditions. CONCLUSION: Serum CgA is not helpful for the first-line diagnosis of NEN.

IgM and IgA enriched polyclonal immunoglobulins reduce short term mortality in extremely low birth weight infants with sepsis: a retrospective cohort study.

BACKGROUND: Immunoglobulin supplementation is a debated strategy in fighting sepsis. We evaluated a polyclonal IgM and IgA enriched immunoglobulin (IgMeIVIG) preparation in reducing the short-term mortality in extremely low birth weight neonates (ELBW) with proven infection. METHODS: ELBW infants born from January 2008 to December 2014 were eligible for this retrospective case-control analysis if they were symptomatic and had a positive blood culture after 72 hours of life. Patients received antibiotic treatment with or without IgMeIVIG (intravenously, 250 mg/kg/day for 3 days) within the 24 hours from clinical suspicion as per indication of the attending physician. Short-term (7 and 21 days) mortality was the study primary outcome while secondary outcomes were: mortality at discharge, intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, periventricular leukomalacia, and retinopathy of prematurity. RESULTS: Each group was composed by thirty-nine infants. Both groups were similar for antenatal steroids, mode of delivery, birth weight, gestational age and SNAPII score as indicator of disease severity. Infants receiving IgMeIVIG had a significantly lower short-term mortality compared with neonates receiving antibiotics alone: 6/39 (15%) vs. 14/39 (36%); P=0.038. No differences in other outcomes were found. CONCLUSIONS: This study shows that IgMeIVIG may have a role as adjuvant therapy in ELBW infants with proven sepsis. We warrant future prospective, blinded RCT studies where IgMeIVIG can be consistently used if needed throughout the NICU admission in ELBW septic neonates to appropriately evaluate its effect on mortality at discharge.

Irradiation of pacemakers and cardio-defibrillators in patients submitted to radiotherapy: a clinical experience.

AIMS AND BACKGROUND: A prospective analysis was carried out on a group of irradiated patients with pacemakers or implantable cardioverter-defibrillators to identify any relationship between the various types of devices and physical and dosimetric parameters. Cardiac toxicity of the treatment was also investigated. METHODS AND STUDY DESIGN: Forty-five irradiated patients, implanted with pacemakers or implantable cardioverter-defibrillators, were prospectively investigated from 1999 to 2007. An analysis of radiation damage to pacemakers, depending on the geometric and dosimetric characteristics of the radiation beams, was carried out. The electric and magnetic fields of linear accelerators (LINACs) were measured to evaluate any interference. The calculation of dose received by pacemakers was evaluated by dose-volume histograms. RESULTS: No dysfunction was observed in any pacemaker, nor were the substitution times negatively affected. We did not find problems with the devices due to the interaction with the electromagnetic fields. Dose-volume histograms calculated for patients treated in regions close to devices (head & neck, thorax) showed an average maximum dose equal to 2.5 Gy for the head & neck area and equal to 1.8 Gy for the thoracic area. Acute (3 cases) and late (2 cases) cardiac events were observed only in 5 patients who underwent chemoradiation treatment, but no dysfunction was observed in any pacemaker. CONCLUSIONS: Our study confirms the safety of radiotherapy for patients implanted with pacemakers or implantable cardioverter-defibrillators but suggests that chemoradiation represents a probable risk factor for cardiac toxicity. Furthermore, all cardiac events were observed in patients treated in the head and'neck or left thoracic areas. A standardized protocol is advisable in order to improve patient control during the radiotherapy treatment. It is mandatory to calculate the dose received at the pacemaker/heart, even in the case of palliative treatment.

Radiotherapy after partial laryngectomy: an analysis of 36 cases and a proposal to optimize radiotherapy.

AIMS AND BACKGROUND: Laryngeal cancer treatment options include radical surgery, "organ preservation surgery", radiotherapy and chemotherapy. There is no proven evidence of a significant increase in late toxicity with adjuvant radiotherapy after conservative surgery. The aim of this retrospective study was to evaluate the toxicity, local-regional control and overall survival of adjuvant radiotherapy after conservative surgery. METHODS: A total of 36 patients was treated with radiotherapy after partial laryngectomy at the Radiotherapy Department of the Institute for Cancer Treatment and Research (IRCC) of Candiolo and of the Mauriziano Hospital in Turin, between 1994 and 2007. The postoperative treatment doses ranged from 45 to 70.2 Gy with conventional fractionation. The Kaplan-Meier method was applied for statistical analysis. The RTOG-EORTC scale was used to evaluate late and acute toxicity. RESULTS: Overall 5- and 10-year survival was 93% and 47%, respectively. Local control was 93.5% at 5 and was unchanged at 10 years. Grade 2 acute cutaneous and mucous toxicity was 41% and 62%, and grade 3, 6.9% and 3.5%, respectively. Only one patient required percutaneous endoscopic gastrostomy due to severe dysphagia and one patient required temporary tracheostomy for severe acute laryngeal edema (grade 3). Two patients experienced late toxicity greater than grade 3. The median dose to the residual larynx was 59.5 Gy (range, 45-70.2), and the median dose to the neck was 50.4 Gy (range, 39.6 -55.8). CONCLUSIONS: The results of our study showed a dose-dependent increase in the late toxicity trend at doses over and above 60 Gy, which is higher than the cutoff dose reported in the literature. There was no indication from our data that adjuvant postoperative radiotherapy means additional toxicity. The use of highly conformal techniques can further reduce toxicity of the radiotherapy.

Bilirubin exposure is associated with neonatal sepsis in the eight days preceding symptoms: a retrospective study.

OBJECTIVE: To compare levels of bilirubin (using the area under the curve, AUC) in preterm infants before the onset of sepsis with healthy matched-controls. METHODS: Preterm infants born between January 2011 and December 2015 with late-onset sepsis were enrolled in our retrospective study and were matched with healthy controls (sex, birth weight and gestational age). Levels of bilirubin were registered in the eight days preceding the onset of sepsis and the AUC was calculated for both groups. RESULTS: Eighty-eight neonates (44 cases) were studied. GA and BW did not differ between cases and controls. In cases, we found a higher value of AUC (30.7 versus 22.5; p = 0.021). CONCLUSION: In our retrospective cohort, we found that the levels of bilirubin and the AUC in the first eight days before the onset of sepsis in preterm infants were significantly higher than the healthy controls. These data suggest that the prolonged exposition to high levels of bilirubin could increase the infection susceptibility in preterm infants.

Outcomes of congenital cytomegalovirus disease following maternal primary and non-primary infection.

BACKGROUND: Natural history and long term prognosis of congenital cytomegalovirus (CMV) disease according to maternal primary versus non-primary infection are not clearly documented. OBJECTIVE: To investigate clinical, laboratory and neuroimaging features at onset and long term outcome of congenitally CMV-infected patients born to mothers with non-primary infection compared with a group of patients born to mothers with primary infection. STUDY DESIGN: Consecutive neonates born from 2002 to 2015 were considered eligible for the study. Patients underwent clinical, laboratory and instrumental investigation, and audiologic and neurodevelopmental evaluation at diagnosis and during the follow up. RESULTS: A cohort of 158 congenitally infected children was analyzed. Ninety-three were born to mothers with primary CMV infection (Group 1) and 65 to mothers with a non-primary infection (Group 2). Eighty-eight infants had a symptomatic congenital CMV disease: 49 (46.2%) in Group 1 and 39 (60%) in Group 2. Maternal and demographic characteristics of patients of Group 1 and Group 2 were comparable, with the exception of prematurity and a 1-min Apgar score less than 7, which were more frequent in Group 2 compared to Group 1. Prevalence of neuroimaging findings did not significantly differ between the two groups. An impaired neurodevelopmental outcome was observed in 23.7% of patients of Group 1 and in 24.6% cases of Group 2. Similarly, the frequency of hearing loss did not differ between the two groups (25.8% versus 26.2%, respectively). CONCLUSIONS: Neurodevelopmental and hearing sequelae are not affected by the type of maternal CMV infection. Preventing strategies should be developed for both primary and non-primary infections.

Noma Neonatorum From Multidrug-Resistant Pseudomonas aeruginosa: An Underestimated Threat?

We present the case of an extremely low birth weight infant with diffuse gingival noma, initially misdiagnosed as thrush. Multidrug-resistant Pseudomonas aeruginosa strain was cultured and treated with systemic and local colistin with complete healing. Noma neonatorum from multidrug-resistant pathogens may appear in neonatal intensive care units. Old antibiotics may help.Noma (cancrum oris) is a devastating gangrenous disease that leads to destruction of facial tissue with significant morbidity and mortality in children and young adults. Noma has virtually disappeared from Europe and North America, but it is still common among children and young adults in India, Africa, and South America. Noma is a polymicrobial opportunistic infection related to malnutrition and immune dysfunction. In the neonate, a similar but distinct condition, known as "noma neonatorum" was described in 1977, in which gangrenous lesions involve the mucocutaneous junctions of oral, nasal, and anal area, and, occasionally, the eyelids and the scrotum. The neonatal disease has been linked to Pseudomonas aeruginosa, prematurity, and low birth weight. There is no established treatment, and mortality is almost inevitable in the few reported cases. In this study, we present the first European case of noma neonatorum from a multidrug-resistant strain of P aeruginosa.

Use of neonatal chest ultrasound to predict noninvasive ventilation failure.

BACKGROUND: Noninvasive ventilation is the treatment of choice for neonatal moderate respiratory distress (RD). Predictors of nasal ventilation failure are helpful in preventing clinical deterioration. Work on neonatal lung ultrasound has shown that the persistence of a hyperechogenic, "white lung" image correlates with severe distress in the preterm infant. We investigate the persistent white lung ultrasound image as a marker of noninvasive ventilation failure. METHODS: Newborns admitted to the NICU with moderate RD and stabilized on nasal continuous positive airway pressure for 120 minutes were enrolled. Lung ultrasound was performed and blindly classified as type 1 (white lung), type 2 (prevalence of B-lines), or type 3 (prevalence of A-lines). Chest radiograph also was examined and graded by an experienced radiologist blind to the infant's clinical condition. Outcome of the study was the accuracy of bilateral type 1 to predict intubation within 24 hours from scanning. Secondary outcome was the performance of the highest radiographic grade within the same time interval. RESULTS: We enrolled 54 infants (gestational age 32.5 ± 2.6 weeks; birth weight 1703 ± 583 g). Type 1 lung profile showed sensitivity 88.9%, specificity 100%, positive predictive value 100%, and negative predictive value 94.7%. Chest radiograph had sensitivity 38.9%, specificity 77.8%, positive predictive value 46.7%, and negative predictive value 71.8%. CONCLUSIONS: After a 2-hour nasal ventilation trial, neonatal lung ultrasound is a useful predictor of the need for intubation, largely outperforming conventional radiology. Future studies should address whether including ultrasonography in the management of neonatal moderate RD confers clinical advantages.

Immunoglobulins in neonatal sepsis: has the final word been said?

Systemic infection is a major cause of mortality and morbidity among premature neonates. In this fragile population, the immaturity of the innate immune response relates inversely to gestational age and is one of the determinants of susceptibility to infections. Antibiotic therapy, even when appropriately and timely instituted, may fail to prevent death or significant sequelae. The quest for additional strategies is still open; in this scenario, the supplementation with exogenous immunoglobulins represents an attractive additional strategy of defence. As current data are conflicting, we provide a critical appraisal with a focus on IgM enriched immunoglobulins preparations.

New perspectives in Respiratory Syncitial Virus infection.

Respiratory syncitial virus (RSV) is the most common cause of lower respiratory tract infections (LRTI) in children worldwide and it is associated with significant childhood morbidity. Acute infection may result in respiratory failure with varying degrees of severity, and increasing evidence supports a role of RSV infection as a key determinant for the development of subsequent chronic respiratory disease. Independent predictors of RSV severity include; prematurity, congenital heart disease, cystic fibrosis, immune defects and neuromuscular disorders. Passive immunization with palivizumab has proven to be safe and effective for preventing RSV hospitalization in infants at higher risk of acquiring severe RSV infection, but its expense and cumbersome monthly intravenous delivery schedule make it inaccessible to many. Furthermore, implementing prophylaxis in 32- to 35-week-gestational age infants and the mode of its administration still represent areas of uncertainty. In this review, we describe several aspects of RSV infection and analyze recent advances in the assessment of cost-effective palivizumab prophylaxis.

Are IgM-enriched immunoglobulins an effective adjuvant in septic VLBW infants?

AIM: To investigate the effectiveness of IgM-enriched immunoglobulins (IgM-eIVIG) in reducing short-term mortality of neonates with proven late-onset sepsis. METHODS: All VLBW infants from January 2008 to December 2012 with positive blood culture beyond 72 hours of life were enrolled in a retrospective cohort study. Newborns born after June 2010 were treated with IgM-eIVIG, 250 mg/kg/day iv for three days in addition to standard antibiotic regimen and compared to an historical cohort born before June 2010, receiving antimicrobial regimen alone. Short-term mortality (i.e. death within 7 and 21 days from treatment) was the primary outcome. Secondary outcomes were: total mortality, intraventricular hemorrhage, necrotizing enterocolitis, periventricular leukomalacia, bronchopulmonary dysplasia at discharge. RESULTS: 79 neonates (40 cases) were enrolled. No difference in birth weight, gestational age or SNAP II score (disease severity score) were found. Significantly reduced short-term mortality was found in treated infants (22% vs 46%; p = 0.005) considering all microbial aetiologies and the subgroup affected by Candida spp. Secondary outcomes were not different between groups. CONCLUSION: This hypothesis-generator study shows that IgM-eIVIG is an effective adjuvant therapy in VLBW infants with proven sepsis. Randomized controlled trials are warranted to confirm this pilot observation.

Neonatal hyperbilirubinaemia: time for Italian recommendations?

The introduction of effective therapies for hyperbilirubinemia might have led to a general overconfidence among neonatal healthcare providers. National guidelines have been issued in many countries though they hardly stand the challenge of evidence-based medicine. A comparative appraisal shows significant discrepancies among different documents. As new, compelling evidence sheds a different light on bilirubin toxicity, this heterogeneity that borders confusion should be solved by implementing both clinical and basic research on the complex issue of neonatal hyperbilirubinemia.

Why should we care about neonatal hyperbilirubinemia in 2011?

Recent research links serum bilirubin levels to a positive function in human health. Yet in the neonate hyperbilirubinemia is associated to damage to the CNS and beyond. This article summarizes the evidence for the double edged role of bilirubin with a focus on the neonatal period. Also we briefly describe some of the current shortcomings in the treatment of neonatal hyperbilirubinemia.

Target volume delineation for preoperative radiotherapy of rectal cancer: inter-observer variability and potential impact of FDG-PET/CT imaging.

To analyze the inter-observer variability and the potential impact of (18)F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) imaging for target volume delineation in preoperative radiotherapy of rectal cancer. Gross tumor volume (GTV) and clinical target volume (CTV) in 2 cases of rectal cancer were contoured by 10 radiation oncologists, 5 on CT and 5 on PET/CT images. Resulting volumes were analyzed by coefficient of variation (CV) and concordance index (CI). Mean GTV was 120 cc +/- 20.4 cc in case A and 119 cc +/- 35.7 cc in case B. Mean CTV was 723 cc +/- 147.5 cc in case A and 739 cc +/- 195.6 cc in case B. CV was lower and CI was similar or higher across the observers contouring GTV on PET/CT. CTV variability was less influenced by the use of PET/CT. PET/CT may allow reducing inter-observer variability in GTV delineation.