Neuroendocrine hyperplasia of infancy; a rare form of childhood interstitial lung disease: a case report.

Interstitial lung disease in infancy is rare. In this case report, we discuss the case of a six-week-old male infant who presented with persistent tachypnoea, retraction and mild hypoxaemia corrected by low-dose supplemental oxygen since the age of 2 weeks. Birth history was unremarkable. Routine workup was done which turned out to be non-contributory. The child received multiple rounds of antibiotics along with bronchodilators and corticosteroids. There was no evidence of severe gastroesophageal reflux. Computed tomography of chest showed ground glass appearance, which was especially prominent in the right middle lobe and lingula ,and accompanied with air trapping. He was managed with mild respiratory supportive care, without positive pressure ventilation and nutritional management. He was discharged home, with instructions for in clinic follow up. A distinctive topographical picture and typical clinical symptoms were consistent with neuroendocrine hyperplasia of infancy (NEHI), which has a favourable prognosis. A high index of suspicion may enable a timely diagnosis. Adequate long-term respiratory and nutritional management without lung biopsy improves the outcome.

Unexpected effect of probiotics by Lactococcus lactis subsp. lactis against colitis induced by dextran sulfate sodium in mice.

Ulcerative colitis (UC) is a representative intestinal chronic inflammatory disease whose incidence is rapidly increasing worldwide. It was previously shown that some specific probiotics help to guard against UC. In this study, we analyzed the effect of Lactococcus lactis subsp. lactis JCM5805 (L. lactis), which has been put to practical use as a probiotic, on the pathogenesis of UC using a dextran sulfate sodium-induced colitis mouse model. Survival rate, length, and histopathological parameters of the colon were elucidated. Further, the concentrations of inflammatory cytokines in serum were measured. As a result, the oral administration of high-dose L. lactis showed significant decreases in survival rate and colon length. Histopathological analysis showed that a bleeding appearance was observed in the L. lactis group, and the histology scores in the L. lactis group were significantly higher than those in the normal saline group. Furthermore, the levels of interferon gamma, tumor necrosis factor alpha, and interleukin-6 were significantly elevated in the L. lactis group. These results support that high-dose administration of L. lactis deteriorates intestinal inflammation and suggest that the careful selection of probiotics strains and administration dose is important for improving colitis including UC.

Drug Targeting and Biomarkers in Head and Neck Cancers: Insights from Systems Biology Analyses.

The head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world, but robust biomarkers and diagnostics are still not available. This study provides in-depth insights from systems biology analyses to identify molecular biomarker signatures to inform systematic drug targeting in HNSCC. Gene expression profiles from tumors and normal tissues of 22 patients with histological confirmation of nonmetastatic HNSCC were subjected to integrative analyses with genome-scale biomolecular networks (i.e., protein-protein interaction and transcriptional and post-transcriptional regulatory networks). We aimed to discover molecular signatures at RNA and protein levels, which could serve as potential drug targets for therapeutic innovation in the future. Eleven proteins, 5 transcription factors, and 20 microRNAs (miRNAs) came into prominence as potential drug targets. The differential expression profiles of these reporter biomolecules were cross-validated by independent RNA-Seq and miRNA-Seq datasets, and risk discrimination performance of the reporter biomolecules, BLNK, CCL2, E4F1, FOSL1, ISG15, MMP9, MYCN, MYH11, miR-1252, miR-29b, miR-29c, miR-3610, miR-431, and miR-523, was also evaluated. Using the transcriptome guided drug repositioning tool, geneXpharma, several candidate drugs were repurposed, including antineoplastic agents (e.g., gemcitabine and irinotecan), antidiabetics (e.g., rosiglitazone), dermatological agents (e.g., clocortolone and acitretin), and antipsychotics (e.g., risperidone), and binding affinities of the drugs to their potential targets were assessed using molecular docking analyses. The molecular signatures and repurposed drugs presented in this study warrant further attention for experimental studies since they offer significant potential as biomarkers and candidate therapeutics for precision medicine approaches to clinical management of HNSCC.

Robust suppression of cardiac energy catabolism with marked accumulation of energy substrates during lipopolysaccharide-induced cardiac dysfunction in mice.

BACKGROUND: Myocardial contractile dysfunction in sepsis has been attributed mainly to increased inflammatory cytokines, insulin resistance, and impaired oxidative phosphorylation of fatty acids (FAs). However, precise molecular mechanisms underlying the cardiac dysfunction in sepsis remain to be determined. We previously reported major shift in myocardial energy substrates from FAs to glucose, and increased hepatic ketogenesis in mice lacking fatty acid-binding protein 4 (FABP4) and FABP5 (DKO). PURPOSE: We sought to determine whether a shift of energy substrates from FAs to glucose and increased availability of ketone bodies are beneficial or detrimental to cardiac function under the septic condition. METHODS: Lipopolysaccharide (LPS, 10mg/kg) was intraperitoneally injected into wild-type (WT) and DKO mice. Twelve hours after injection, cardiac function was assessed by echocardiography and serum and hearts were collected for further analyses. RESULTS: Cardiac contractile function was more deteriorated by LPS injection in DKO mice than WT mice despite comparable changes in pro-inflammatory cytokine production. LPS injection reduced myocardial uptake of FA tracer by 30% in both types of mice, while uptake of the glucose tracer did not significantly change in either group of mice in sepsis. Storage of glycogen and triacylglycerol in hearts was remarkably increased by LPS injection in both mice. Metabolome analysis revealed that LPS-induced suppression of pool size in the TCA cycle was more enhanced in DKO hearts. A tracing study with 13C6-glucose further revealed that LPS injection substantially reduced glucose-derived metabolites in the TCA cycle and related amino acids in DKO hearts. Consistent with these findings, glucose oxidation in vitro was similarly and markedly reduced in both mice. Serum concentration of ß-hydroxybutyrate and cardiac expression of genes associated with ketolysis were reduced in septic mice. CONCLUSIONS: Our study demonstrated that LPS-induced cardiac contractile dysfunction is associated with the robust suppression of catabolism of energy substrates including FAs, glucose and ketone bodies and accumulation of glycogen and triacylglycerol in the heart. Thus, a fuel shift from FAs to glucose and/or ketone bodies may be detrimental rather than protective under septic conditions.

Clinical Profile and Short-Term Outcome of Pediatric Hyperleukocytic Acute Leukemia from a Developing Country.

This study was conducted to determine the frequency, clinical profile, and short-term outcome of children with hyperleukocytosis at two pediatric oncology centers in Karachi. Of a total 1,045 patients, 13.97% (n=146) patients had hyperleukocytosis. Majority (61.7%, n=90) were under 10 years of age and 76% (n=146) were male. The symptom duration before diagnosis was more than 30 days in 49.3% (n=72). The median WBC count was 181 x109/L(IQR=130.45298.3) and extreme hyperleukocytosis (>200 x109/L) was observed in 44.5% (n=65) patients. Majority (94.5%, n=138) of patients were diagnosed with acute lymphoblastic leukemia. One or more complications developed in 78% (n=114) of cases. Clinical and laboratory tumor lysis syndrome (TLS) was observed in 17.1% (n=25) and 39% (n=57) patients, respectively. Pulmonary and neurological complications related to leukostasis were noted in 9.5% (n=14) and 27.3% (n=40) of cases, respectively. Infectious complications occurred in 23.2% (n=34) patients. The case-specific mortality was 20.5% (n=30). No mortality was related to early complications of hyperleukocytosis.

Transfusion-Related Acute Lung Injury In A Paediatric Intensive Care Unit Of Pakistan.

BACKGROUND: Transfusion-Related Acute Lung Injury (TRALI) is a major cause of transfusionrelated morbidity and mortality in the intensive care unit setting. There is a paucity of such data from Pakistan. The purpose of this study is to assess the incidence and outcome of TRALI in critically ill children admitted in a pediatric intensive care unit (PICU) of Pakistan. METHODS: This is a retrospective cohort study of all critically ill or injured children who developed TRALI or "possible" TRALI after blood transfusion based on Canadian Conference Consensus criteria in a closed multidisciplinary-cardiothoracic PICU from January 2012 to June 2016. The demographic, pertinent clinical data, transfusion-related variables and outcome of all cases of TRALI were recorded. RESULTS: Of total 2975 admissions in the PICU during study period, 35.8% (1066) received 5124 blood components. Eleven cases developed TRALI in our cohort. The incidence of TRALI was 1.03% per patient transfused and 0.19% (19/100,000 per blood product transfused). Median age was 8 (range 1-14) yr., 70 % (n=8) were male. Mean PRISM-III score was 16.3±6.7. Mean time interval for onset of TRALI was 2.73±1.67 hr. The postoperative cardiac surgical and hematology-oncology patients were most common categories (63.6%). Plasma and platelets were the most commomly identified trigger of TRALI. The case-specific mortality was 63.6% and the overall mortality was 10.7% (p<0.0001). CONCLUSIONS: The incidence of TRALI in critically ill children is low, but is associated with high mortality. Critically ill children with high PRISM-III score, postoperative cardiac surgical and hematology-oncology patients are often affected by TRALI.

On-table Extubation after Open Heart Surgery in Children: An Experience from a Tertiary Care Hospital in a Developing Country.

BACKGROUND: Recent advances in various disciplines of medicine have significantly changed the courses following cardiac surgery in children. On-table extubation (OTE) after open heart surgery in children is evolving. OBJECTIVE: To assess the rate of postoperative complications in children extubated on table after open heart surgery. DESIGN: This is a retrospective, descriptive study. SETTING: Operating room (OR) then admitted to the pediatric intensive care unit (PICU). PATIENTS: All pediatric patients (between 0 and 18 years) undergoing open heart surgery between January 2011 and June 2013. INTERVENTION: On-table extubation. OUTCOME MEASURES: Rates of immediate postoperative complications, i.e., re-intubation, significant bleeding, low cardiac output syndrome, and arrhythmia in PICU, were assessed. Data are presented as frequencies and mean ± standard deviation. RESULTS: A total of 82 patients were included. Mean age at time of operation was 7.25 ± 6.6 years. Fifty-three percent (n = 44) were <5 years old and 64% (n = 53) were men. Ventricular septal defect (47%, n = 39) was the most common lesion, followed by atrial septal defect (36%, n = 30), and tetralogy of Fallot (15%, n = 12), which were repaired. Cardiopulmonary bypass and aortic cross clamp time were 72.3 ± 34.2 and 47.3 ± 27.8 minutes, respectively. The mean inotrope score was 2.66 ± 3.53. There was no mortality in the cohort, whereas 97.8% (n = 80) had no complications during PICU stay. One patient (1.1%) required re-intubation for respiratory failure and one patient (1.1%) had arrhythmia that was medically managed. The mean length of PICU stay was 1.77 ± 0.985 days. CONCLUSION: On-table extubation in children after open heart surgery was feasible and safe in selected group of patients. There was no major complication observed in the PICU.

Accidental phosphine gas poisoning with fatal myocardial dysfunction in two families.

Aluminum phosphide is commonly used as a rodenticide and insecticide and is one of the most fatal poisons. The active ingredient is Phosphine gas which inhibits cytochrome oxidase and cellular oxygen utilization. The clinical symptoms are due to multiorgan involvement including cardiac toxicity which is the most common cause of mortality. Severity of clinical manifestations depends upon the amount of the gas to which a person is exposed. There is no specific antidote available. High index of suspicion and early aggressive treatment is the key to success. We report 2 cases of aluminum phosphide toxicity in 2 families due to incidental exposure after fumigation.

Outcome of infants with unrepaired heart disease admitted to the pediatric intensive care unit: single-center developing country perspective.

OBJECTIVE: Congenital heart disease (CHD) has an incidence of ∼0.8-1%. Outcome of previously diagnosed CHD patients awaiting surgery (either correction or palliation) in a developing country setting is unknown. We strive to determine the outcome of patients with CHD awaiting surgery who present to pediatric intensive care unit (PICU) setting with an acute illness. DESIGN: Retrospective cross-sectional chart review. SETTING: Pediatric intensive care unit of The Aga Khan University Hospital, Karachi, Pakistan. PATIENT: Medical records of infants (1-12 months) with CHD awaiting surgery presenting to the PICU with an acute illness between January 2009 and June 2012 were included. Newly diagnosed CHD patients, those not requiring PICU admission, and those transferred to another hospital were excluded. RESULTS: A total of 34 infants met the inclusion criteria. Median age at presentation was 5 months. Seventy-four percent of the infants had CHD lesion characterized by increased pulmonary blood flow (shunt lesions). Though none of the patients met the strict criteria for sepsis or pneumonia, 74% were admitted with a diagnosis of pneumonia or sepsis. Only 15% of patient had congestive heart failure as an admitting diagnosis. Oxygen therapy was given to 94% of these patients. Fifty-nine percent of these patients expired during the admission, 95% of those expired had multiorgan dysfunction. CONCLUSION: Patients with CHD awaiting surgery and who admitted to the PICU with acute illness are at high risk for mortality. Stringent criteria to diagnose pneumonia or sepsis should be used in these patients.

A rare aetiology of respiratory failure in a 10-year-old boy: inflammatory myofibroblastic tumour.

Primary neoplasms of the respiratory tract are rarely encountered in the paediatric population. Inflammatory myofibroblastic tumour (IMT) is a rare soft tissue mesenchymal tumour but a distinct disease entity accounting for less than 1% of all primary lung tumours. We report a case of a 10-year-old boy who presented with respiratory failure and left lung collapse. On flexible fiberoptic bronchoscopy, a pedunculated mass in the lower part of the trachea originating from the left main stem bronchus was identified. The patient subsequently underwent a left-sided pneumonectomy with complete resection of the mass. The histopathological analysis was consistent with IMT. Two years of follow-up and the patient remains well.

Healthcare-associated infections among pediatric oncology patients in Pakistan: risk factors and outcome.

INTRODUCTION: Pediatric oncology patients are at increased risk of contracting healthcare-associated infections (HAIs), which are responsible for increased morbidity and mortality rates as well as treatment costs.  This study aimed to identify the frequency of HAIs among pediatric oncology patients and their outcome. METHODOLOGY: Pediatric oncology patients admitted between January 2009 and June 2010 in a pediatric ward at Aga Khan University Hospital, Karachi, Pakistan, who developed HAIs, were analyzed. RESULTS: A total of 90 HAIs were identified in 32 patients in 70 admissions. The HAI rate among pediatric oncology patients was 3.1/100 admission episodes. Bloodstream infections (63 episodes, 90.0%) were the most common, followed by urinary tract infection (two episodes, 2.9%). Gram-positive infections were seen in 54 (60%) patients, followed by Gram-negative infection in 34 (37.8%), and fungi in 2 (2.8%) cases. Coagulase negative staphylococci was the most common Gram-positive and Escherichia coli and Pseudomonas aeruginosa were most common Gram-negative infections. Mortality rate among pediatric oncology patients who developed HAIs was 12.5% (4/32). Total parental nutrition use and length of stay longer than 30 days were the identified risk factors associated with increased mortality among pediatric oncology patients who developed HAIs. CONCLUSION: We report an HAI rate among pediatric oncology patients of 3.1/100 admission episodes with a mortality rate of 12.5% in Pakistan. Further studies should be done, especially in the developing world, to identify the risk factors associated with increased mortality among pediatric oncology patients so that adequate measures can be taken to reduce the mortality among these patients.

High mobility group box 1 levels in on and off-pump cardiac surgery patients.

High mobility group box 1 (HMGB1), which has properties similar to those of proinflammatory cytokines, is released from activated immune cells and necrotic cells. It is known that cardiopulmonary bypass (CPB) induces systemic inflammation and aortic cross-clamping induces myocardial ischemia. This study was conducted to clarify whether HMGB1 is released in CPB-supported cardiac surgery in comparison to off-pump coronary artery bypass grafting (OPCAB) where CPB is not used.Nineteen adult patients undergoing cardiac surgery involving CPB (CPB group) and 5 OPCAB patients (OPCAB group) were included in this study. Plasma concentrations of proinflammatory cytokines including HMGB1 were measured before, during, and after cardiac surgery. The plasma HMGB1 level was significantly increased at one hour after aortic declamping in the CPB group and at 30 minutes after revascularization in the OPCAB group. The peak HMGB1 level was slightly higher in the CPB group than that in the OPCAB group. These values decreased toward baseline value after surgery in both groups. TNF-α and IL-1ß were not detectable throughout the study period in either group. IL-6 and IL-10 increased after aortic declamping in the CPB group and after coronary revascularizations in the OPCAB group.Based on these results, we conclude that the major factor involved in the increase in HMGB1 level might be myocardial ischemia/reperfusion during cardiac surgery. Activation of immune cells, altered tissue perfusion, and pulmonary ischemia and reperfusion could be additional factors that increase the HMGB1 level in CPB-supported cardiac surgery.

Outcome and prognostic factors seen in pediatric oncology patients admitted in PICU of a developing country.

OBJECTIVE: To evaluate the outcome and prognostic factors for oncology patients in the PICU of a tertiary care centre in a developing country. METHODS: A retrospective chart review was done to assess the outcome of children with cancer in the pediatric intensive care unit (PICU) of a developing country from January 2000 through December 2009. 74 medical records were reviewed for data regarding demographics, admitting diagnosis, Pediatric Risk of Mortality (PRISM) III score and the therapeutic modalities used. RESULTS: Of the 74 children admitted with mean age of 6.3 years (range 1-14); 53 were boys (71.6%) and 21 were girls (28.4%). Majority of the patients (37%) had hematological malignancy. The major indication for PICU admission was post-operative care (32%) followed by acute respiratory failure (24.3%), neurological complications (20.3%). The median PRISM III score was 7.0 (range 0-30). The overall mortality was 32.4% (24/74). The mean length of PICU stay was 6.3 days (ranging from 0-28 days). Seventy percent (52/74) of the children had multi organ failure (MOF). Mortality was significantly related to presence of multi-organ dysfunction syndrome and high PRISM III scores on admission and use of inotropic support with mechanical ventilation. CONCLUSIONS: The mortality in children with cancer in PICU in the present study is comparable to previous reports and is related to higher PRISM III score, presence of multiorgan dysfunction syndrome and use of ICU therapies.

Efficacy and safety of procedural sedation and analgesia by paediatric intensivist in paediatric oncology unit.

Children with cancer especially acute leukaemia undergo multiple painful procedures like bone marrow biopsy (BM) and lumber puncture (LP) for intrathecal chemotherapy during their first year of treatment. The purpose of this study is to report safety and efficacy of Procedural Sedation and Analgesia (PSA) by paediatric intensivist for oncology procedures in controlled setting in paediatric oncology unit. During 20 months, 124 children received PSA for 499 procedures. 324 LP alone, 175 BM alone and 40 combined LP and BM were done. The most common diagnosis was acute leukaemia and lymphoma. All procedures were in compliance with American Society of Anaesthesiology guidelines. A small-dose of ketamine and intermittent doses of propofol was administered intravenously until needed. No procedure was aborted due to sedation. All patients tolerated the procedure well without any major adverse events. There were few transient respiratory adverse events which resolved with minor interventions. PSA for children undergoing oncology procedures, can safely and effectively be provided by paediatric intensivist in controlled setting by using a standardized sedation protocol outside the operating room.

Surface area in children: a simple formula.

We retrospectively compared body surface area (BSA) using the Mosteller formula square root(H x (w/360)) and a simple weight-based BSA formula ([4Wkg+7]/ [90+Wkg]). The participants were 363 children who underwent cardiac surgery from 1991 to 2000. Their age ranged from 5 days to 18 years, weight ranged from 1.2 kg to 98 kg and height ranged from 38 cm to 178 cm. There was excellent correlation (r(2)=0.991) between Mosteller formula and the new formula (P < 0.001). We propose that the weight-based formula is easy to use and accurate. It can safely replace Mosteller formula and dispense the need for time-consuming calculations.

Production of reactive oxygen species in peripheral blood is increased in individuals with Helicobacter pylori infection and decreased after its eradication.

BACKGROUND: Helicobacter pylori infection has been reported to cause gastroduodenal ulcer, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. Recent studies have suggested that H. pylori infection may also associate with other diseases, including hematologic and dermatologic disorders, and cardiovascular injury, by unknown mechanisms. METHODS: Production of reactive oxygen species (ROS) was determined in peripheral blood samples from 86 patients (34 H. pylori-negative and 52 H. pylori-positive subjects) using a highly sensitive chemiluminescence probe, L-012 (8-amino-5-chloro-7-phenylpyrido(3,4-d) pyridazine-1 and 4 (2H, 3H) dione). Eleven H. pylori-positive individuals were also analyzed their ROS production in peripheral blood after H. pylori eradication. RESULTS: ROS production was significantly higher in individuals with H. pylori infection than in those without infection. Enhanced production of ROS was decreased significantly after eradication of H. pylori. No correlation was found between the extent of ROS production and sex, age, smoking status, alcohol ingestion, use of medications, or serum level of C-reactive protein. CONCLUSION: These findings suggest that ROS production was enhanced in peripheral blood by H. pylori infection. Chemiluminescence analysis of blood samples using L-012 permits evaluation of systemic oxidative stress in patients with H. pylori infection.

Lack of mitochondrial DNA enhances growth of hepatocellular carcinoma in vitro and in vivo.

To elucidate the role of mitochondrial DNA (mtDNA) in determination of growth of hepatocellular carcinoma, we examined wild-type Hepa1-6 cells and their rho(0) cells with depleted mtDNA in vitro and in vivo. Cultured rho(0) cells grew more rapidly than did wild-type cells. Production of reactive oxygen species (ROS) was higher in wild-type cells than in rho(0) cells. Hypoxia inhibited the growth of wild-type cells more markedly than that of rho(0) cells. Resistance to mitochondrial respiratory inhibitor-induced cell death was stronger in rho(0) cells than in wild-type cells. rho(0) cells subcutaneously inoculated in the hind thigh of mice grew more rapidly and formed larger solid tumors. These findings indicate that lack of mtDNA increases growth of hepatocellular carcinoma by decreasing ROS production and increasing resistance to mitochondrial respiratory inhibition.

Late presentation of alveolar capillary dysplasia in an infant.

OBJECTIVE: To report a case of late presentation of alveolar capillary dysplasia and misalignment of pulmonary veins. DESIGN: Descriptive case report. SETTING: Pediatric intensive care unit of a tertiary care children's hospital. PATIENT: Seven-week-old female infant with severe hypoxemic respiratory failure. CONCLUSION: Alveolar capillary dysplasia with misalignment of pulmonary veins is a cause of primary pulmonary hypertension in newborns that can rarely present past the newborn period. Early lung biopsy can be helpful in establishing the diagnosis and avoiding ineffective, futile, and expensive therapeutic interventions.

Mitochondrial density determines the cellular sensitivity to cisplatin-induced cell death.

We studied the relationship between the mitochondrial density in the cells and the cellular sensitivity to the toxicity of cis-diaminedichloroplatinum II (cisplatin), a potent anticancer agent. Biochemical analyses revealed that the density of mitochondria in the intestinal epithelium changed markedly along its entire length. The density was the highest at the duodenum, medium at the jejunum, and the lowest at the ileum. The sensitivity of epithelial cells to cisplatin toxicity was the highest at the duodenum, medium at the jejunum, and the lowest at the ileum as judged from the occurrence of apoptosis. Similar correlation between the cisplatin sensitivity and mitochondrial density was also observed with in vitro experiments, in which intestinal epithelial cells (IEC-6) and their rho0 cells with reduced number of mitochondria were used. The rho0 cells had a strong resistance to cisplatin compared with the control cells. Cisplatin markedly increased mitochondrial generation of reactive oxygen species in IEC-6 but not in rho0 cells. We analyzed the sensitivity of eight cell lines with different density of mitochondria to cisplatin and found the same positive correlation. These observations clearly show that cellular density of mitochondria is the key factor for the determination of the anticancer activity and side effects of cisplatin.