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Lewis Spitz

Publications and source records attributed to Lewis Spitz.

34 records · Page 2Linked to original sources
PubMed2003

Role of Sonic hedgehog in the development of the trachea and oesophagus.

BACKGROUND/PURPOSE: The secreted glycoprotein, Sonic hedgehog (Shh) plays an important patterning role in the development of many organ systems. The authors aimed to study the temporal and spatial pattern of expression of Shh and its receptor Ptc1 during the development of the anterior foregut and to test the hypothesis that the Shh expression pattern is disturbed during the development of oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) in Adriamycin-treated mouse embryos. METHODS: Saline and Adriamycin-treated (4 mg/kg) CBA/Ca embryos were harvested between embryonic days (E) 10.5 and 12.5, and Shh and Ptc1 expression was studied by whole-mount and section in situ hybridisation using digoxygenin-labelled riboprobes. RESULTS: At E10.5, saline-treated embryos had an undivided foregut in which the ventrally placed prospective tracheal epithelium was positive for Shh, whereas the dorsal part was negative. At E11.5, this pattern had reversed with the separated trachea becoming negative and the oesophagus gaining expression of Shh. Ptc1 was expressed in the mesoderm adjacent to Shh expressing endoderm at both stages. Affected Adriamycin-treated embryos had an undivided foregut at E11.5, the epithelium of which showed diffuse Shh staining that lacked the dorso-ventral patterning seen in controls. CONCLUSIONS: The reversal in the dorso-ventral pattern of Shh expression during the narrow embryologic window in which tracheo-oesophageal separation is initiated suggests that Shh may play an important role in this process. Transient disturbance of this pattern may underlie the abnormal organogenesis in the Adriamycin model.

Animals↗
PubMed2003

Body temperature and heat production in suckling rat endotoxaemia: beneficial effects of glutamine.

BACKGROUND/PURPOSE: Sepsis is an important cause of neonatal mortality. The aim of the study was to investigate the metabolism of endotoxic neonatal rats and the potential beneficial effect of glutamine. METHODS: Suckling rats received intraperitoneal saline (control; C), endotoxin (300 microg/g LPS; E), saline+glutamine (2 mmol/g; CG), endotoxin+glutamine (EG), saline+leucine (2 mmol/g; CL) or endotoxin+leucine (EL). Sepsis score (0-8) and rectal temperature were monitored. Hypothermia was defined as rectal temperature less than 32 degrees C. Oxygen consumption (VO2, mL/kg/h), a determinant of heat production, was measured by indirect calorimetry. Data (mean +/- SEM) were compared by analysis of variance (ANOVA), paired t test or Fisher's Exact test. RESULTS: Endotoxic (E) rats had significantly lower VO2 than C rats from 90 minutes postinjection to the end of the experiment, 210 minutes (VO2 from 150 to 210 minutes: C 671 +/- 45; E 429 +/- 36, P <.0004; n = 8; paired t test). VO2 of CL or CG rats was elevated between 90 and 210 minutes compared with control, but significantly (P <.01) only in the L group (C 706 +/- 31; CG 871 +/- 63; CL 984 +/- 31; n = 7-9, ANOVA). VO2 was significantly higher (P <.05) in EG rats than E rats (E 460 +/- 29; EG 654 +/- 68; n = 9-10). In the EL group, VO2 was raised but was not significantly different from E (E 460 +/- 29; EL 637 +/- 52; n = 8-10). EG rats were significantly less hypothermic between 90 and 210 minutes (58 of 132 measurements) compared with E (95 of 147; P =.0007, Fisher's Exact test), whereas the EL group were similarly hypothermic (74 of 120) to E (P =.7). Sepsis score was significantly lower in the EG group than both E and EL groups (E 4.9 +/- 0.3; EG 3.6 +/- 0.3; EL 5.0 +/- 0.3; n = 40; P <.01; ANOVA). CONCLUSIONS: Neonatal endotoxaemia lowers VO2, heat production, and body temperature. Glutamine and leucine both cause nutrient-induced thermogenesis in control animals and restore VO2 of endotoxic animals. Glutamine additionally increases rectal temperature, reduces incidence of hypothermia, and improves clinical signs of endotoxic rats. This suggests that glutamine may be beneficial for nutrition in neonatal sepsis.

Animals↗
PubMed2003

Quality of life after gastric transposition for oesophageal atresia.

BACKGROUND/PURPOSE: A small proportion of infants born with oesophageal atresia in which the gap between the 2 ends of the oesophagus is too great for an end-to-end anastomosis will require oesophageal replacement. Since 1981 the author's procedure of choice for oesophageal replacement has been gastric transposition. The long-term functional outcome appears to be satisfactory, but the quality of life of these patients has not been investigated formally. This report assesses the health-related quality of life (QOL) of 2 groups of patients born with oesophageal atresia who have undergone gastric transposition. METHODS: The study group comprised 28 patients aged 2 to 22 years who resided in England. Group 1 (n = 13), comprised patients who had undergone cervical oesophagostomy and gastrostomy without attempt at oesophageal anastomosis; group 2 (n = 15), comprised patients who had undergone previous attempts at reconstruction or replacement. QOL was assessed using modified versions of the Gastrointestinal Quality Of Life Index (GIQLI). RESULTS: QOL scores based on patients' responses showed no significant differences between the groups (124 v 119). However, the disease-specific symptom scores showed that patients in group 1 experienced fewer symptoms compared with those in group 2. Additionally, based on parental responses, patients in group 1 had higher QOL scores than those in group 2. QOL scores for patients aged 2 to 4 years (n = 5) did not differ between the groups (81 v 92, not significant). CONCLUSIONS: The quality of life for patients with oesophageal atresia undergoing gastric transposition was generally unimpaired by any side effects of gastric transposition. Patients undergoing gastric transposition as a primary procedure experienced fewer disease-specific symptoms in the medium term compared with patients who had undergone previous unsuccessful attempts at reconstruction or replacement of their oesophagus.

Adolescent↗
PubMed2003

Hypothermia throughout intestinal ischaemia-reperfusion injury attenuates lung neutrophil infiltration.

BACKGROUND/PURPOSE: Secondary organ damage to the lungs is an important consequence of intestinal ischaemia reperfusion (IIR) injury. Moderate hypothermia ameliorates gut necrosis and liver energy failure after IIR but potential beneficial effects on lung neutrophil infiltration after reperfusion of ischaemic bowel have not been investigated. METHODS: Adult Sprague-Dawley rats underwent 60 minutes intestinal ischaemia followed by 120 minutes of reperfusion. The animals were maintained at either normothermia (36 degrees to 38 degrees C) or moderate hypothermia (30 degrees to 32 degrees C). Four groups were studied: (A) sham normothermia; (B) IIR normothermia; (C) sham hypothermia; and (D) IIR hypothermia. Lungs and terminal ileum were removed for measurement of myeloperoxidase activity (a marker of neutrophil infiltration). Results are expressed as milliunits per milligrams protein, mean +/- SEM, and one-way analysis of variance (ANOVA) with Tukey post-test was used for group comparisons. RESULTS: Lungs: IIR at normothermia significantly increased lung neutrophil infiltration assessed by myeloperoxidase activity compared with sham-operated controls (normothermia sham 4.6 +/- 1.0, n = 8; normothermia IIR 37.7 +/- 13.8, n = 8; P =.011). Moderate hypothermia during IIR significantly attenuated lung neutrophil infiltration (7.2 +/- 2.1, n = 9) compared with normothermia IIR (P =.016) such that myeloperoxidase activity was similar to that found in sham normothermia (4.6 +/- 1.0, n = 8) and sham hypothermia (3.1 +/- 1.3, n = 8). Intestine: Gut myeloperoxidase activity was 0.9 +/- 0.5 in sham normothermia (n = 9) and 2.3 +/- 0.6 after normothermic IIR (n = 8). After IIR at hypothermia gut myeloperoxidase activity (0.5 +/- 0.2; n = 8) was significantly less than normothermic IIR (P =.035) and higher than sham hypothermia (0.2 +/- 0.1, n = 9; P =.01). CONCLUSIONS: These results indicate that moderate hypothermia may prevent damage to another distant organ, ie the lungs, by preventing recruitment of neutrophils. This may be of benefit in decreasing distal organ damage in diseases in which intestinal ischaemia-reperfusion is implicated in the pathogenesis.

Animals↗
PubMed2003

Carbon dioxide elimination during laparoscopy in children is age dependent.

UNLABELLED: The absorption of carbon dioxide (CO2) used for positive pressure pneumoperitoneum may lead to an increased CO2 load. CO2 elimination during laparoscopy has not been investigated previously in paediatrics. The aim of this study was to characterise the pattern of CO2 elimination during laparoscopic surgery in infants and children. METHODS: Twenty children undergoing laparoscopy and 19 children undergoing laparotomy for elective abdominal operations were studied. Pneumoperitoneum was achieved using insufflation of unheated CO2. CO2 elimination (metabolically produced + absorbed; milliliters per kilogram per minute) was measured minute by minute during the operation by indirect calorimetry. End-tidal CO2 (kPa) was recorded every 10 minutes. The above variables were assessed before CO2 insufflation, during pneumoperitoneum, and after desufflation. RESULTS: Before insufflation, CO2 elimination was 4.6 +/- 0.3 ml/kg/min and increased after 15 minutes of pneumoperitoneum to 5.2 +/- 0.3 (P <.001). Post desufflation, CO2 elimination decreased toward preinsufflation values, but did not return to baseline by the end of operation (5.8 +/- 0.3; P <.001). End-tidal CO2 was 4.7 +/- 0.2 preinsufflation, peaked at 1 hour (5.3 +/- 0.2; P <.001) and subsequently decreased in response to ventilatory adjustments. The total amount of CO2 insufflated was positively correlated with patient age (r2 = 0.27; P <.01). CO2 elimination was age related, as indicated by multilevel model analysis and by negative correlations between maximum increase in CO2 elimination and both age (r2 = 0.27; P <.01) and weight (r2 = 0.29; P <.01). These data suggest that the younger or smaller the child, the larger the increase in CO2 elimination. Seven patients (35%) responded to desufflation with a sharp transient increase in CO2 elimination, which did not appear to be related to patient age, length of pneumoperitoneum, abdominal pressure, or type of operation. CONCLUSIONS: During pneumoperitoneum, younger children absorb proportionately more CO2 than older individuals. The short-lived increase in CO2 elimination postdesufflation may be related to an increase in venous return from the lower limbs after release of the abdominal pressure. These findings suggest that small children warrant close monitoring during laparoscopy and during the immediate postoperative period.

Adolescent↗
PubMed2003

Is intralesional injection of OK-432 effective in the treatment of lymphangioma in children?

BACKGROUND: Intralesional injection of OK-432 has been proposed as an effective treatment of lymphangioma. The aim of this study was to review our experience with OK-432 injection of lymphangioma and to identify factors associated with successful outcome. METHODS: We made a case note review of 19 children who received OK-432 injection. Median duration of follow-up was 17 months. RESULTS: Lesions were diagnosed antenatally in 4 children, at birth in 4 children, and between 1 month and 11 years in the remainder. Anatomic locations were head/neck in 14, axilla in 1, and multiple locations in 4. Median number of injections per child was 2 (range, 1 to 5). Disappearance of the lesion was achieved after OK-432 injection in 2 patients (11%) and a marked reduction in 5 (26%); all these lesions were in the head and neck. Lesions larger than 5 cm and those outside the head and neck region did not respond well to OK-432 injection. Fourteen children (74%) required surgical excision after injection. Complications of OK-432 injection included partial tracheal obstruction, fever, local inflammatory response, and abscess formation. CONCLUSIONS: OK-432 injection was effective in approximately one third of children with lymphangioma. Lesions outside the head and neck and those larger than 5 cm are unlikely to respond to this therapy. Injection of lymphangioma surrounding the airways may be hazardous.

Antineoplastic Agents↗
PubMed2002

Gastrostomy feeding in infants and children on peritoneal dialysis.

The majority of infants and young children on peritoneal dialysis (PD) require enteral feeding to achieve their growth potential. We report our experience of gastrostomy feeding in 29 children on PD over 11 years. Fifteen children, median age 3.9 (0.5-13.3) years had a percutaneous gastrostomy (PEG) or Nissen fundoplication and gastrostomy (N and G) or open gastrostomy (OG) before starting PD (group1). Nine children, age 0.7 (0.5-12.4) years, had a N and G or OG (group 2) and 5, age 5.1 (1-15.1) years, a PEG (group 3) after PD catheter insertion/start of PD. In group 1 (257 months gastrostomy feeding with PD), there were 0.6 episodes of peritonitis/patient year. Nine PEGs were replaced electively after 27 (19-50) months, with bleeding from an embedded flange the only complication. One PEG replaced by a button ruptured the track, causing Candida peritonitis. In group 2 (130 months G and PD), there were 1.4 episodes of peritonitis/patient year. Two children developed paraoesophageal hernias, which were successfully repaired. Four children in group 3 developed peritonitis soon after PEG placement. Two transferred to haemodialysis, 1 remained on PD after treatment of Candida peritonitis and 1 subsequently died. Only 2 of the 17 children who have had renal transplants still need gastrostomy feeds. We recommend placement of a PEG or OG if an anti-reflux procedure is necessary prior to starting PD. Placement of a PEG while on PD is contraindicated, but an OG is a safe alternative procedure.

Bacterial Infections↗
PubMed2002

Hepatic glutamine metabolism during endotoxemia in neonatal rats.

OBJECTIVES: The liver plays a central role during endotoxemia. We investigated the biochemical changes that occur in neonatal liver during early stages of endotoxemia. METHODS: Twenty neonatal rats (10 to 15 d; n = 10/group) were studied. Endotoxemic rats received intraperitoneal injections of 300 microg/kg of 12.5 mg/L of lipopolysaccharide and control rats received isovolemic normal saline. Two hours after injection, all lipopolysaccharide-injected animals exhibited signs of endotoxemia. Livers were removed and extracted into 12% perchloric acid. 1H and 31P magnetic resonance spectroscopy measured hepatic levels of glutamine, glutamate, alanine, lactate, glucose, beta-hydroxybutyrate, adenosine triphosphate, and adenosine diphosphate. Unpaired t test compared groups. RESULTS: No mortality occurred during the first 2 h after injection. Endotoxemia significantly decreased hepatic levels of glutamine (P < 0.001), glucose (P = 0.047), and beta-hydroxybutyrate (P < 0.001). There was no difference in hepatic levels of glutamate (P = 0.050), alanine (P = 0.165), lactate (P = 0.478), adenosine triphosphate (P = 0.165), and adenosine diphosphate (P = 0.136) between groups. CONCLUSIONS: Early endotoxemia caused significant changes in the hepatic metabolism of glutamine, glucose, and beta-hydroxybutyrate. These findings increase our understanding of the pathophysiology of neonatal endotoxemia.

Animals↗
PubMed2002

Fatty acid oxidation in neonatal hepatocytes: effects of sepsis and glutamine.

OBJECTIVE: Little is known about fat use during sepsis during the neonatal period. Intramitochondrial O(2) consumption is inhibited in isolated hepatocytes from suckling septic rats and this impairment is reversed by glutamine. We investigated the effect of neonatal sepsis on fat oxidation and whether glutamine can directly affect fatty acid oxidation. METHODS: Suckling Wistar rats (11 d) received an intraperitoneal injection of 300 microg/kg of lipopolysaccharide (Escherichia coli 055:B5); controls received normal saline. At 2 h, hepatocytes were isolated. Hepatocytes were incubated at 37 degrees C with 0.5 mM [1-(14)C]palmitate or 0.5 mM [1-(14)C]palmitate plus 10 mM glutamine. After 1 h, the perchloric acid-soluble (14)C-radioactivity (representing mainly ketone bodies) and (14)CO(2) were measured. Hepatocyte O(2) consumption from 0.5 mM palmitate was measured with and without 2.5 ng/mL myxothiazol to estimate intramitochondrial O(2) consumption. RESULTS: There were no significant differences in fatty acid oxidation between control and endotoxemic hepatocytes measured as acid-soluble radioactivity (which represents mainly ketogenesis, plus Krebs cycle intermediates), as (14)CO(2) production, or as the sum of acid-soluble radioactivity plus (14)CO(2) generation. Glutamine significantly increased fatty acid oxidation (acid-soluble radioactivity plus (14)CO(2)) in hepatocytes from control and endotoxic animals. CONCLUSIONS: The finding of no significant difference in fatty acid oxidation between hepatocytes from control and endotoxemic rats is surprising given that intramitochondrial O(2) consumption from palmitate is decreased. This may reflect altered use of acetyl-coenzyme A to ketone bodies and Krebs cycle intermediates. Glutamine enhanced fatty acid oxidation from control and endotoxemic hepatocytes, suggesting that it may promote substrate oxidation during endotoxemia.

Animals↗
PubMed2002

Dorsoventral patterning in oesophageal atresia with tracheo-oesophageal fistula: Evidence from a new mouse model.

BACKGROUND/PURPOSE: The well-established Adriamycin rat model of oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) complements recently described mouse genetic models in which loss of function mutations in foregut patterning genes, such as Nkx2.1 (Ttf 1), lead to OA/TOF. The authors aimed to integrate the 2 systems by adapting the Adriamycin model to the mouse to study molecular aspects of tracheo-oesophageal development. METHODS: Pregnant CBA/Ca mice were injected intraperitoneally with 4 mg/kg of Adriamycin on embryonic days 7.5 and 8.5. Embryos and fetuses of various gestational ages were subjected to morphologic or histologic examination. Sections were stained with H & E or processed for immunohistochemistry using an antibody specific for Nkx2.1. RESULTS: Tracheo-oesophageal malformations were observed in 47% of Adriamycin-treated embryos. Early foregut development was similar in Adriamycin-exposed and control embryos but, by E11.5, many treated embryos had an undivided oesophago-trachea, which gave rise to the lung buds and a fistula to the stomach. The fistula originated from the dorsal aspect of the undivided tube and was negative for Nkx2.1, or showed only transient Nkx2.1 expression, compared to the strongly positive bronchi ventrally. CONCLUSIONS: The Adriamycin model of OA is adaptable to the mouse. In the absence of tracheo-oesophageal separation, the dorsal fistula retains its nonrespiratory commitment suggesting that dorsoventral patterning of foregut development is undisturbed by Adriamycin exposure.

Animals↗
PubMed2002

Differential effects of neonatal endotoxemia on heart and kidney carnitine palmitoyl transferase I.

BACKGROUND/PURPOSE: The heart and kidney are both affected in sepsis-related multiple organ failure. Both utilize fatty acid substrates during the neonatal period, and impairment of oxidative metabolism during sepsis could lead to bioenergetic failure. The enzyme carnitine palmitoyl transferase I (CPT I) is important in the control of fat oxidation in the neonatal period. The aim of this study was to determine the effects of sepsis on neonatal cardiac and renal CPT I. METHODS: Suckling rats received 300 microgram/kg lipopolysaccharide intraperitoneally. Mitochondria were isolated from the heart and kidney after 2 hours. CPT I and II activity were measured radiochemically. Protein levels of M- and L- isoforms of CPT I, both of which are present in heart, were determined by Western blotting. RESULTS: CPT I activity was decreased significantly in the heart but not in the kidney by endotoxemia, whereas CPT II activity was the same in each organ. To investigate the mechanism of this decrease, we carried out Western blotting of the CPT I isoforms in heart mitochondria. Neither M- nor L- isoform was decreased in amount. To determine whether free-radical attack could directly inhibit CPT I activity, control heart mitochondria were incubated with free-radical generating systems. Although hydrogen peroxide had no effect on CPT I activity, the reactive oxygen species nitric oxide, superoxide, and peroxynitrite, all of which are generated in the heart during sepsis, significantly inhibited CPT I activity. CONCLUSIONS: The activity of CPT I, a rate-controlling step of fat oxidation, is significantly impaired in heart but not in kidney during neonatal sepsis. This may be caused by direct attack by free radicals, suggesting that antioxidant strategies could be of use in preventing sepsis-related cardiac damage.

Animals↗
PubMed2002

Intestinal energy metabolism after ischemia-reperfusion: Effects of moderate hypothermia and perfluorocarbons.

PURPOSE: This study investigated the roles of moderate hypothermia and extraluminal oxygenated perfluorcarbon (PFC) on intestinal metabolism after ischemia-reperfusion. METHODS: A model of 30-minute intestinal ischemia followed by 60 minutes of reperfusion was used. The animals were maintained at either normothermia (36.5 to 37.5 degrees C) or moderate hypothermia (31 to 32 degrees C). Four groups of adult rats were studied (n = 8 per group): (A) sham at normothermia, (B) ischemia-reperfusion at normothermia, (C) ischemia-reperfusion at hypothermia and, (D) ischemia-reperfusion with extraluminal oxygenated PFC perfusion during ischemia at normothermia. Intestinal phosphocreatine, ATP and lactate levels were measured. Histologic changes in the intestine were evaluated. RESULTS: Intestinal ischemia-reperfusion at normothermia caused a marked reduction in phosphocreatine and ATP with an increase in lactate. Moderate hypothermia exerted beneficial effects by attenuating the depletion of high-energy phosphates and the elevation of lactate. Extraluminal PFC perfusion during ischemia failed to produce a protective effect on high-energy phosphates, although it reduced lactate accumulation. Moderate hypothermia significantly decreased the degree of mucosal damage. CONCLUSIONS: Whole-body moderate hypothermia protects the small intestine from reperfusion injury as measured both biochemically and histologically. Extraluminal oxygenated PFC administration during ischemia did not protect the intestine from reperfusion injury in this model.

Adenosine Triphosphate↗