This paper explores the evolution over time in the marginal effects of age and education on moonlighting in Canada using the Labour Force Survey public-use files for the 1987/88, 1998/99, 2005/06, and 2013/14 periods. A discrete choice model is estimated by gender for the full sample and separately for each period. I find that the marginal effects of college and university education are larger in the later sample periods. The results also show significant differences across gender.

P eliosis is characterized by blood-filled cavities with an incomplete endothelial lining and can present with cholestasis, acute liver failure, or liver rupture. We present a case of neonatal peliosis likely secondary to maternal pesticide ingestion, causing liver failure, and requiring transplant. The patient was the product of an induced delivery at 35 weeks’ gestation because of severe intrauterine growth restriction and oligohydramnios. He was the fourth child of Vietnamese parents. The mother did not smoke, drink alcohol, or use illicit drugs. Standard prenatal serological tests were negative. Family history revealed absence of consanguinity and absence of liver and renal diseases. Parents had a history of positive tuberculosis skin tests, but normal chest x-rays. The patient was transferred after birth to a pediatric hospital for progressive cholestasis. Maximum bilirubin levels were 341 and 19 (total and conjugated) before transfer. He received phototherapy from day 3 to 5 of life. On physical examination, birth weight was

We describe the case of a 10 years old true hermaphrodite in which a scrotal müllerian derivative and ovarian and testicular tissue within the same gonad were detected preoperatively by ultrasound.

Lipoprotein assembly is critical for the intestinal absorption of dietary lipids and of fat-soluble vitamins. Through their inhibition of chylomicron secretion, mutations of the Sar1B gene coding for Sar1 GTPase are associated with chylomicron retention disease (CRD). The aim of this study was to describe the phenotypic expression of CRD in two clinically and genetically well characterized cohorts, and to compare their long term evolution. The study in 7 children from France (X¯ age 11.3±1.7years) and 9 from Quebec, Canada (X¯ age 12±2.5years) involved data collection from medical records for growth evaluation, neurological and ophthalmological status as well as bone density over an average follow-up period of 4.9years for the French cohort and of 10.6years for the Canadian one. All CRD patients presented within the first few months of life with diarrhea and failure to thrive. Severe hypocholesterolemia coupled with normal triglycerides was associated with low LDL and HDL-cholesterol, as well as with low apolipoproteins A-I and B. Varying degrees of essential fatty acid and of vitamin E deficiency were observed. The earlier diagnosis in the Canadian cohort (1.3±0.04years) than in the French one (6.3±1.3years) was unrelated with the severity of presenting symptoms. The fact that the disease had more impact on growth and bone density in the latter group may be related to delayed diagnosis of the disease. Vitamin E deficiency led to functional neurological and ophthalmic changes in a small number of patients but only one developed areflexia. Finally, genotype–phenotype correlation is not obvious in our cohort with CRD; even if, the Canadian subjects with the allele 409G>A had a more severe degree (P<0.001) of hypocholesterolemia than the other patients, many clinical data are inconsistent with a hypothetical genotype–phenotype correlation. This study provides new insights on the phenotypic expression of CRD over time and emphasizes the need to screen the lipid profile of infants with chronic diarrhea and failure to thrive.

Mitochondrial diseases are a heterogeneous group of energy metabolism disorders that can affect almost any organ.1Munnich A. Rötig A. Chretien D. Saudubray J.M. Cormier V. Rustin P. Clinical presentations and laboratory investigations in respiratory chain deficiency.Eur J Pediatr. 1996; 155: 262-274Crossref PubMed Scopus (157) Google Scholar Kidney disease is well-known in patients with mitochondrial disorders, most commonly manifesting as proximal tubulopathy with chronic tubular acidosis, typically a minor feature in pediatric patients with severe involvement of brain, liver, heart, or other organs.2Niaudet P. Rötig A. The kidney in mitochondrial cytopathies.Kidney Int. 1997; 51: 1000-1007Crossref PubMed Scopus (81) Google Scholar, 3Rötig A. Renal diseases and mitochondrial genetics.J Nephrol. 2003; 16: 286-292PubMed Google Scholar, 4Martin-Hernandez E. Garcia-Silva M.T. Vara J. et al.Renal pathology in children with mitochondrial diseases.Pediatr Nephrol. 2005; 20: 1299-1305Crossref PubMed Scopus (92) Google Scholar, 5Neiberger R.E. George J.C. Perkins L.A. Theriaque D.W. Hutson A.D. Stacpoole P.W. Renal manifestations of congenital lactic acidosis.Am J Kidney Dis. 2002; 39: 12-23Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Other renal presentations include chronic tubulointerstitial nephropathy,6Szabolcs M.J. Seigle R. Shanske S. Bonilla E. DiMauro S. D'Agati V. Mitochondrial DNA deletion: A cause of chronic tubulointerstitial nephropathy.Kidney Int. 1994; 58: 1388-1396Crossref Scopus (86) Google Scholar, 7Rötig A. Goutières F. Niaudet P. et al.Deletion of mitochondrial DNA in patient with chronic tubulointerstitial nephritis.J Pediatr. 1995; 126: 597-601Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar progressive glomerular diseases,8Jansen J.J. Maassen J.A. Van der Woude F.J. et al.Mutation in mitochondrial tRNAleu(UUR) gene associated with progressive kidney disease.J Am Soc Nephrol. 1997; 8: 1118-1124PubMed Google Scholar, 9Hotta O. Inoue C.N. Miyabayashi S. Furuta T. Takeuchi A. Taguma Y. Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation.Kidney Int. 2001; 59: 1236-1243Crossref PubMed Scopus (121) Google Scholar and nephrotic syndrome.10Goldenberg A. Huynh Ngoc L. Thouret M.C. et al.Respiratory chain deficiency presenting as congenital nephrotic syndrome.Pediatr Nephrol. 2005; 20: 465-469Crossref PubMed Scopus (36) Google Scholar Acute, severe, and fluctuant tubular dysfunction has not been previously described. A girl born to first-cousin Turkish parents was admitted at age 2 weeks for failure to thrive, tachypnea, and fever. Blood chemistry results were as follows: pH, 7.07; Pco2, 57.6 mm Hg; bicarbonate, 16 mEq/L (mmol/L); anion gap, 16 mEq/L (mmol/L); lactate, 74 mg/dL (8.27 mmol/L; normal, <20 mg/dL); and lactate-pyruvate molar ratio, 41.9 (normal, <17). She received antibiotics for suspected sepsis. Acid-base status thereafter normalized. Plasma phosphorus level was 6.9 mg/dL (2.3 mmol/L), and tubular reabsorption of phosphate was 91%. The patient was readmitted at 4 months for fever. Blood chemistry showed pH of 7.19; Pco2 of 43.2 mm Hg; bicarbonate of 15.3 mEq/L (mmol/L); anion gap of 10.1 mEq/L (mmol/L); and lactate level of 17.7 mg/dL (1.97 mmol/L). Urinary pH was 6.0 and glycosuria was absent. Renal tubular acidosis was suspected and bicarbonate was administered. Psychomotor delay and neurosensory deafness were documented, and she required nasogastric tube feeding. Because of multisystemic involvement, a mitochondrial disease was suspected, and at 7 months, the patient was electively admitted for investigations. Blood analyses showed the following values: pH, 7.33; Pco2, 39 mm Hg; bicarbonate, 22.0 mEq/L (mmol/L); and anion gap, 12.0 mEq/L (mmol/L). Urinary pH was 8.0, and there was generalized aminoaciduria without glycosuria (Fig 1A). Plasma phosphorus level was 3.3 mg/dL (1.10 mmol/L; normal, 1.45 to 2.1 mmol/L), and tubular reabsorption of phosphate was 72%. Muscle biopsy results were normal, but liver showed marked mitochondrial proliferation and ultrastructural anomalies. At 1 year, the patient was readmitted for fever. Blood analysis results were as follows: pH, 7.35; Pco2, 26.2 mm Hg; bicarbonate, 14.4 mEq/L (mmol/L); anion gap, 15.6 mEq/L (mmol/L); and lactate, 40 mg/dL (4.44 mmol/L). Urinary pH was 6.0, and glycosuria showed glucose of 252 mg/dL (14 mmol/L). Bicarbonate administration was transiently doubled. Two weeks later, electrolyte imbalances resolved, and she returned to her previous level of bicarbonate supplementation. At this age, renal investigations repeatedly showed generalized aminoaciduria, normoglycemic glycosuria (glucose, 180 mg/dL [10 mmol/L]), proteinuria (protein, 0.12 g/dL [1.19 g/L]), hypophosphatemia (phosphate, 1.5 mg/dL [0.5 mmol/L]), low tubular reabsorption of phosphate (52%), hypercalciuria (urinary calcium-creatinine ratio, 5.96), and mild nephrocalcinosis. Blood pH was 7.31, plasma bicarbonate level was 19 mEq/L (mmol/L), and urinary pH was 7.0. Plasma creatinine level was 0.2 mg/dL (18 μmol/L), and glomerular filtration rate measured by using creatinine clearance was 110 mL/min/1.73 m2 (1.83 mL/s/1.73 m2). Phosphorus was administered. At 15 months, another major metabolic crisis occurred. Initial laboratory values were pH, 7.11; Pco2, 31 mm Hg; bicarbonate, 11 mEq/L (mmol/L); anion gap, 14 mEq/L (mmol/L); lactate, 62 mg/dL (6.88 mmol/L); and urinary pH, 7.0. Bicarbonate requirements increased 10-fold (to 22 mEq [mmol]/kg/d intravenously), and phosphorus, to 95 mg/kg/d (Fig 2A). Glycosuria exceeded 1 g/L (>55 mmol/L). Unexpectedly, tubular losses improved and all electrolyte supplements were stopped within 5 weeks. For 5 additional weeks, mean plasma bicarbonate and phosphorus concentrations were 24.8 ± 1.9 (SD) mEq/L (mmol/L) and 5.1 ± 0.3 mg/dL (1.7 ± 0.1 mmol/L), respectively. Glycosuria disappeared. Hypophosphatemia and acidosis recurred thereafter, with intermittent glycosuria (glucose, 0 to 100 mg/dL [0 to 5 mmol/L]), and supplementations were reintroduced (Fig 1A). The patient had severe encephalopathy and developed hypsarrhythmia and sideroblastic anemia requiring multiple transfusions. At 21 months, the patient was admitted for vomiting and fever and rapidly developed profound metabolic acidosis uncontrolled by bicarbonate infusion. Lactic acidemia increased to 315 mg/dL (35 mmol/L), and she died of multiple organ failure. Autopsy included muscle and kidney biopsies performed 1 hour postmortem. Muscle was normal, but proximal tubular cells showed massive mitochondrial proliferation (Fig 3A). This girl born to unrelated French-Canadian parents at 35 weeks of gestation was admitted at age 2 months for irritability and poor weight gain. Blood analysis showed the following values: pH, 7.42; Pco2, 26 mm Hg; bicarbonate, 17.0 mEq/L (mmol/L); anion gap, 11 mEq/L (mmol/L); lactate, 70 mg/dL (7.73 mmol/L), and lactate-pyruvate ratio, 40.6. Glycosuria and aminoaciduria were absent. Nasogastric tube feeding was introduced and bicarbonate was administered (Fig 1B). At age 9 months, serum creatinine level was 0.73 mg/dL (65 μmol/L), and isotopic glomerular filtration rate was 42 mL/min/1.73 m2 (0.70 mL/s/1.73 m2). Urinalysis showed normoglycemic glycosuria (glucose, 100 mg/dL [5.5 mmol/L]), proteinuria (protein, 0.63 g/L), pH of 7, and generalized aminoaciduria. Plasma phosphorus concentration was normal (4.5 mg/dL [1.50 mmol/L]), and plasma bicarbonate level was 20 mEq/L (mmol/L). Renal biopsy at 9 months, normal by means of light microscopy, showed mitochondrial proliferation and abnormalities by electron microscopy in proximal tubular cells (Fig 3B). During the following months, bicarbonate supplementation was increased to 7 mEq (mmol)/kg/d, but growth remained impaired. She walked unaided at 16 months and language development was normal. At 30 months, the patient presented with a severe acidotic crisis requiring continuous intravenous bicarbonate infusion (up to 33 mEq [mmol]/kg/24 h) for nearly 1 month (Fig 2B). At admission, she was polypneic and mildly dehydrated (weight loss < 3%). Laboratory values were as follows: pH, 7.07; Pco2, 26.9 mm Hg, bicarbonate, 3.3 mEq/L (mmol/L); lactate 195 mg/dL (21.7 mmol/L); anion gap, 23.7 mEq/L (mmol/L); and glucose, 150 mg/dL (8.3 mmol/L). Urinalysis showed pH 5.0, glycosuria with glucose of 252 mg/dL (14 mmol/L), and proteinuria with protein of 0.10 g/dL (1 g/L). There were no neurological signs, and after an initial period of hydration and bicarbonate infusion, she appeared clinically well, energetic, and in no distress. Bicarbonate administration was progressively decreased over 4 weeks to 6 mEq (mmol)/kg/d orally. She had a milder acidotic episode at age 4 years, but none thereafter. Chronic renal failure has progressively developed (Fig 1B). In the last 6 months, plasma phosphorus level decreased, with tubular reabsorption of phosphate of 50% and radiological evidence of early rickets. At 11 years, renal evaluation shows proteinuria with protein of 0.15 g/dL (1.48 g/L), massive aminoaciduria and glycosuria (glucose > 1 g/L), plasma creatinine level of 2.34 mg/dL (207 μmol/L), and creatinine clearance of 29.2 mL/min/1.73 m2 (0.03 mL/s/1.73 m2). She receives phosphorus and 1,25-hydoxyvitamin D3. Of note, development and neurological examination findings are normal. Respiratory chain enzyme activities were measured in fibroblasts and liver as reported.11Carter S.L. Rennie C.D. Hamilton S.J. Changes in skeletal muscle in males and females following endurance training.Can J Physiol Pharmacol. 2001; 79: 386-389Crossref PubMed Scopus (166) Google Scholar, 12Cameron J.M. Levandovskiy V. MacKay N. Robinson B.H. Respiratory chain analysis of skin fibroblasts in mitochondrial disease.Mitochondrion. 2004; 4: 387-394Crossref PubMed Scopus (23) Google Scholar Blue native gel studies were performed in fibroblast and liver, as described.13Nijtmans L.G.J. Henderson N.S. Holt I.J. Blue native electrophoresis to study mitochondrial and other protein complexes.Methods. 2002; 26: 327-334Crossref PubMed Scopus (319) Google Scholar Spectrophotometric assays showed complex IV deficiency in the liver of patient 1 (0.2 μmoles of reduced cytochrome c per gram of wet weight tissue per minute; controls, 0.6 to 2.4). Blue native gel studies confirmed decreased levels of complex IV in the liver of patient 1 and showed deficiency of complex I in fibroblasts of patient 2 (not shown). Metabolic parameters and tubular function were assessed from the patients' medical charts. The clinical course was divided into periods during which parameters of tubular function remained constant, shown in Fig 1. Major changes in treatment, such as initiation or cessation of electrolyte supplementation, were used to define new periods. Acute acidotic episodes are presented chronologically (Fig 2). Both patients fulfilled the diagnostic criteria of Fanconi syndrome: aminoaciduria, normoglycemic glycosuria, chronic tubular acidosis, and impaired renal phosphate reabsorption. In stable periods, when the patients were acidotic, urinary pH was appropriate for the level of acidosis, indicating preserved distal tubular acidifying capacity. Conversely, in other instances, alkaline urine was observed with normal plasma bicarbonate levels, suggesting a proximal origin of tubular acidosis. In addition to chronic tubulopathy, both experienced major acidotic crises requiring massive bicarbonate administration (up to 22 and 33 mEq/kg/d). Without consideration of renal function, such episodes might falsely be attributed solely to hyperlactatemia. Although lactic acid levels increased during episodes and contributed to the metabolic acidosis, anion gaps remained normal or only modestly increased, indicating that in the absence of digestive losses, acidosis most probably was related to renal tubular dysfunction. Taken together with other signs of proximal tubulopathy, the huge amount of bicarbonate required to maintain acid-base equilibrium and observation of alkaline urine at admission of crisis in patient 1 suggest that acidotic crises were caused by renal bicarbonate losses. In patients with mitochondrial diseases, tubulopathy is often considered a biological marker of little clinical significance, but this report shows that acute tubular failure can be life threatening. In patients with Fanconi syndrome, tubular losses generally are considered fairly constant.14Brodehl J. The Fanconi syndrome.in: Edelman Pediatric Kidney Disease. Little, Brown, Boston, MA1996: 1841-1871Google Scholar In addition to acidotic crises, patient 1 had transient phosphaturia and glycosuria that resolved in parallel with the tubular acidosis. Patient 2 presented with very late-onset hypophosphatemic rickets, unusual in patients with Fanconi syndrome and particularly surprising regarding her chronic renal failure. Mitochondrial diseases should be considered in patients with atypical Fanconi syndromes and unexplained multiple tubular dysfunctions. The reported spectrum of renal disease in patients with mitochondrial diseases is listed in Table 1, with usual age at presentation, occurrence of extrarenal symptoms, and biochemical or molecular findings. End-stage renal failure is rare in patients with mitochondrial diseases. In 39 patients with mitochondrial disease and tubulopathy, only 2 had moderate renal failure.2Niaudet P. Rötig A. The kidney in mitochondrial cytopathies.Kidney Int. 1997; 51: 1000-1007Crossref PubMed Scopus (81) Google Scholar In another prospective study, none of 35 patients had serum creatinine levels greater than 0.8 mg/dL (>71 μmol/L).5Neiberger R.E. George J.C. Perkins L.A. Theriaque D.W. Hutson A.D. Stacpoole P.W. Renal manifestations of congenital lactic acidosis.Am J Kidney Dis. 2002; 39: 12-23Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar Chronic renal failure was described in a patient with mitochondrial diseases and tubulointerstitial nephritis without tubulopathy.7Rötig A. Goutières F. Niaudet P. et al.Deletion of mitochondrial DNA in patient with chronic tubulointerstitial nephritis.J Pediatr. 1995; 126: 597-601Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Mitochondrial DNA mutations can cause segmental glomerulosclerosis,8Jansen J.J. Maassen J.A. Van der Woude F.J. et al.Mutation in mitochondrial tRNAleu(UUR) gene associated with progressive kidney disease.J Am Soc Nephrol. 1997; 8: 1118-1124PubMed Google Scholar leading to end-stage renal failure.9Hotta O. Inoue C.N. Miyabayashi S. Furuta T. Takeuchi A. Taguma Y. Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation.Kidney Int. 2001; 59: 1236-1243Crossref PubMed Scopus (121) Google Scholar In these cases, renal insufficiency manifested later than in our patient 2, and without tubulopathy. The kidney biopsy of patient 2 was performed at age 9 months, and her current glomerular histological state is unknown. Patient 2 shows that mitochondrial diseases can present as a primary renal disease without neurological, hepatic, or cardiac involvement. She also shows that chronic renal failure, rare in patients with mitochondrial diseases, can become the major problem of some patients.Table 1Renal Manifestations of Mitochondrial DisordersKidney InvolvementAgeExtrarenal SymptomsBiochemical/Molecular DiagnosisReferenceTubulopathy Renal tubular acidosis or Fanconi syndromeI, CNeurological disease, multivisceral involvementNumerous isolated respiratory chain deficiencies (complexes I, II, III, IV)1Munnich A. Rötig A. Chretien D. Saudubray J.M. Cormier V. Rustin P. Clinical presentations and laboratory investigations in respiratory chain deficiency.Eur J Pediatr. 1996; 155: 262-274Crossref PubMed Scopus (157) Google Scholar, 2Niaudet P. Rötig A. The kidney in mitochondrial cytopathies.Kidney Int. 1997; 51: 1000-1007Crossref PubMed Scopus (81) Google Scholar, 3Rötig A. Renal diseases and mitochondrial genetics.J Nephrol. 2003; 16: 286-292PubMed Google Scholar, 4Martin-Hernandez E. Garcia-Silva M.T. Vara J. et al.Renal pathology in children with mitochondrial diseases.Pediatr Nephrol. 2005; 20: 1299-1305Crossref PubMed Scopus (92) Google Scholar, 5Neiberger R.E. George J.C. Perkins L.A. Theriaque D.W. Hutson A.D. Stacpoole P.W. Renal manifestations of congenital lactic acidosis.Am J Kidney Dis. 2002; 39: 12-23Abstract Full Text Full Text PDF PubMed Scopus (14) Google ScholarINeurological and liver diseaseComplex III deficiency, BCS1L mutation15de Lonlay P. Valnot I. Barrientos A. et al.A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure.Nat Genet. 2001; 29: 57-60Crossref PubMed Scopus (274) Google ScholarI, CNeurological diseaseComplex IV deficiency, COX10 mutation16Valnot I. von Kleist-Retzow J.C. Barrientos A. et al.A mutation in the human heme A:farnesyltransferase gene (COX10) causes cytochrome c oxidase deficiency.Hum Mol Genet. 2000; 9: 1245-1249Crossref PubMed Scopus (262) Google ScholarISideroblastic anemia, exocrine pancreas dysfunctionPearson marrow syndrome (mtDNA large deletion)17Rötig A. Cormier V. Blanche S. et al.Pearson's marrow-pancreas syndrome A multisystem mitochondrial disorder in infancy.J Clin Invest. 1990; 86: 1601-1608Crossref PubMed Scopus (412) Google ScholarAdolNeurological disease, pigmentary retinopathy, cardiopathy (heart block)Kearns Sayre syndrome (mtDNA large deletion)2Niaudet P. Rötig A. The kidney in mitochondrial cytopathies.Kidney Int. 1997; 51: 1000-1007Crossref PubMed Scopus (81) Google ScholarTubulointerstitial nephropathyC, AdolNone or late-onset neurological diseaseMt DNA large deletion6Szabolcs M.J. Seigle R. Shanske S. Bonilla E. DiMauro S. D'Agati V. Mitochondrial DNA deletion: A cause of chronic tubulointerstitial nephropathy.Kidney Int. 1994; 58: 1388-1396Crossref Scopus (86) Google Scholar, 7Rötig A. Goutières F. Niaudet P. et al.Deletion of mitochondrial DNA in patient with chronic tubulointerstitial nephritis.J Pediatr. 1995; 126: 597-601Abstract Full Text Full Text PDF PubMed Scopus (60) Google ScholarGlomerulopathy Segmental glomerulosclerosisAdol, adultNone or deafness, diabetes, MELAS syndromeMtDNA point mutation (AC_000021.2:3243G>A)8Jansen J.J. Maassen J.A. Van der Woude F.J. et al.Mutation in mitochondrial tRNAleu(UUR) gene associated with progressive kidney disease.J Am Soc Nephrol. 1997; 8: 1118-1124PubMed Google Scholar, 9Hotta O. Inoue C.N. Miyabayashi S. Furuta T. Takeuchi A. Taguma Y. Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation.Kidney Int. 2001; 59: 1236-1243Crossref PubMed Scopus (121) Google Scholar Glomerulosclerosis, nephrotic syndrome(I), C, AdolNeurological and multivisceral diseaseMtDNA deletion, complex III and CoQ10 deficiency, multiple complex deficiencies4Martin-Hernandez E. Garcia-Silva M.T. Vara J. et al.Renal pathology in children with mitochondrial diseases.Pediatr Nephrol. 2005; 20: 1299-1305Crossref PubMed Scopus (92) Google Scholar, 18Rötig A. Appelkvist E.L. Geromel V. et al.Quinone-responsive multiple respiratory chain dysfunction due to widespread coenzyme Q10 deficiency.Lancet. 2000; 356: 391-395Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar, 23Diomedi-Camassei F. Di Giandomenico S. Santorelli F.M. et al.COQ2 nephropathy: A newly described inherited mitochondriopathy with primary renal involvement.J Am Soc Nephrol. 2007; 18: 2773-2780Crossref PubMed Scopus (286) Google Scholar Congenital nephrotic syndromeNN, IProgressive neurological disease, cardiomyopathySingle or multiple respiratory chain deficiencies10Goldenberg A. Huynh Ngoc L. Thouret M.C. et al.Respiratory chain deficiency presenting as congenital nephrotic syndrome.Pediatr Nephrol. 2005; 20: 465-469Crossref PubMed Scopus (36) Google ScholarAbbreviations: Adol, adolescence; C, childhood; I, infancy; MELAS, mitochondrial encephalomyopathy, lactic acidosis, stroke like episodes; mtDNA, mitochondrial DNA mutation; NN, neonatal period. Open table in a new tab Abbreviations: Adol, adolescence; C, childhood; I, infancy; MELAS, mitochondrial encephalomyopathy, lactic acidosis, stroke like episodes; mtDNA, mitochondrial DNA mutation; NN, neonatal period. The pathophysiological characteristics of acute tubular dysfunction are unclear, but several observations may be pertinent. Proximal tubules have a high metabolic rate, generating more than 95% of their adenosine triphosphate by means of oxidative metabolism.19Epstein F.H. Oxygen and renal metabolism.Kidney Int. 1997; 51: 381-385Crossref PubMed Scopus (210) Google Scholar Recent in vitro experiments showed that nephrotoxicity of some drugs is related to inhibition of mitochondrial respiration, producing adenosine triphosphate depletion and secondary tubular damages.20Engbersen R. Masereeuw R. van Gestel M.A. van der Logt E.M.J. Smits P. Russel F.G.M. Glibenclamide depletes ATP in renal proximal tubular cells by interfering with mitochondrial metabolism.Br J Pharmacol. 2005; 145: 1069-1075Crossref PubMed Scopus (15) Google Scholar Functional coupling between ion transport and aerobic respiration was demonstrated in vitro.21Balaban R.S. Mandel L.J. Soltoff S.P. Storey J.M. Coupling of active ion transport and aerobic respiratory rate in isolated renal tubules.Proc Natl Acad Sci U S A. 1980; 77: 447-451Crossref PubMed Scopus (72) Google Scholar Moreover, even in normal proximal tubule cells, physiological energy demand is close to the capacity for adenosine triphosphate generation, shown by the rapid decrease in adenosine triphosphate level after stimulation of epithelial sodium transport.22Beck J.S. Breton S. Mairbaurl H. Laprade R. Giebisch G. Relationship between sodium transport and intracellular ATP in isolated perfused rabbit proximal convoluted tubule.Am J Physiol. 1991; 261: F634-F639PubMed Google Scholar This constant dependence of proximal tubular cells on high levels of energy supply resembles that of the central nervous system. Acute neurological crises, termed "metabolic stroke," are well-known in patients with mitochondrial diseases and may be related to imbalance between energy requirement and production, leading to cell death. Of note, metabolic strokes in patients with mitochondrial diseases occur after such stresses as minor infections, during which metabolic demands are presumably increased, compromising energy homeostasis in tissues with impaired energy production capacity. Perhaps the episodes of acute tubular dysfunction in our patients fall within a similar framework. The authors thank Dr Eric Shoubridge (McGill University, Montreal, Canada) for blue native gel studies. Support: This work was supported in part by the Brandon Teresi Foundation. Financial Disclosure: None.

S b es itochondrial diseases are a heterogeneous group of energy metabolism disorders hat can affect almost any organ. Kidney disease s well-known in patients with mitochondrial isorders, most commonly manifesting as proxial tubulopathy with chronic tubular acidosis, ypically a minor feature in pediatric patients ith severe involvement of brain, liver, heart, or ther organs. Other renal presentations inlude chronic tubulointerstitial nephropathy, rogressive glomerular diseases, and nephrotic yndrome. Acute, severe, and fluctuant tubular ysfunction has not been previously described.

A common feature of cystic fibrosis (CF) is the functional derangement of the exocrine pancreas, which affects output of pancreatic lipase. This condition results in severe dietary malabsorption due to the poor hydrolysis of triacylglycerol (TG) in the lumen of the small intestine. Despite the benefits of pancreatic enzyme supplements, patients with CF present with persistent intestinal fat malabsorption. The aim of the present investigation was to determine whether defects in the intracellular phase of lipid transport occur in this pathophysiology in addition to the known disturbed digestive processes. Our hypothesis was tested by incubating intestinal biopsies from six CF and six healthy subjects with radiolabeled lipid and protein precursors. Lipid esterification and secretion were markedly decreased by 22-31% and 38-42%, respectively, in CF samples, as noted by the low incorporation of [(14)C]palmitic acid into TGs, phospholipids, and cholesteryl esters in patients' duodenal explants and culture media compared with controls (100%). Accordingly, the output of TG-rich lipoproteins was substantially reduced (P < 0.05), and a similar trend was observed for high-density lipoproteins. Because intestinal lipoprotein assembly/secretion shows an absolute requirement for apolipoprotein (apo) B-48, radioactive labeling experiments were performed; these experiments demonstrated a significantly (P < 0.05) diminished synthesis of apoB-48 (40%) and apoA-I (30%). Given the critical role of microsomal triglyceride transfer protein in the formation of apoB-containing lipoproteins, its activity was determined and not found to be altered in CF intestinal tissue. Together, these results suggest that CF malabsorption may also be caused by defects in mucosal mechanisms leading to abnormal lipoprotein delivery into the blood circulation.

Wilson's disease (WD), caused by a mutation in the P-type copper transporting ATPase (Atp7b) gene, results in excessive accumulation of copper in the liver. Long Evans Cinnamon rats (LEC) bear a mutation in the atp7b gene and share clinical characteristics of human WD. To explore hepatocyte transplantation (HT) as therapy for metabolic liver diseases, 8-week-old LEC rats (n = 12) were transplanted by intrasplenic injection of hepatocytes from donor Long Evans (LE) rats. Immunosuppression was maintained with intraperitoneal tacrolimus. The success of HT was monitored at 24 weeks of life. Serum aminotransferases and bilirubin peaked at 14-21 weeks in both HT rats and nontransplanted controls, but at 24 weeks, survival was 97% in LEC-HT versus 63% in controls. All transplanted rats showed restored biliary copper excretion and reduced liver iron concentration associated with increased ceruloplasmin oxidase activity. Liver tissue expressed atp7b mRNA (11.9 +/- 13.6%) indicative of engraftment of normal cells in 7 of 12 HT rats, associated with a reduced liver copper concentration compared to untreated LEC rats. Periportal islets of normal appearing hepatocytes, recognized by atp7b antibody, were observed in transplanted livers while lobular host cells showed persistent pleomorphic changes and inflammatory infiltrates. In conclusion, transplantation of normal hepatocytes prevented fulminant hepatitis, reduces chronic inflammation, and improved 6-month survival in LEC rats. Engraftment of transplanted cells, which express atp7b mRNA, repopulated the recipient liver with normal functional capacity.

Photooxidation of multivitamin solutions results in the generation of peroxides. Because peroxides are associated with hepatic steatosis and fibrosis as well as cholestasis, we questioned whether multivitamins are implicated in hepatic complications of parenteral nutrition. Guinea pig pups were assigned to groups receiving intravenously either total parenteral nutrition, photo-protected or not, or a control solution (5% dextrose + 0.45% NaCl) supplemented with either a) multivitamins; b) photo-protected multivitamins; c) multivitamins without riboflavin; or d) peroxides (H2O2, tert-butylhydroperoxide). After 4 d, liver was sampled for histology and isoprostane-F2α levels, a marker of radical attack. Multivitamins as well as total parenteral nutrition were associated with steatosis (scored 0–4), the severity of which was reduced (p < 0.05) by photo protection. Although H2O2 is the major peroxide contaminating multivitamins, it did not induce steatosis scores different than the controls. Compared with controls, hepatic isoprostane-F2α content increased in animals infused with H2O2 (p < 0.05), but not in those infused with Multi-12 pediatric multivitamins or total parenteral nutrition. Results suggest that peroxides and/or free radicals are not mediators of the induction of steatosis observed with infusion of photo-exposed multivitamins, as there was no correspondence between histologic findings and hepatic levels of isoprostanes. It is suspected that a component of the multivitamin solution becomes hepato-toxic after photo-exposure, as indicated by the protective effect observed when withdrawing riboflavin. Photo-oxidation of multivitamins might be the common link between reports involving amino acids, lipids, and light exposure in the ethiology of hepatic complications of parenteral nutrition.

Lymphoma constitutes the third most frequently diagnosed malignancy after leukemia and brain tumors in children younger than 15 years of age (1). Lymphoma may be associated with bile duct obstruction in several ways: nodal enlargement secondary to lymphomatous infiltration or extranodal tumor compressing the common bile duct (2), secondary infiltration of the hepatobiliary tract in the case of disseminated lymphoma narrowing the bile duct lumen (3), and paraneoplastic bile duct paucity reported to produce cholestasis in patients treated for lymphoma (4). Primary non-Hodgkin lymphoma of the extrahepatic biliary tract has rarely been recorded. A literature review revealed only 12 reported cases of patients with lymphomatous infiltration of the extra-hepatic biliary tract, the youngest of whom was a 25-year-old woman (5–15). In these cases, the diagnosis was frequently missed at the onset of the disease. Before pathological studies confirmed the diagnosis of lymphoma it was suspected that most of the patients had adenocarcinoma or primary sclerosing cholangitis. Here, we describe an unusual case of a child with a lymphoma infiltrating the extrahepatic biliary tract without extrabiliary localization. The main challenge presented by this exceptional case was the differential diagnosis suggested by the patient's clinical presentation and radiologic studies. We compare the patient's evolution with previously reported cases. CASE REPORT A 4-year-old boy who presented with fluctuating but progressive jaundice was transferred to our institution. For 6 weeks before consultation, the child reported intermittent right upper abdominal pain and nausea. During this period, his mother noticed progressive jaundice, tea-colored urine, and clay-colored stools. The patient was tired and had generalized pain and arthralgia. He did not report fever, night sweat, weight loss, pruritus, skin rash, or respiratory symptoms. His past medical and familial histories were irrelevant. He did not travel and was never in contact with patients suffering from viral hepatitis. Physical examination showed jaundice but no skin lesion. The boy's abdomen was soft with moderate sensitivity in the upper right quadrant. The left lobe of the liver was slightly enlarged, but there were no signs of portal hypertension. The spleen was not palpable and there was no lymphadenopathy. Initial laboratory examinations confirmed cholestasis, with total bilirubin of 4.3 mg/dL, direct bilirubin of 2.7 mg/dL, gamma-glutamyl-transferase (GGT) of 82 U/L (normal: 4–23 U/L), alanine-aminotransferase (ALT) of 3 U/L (normal: 5–25 U/L), and aspartate-aminotransferase (AST) of 77 U/L (normal: 5–60 U/L). The boy's erythrocyte sedimentation rate was elevated at 32 mm/h but his complete blood count, amylase, coagulation studies, and factor V results were normal. Serologic test results were negative for hepatitis A, B, and C viruses, Epstein-Barr virus, cytomegalovirus, and adenovirus. Autoantibody serologic screening results were negative. Throat and stool viral culture results were negative. Ultrasonography and abdominal CT showed a thickened common bile duct and gallbladder wall, and enlarged lumens of the intrahepatic ducts (Fig. 1 and 2). There was no lymph node enlargement or hepatic nodule. Gallium scintigraphy demonstrated radioactive tracer activity only in the region of the hepatic hilum.FIG. 1.: Ultrasonograph of the abdomen. Transverse scan at the level of the gallbladder (gb) and head of the pancreas (p) showing marked thickening of the gallbladder wall (curved arrow) and apparent enlargement of the distal common bile duct (small arrow) caused by hypoechoic infiltration surrounding the lumen (A). Longitudinal scan along the axis of the common bile duct: infiltration of the choledocal wall (small arrow) compresses the lumen (large arrow) of the distal duct (B).Figure 1: ContinuedFIG. 2.: Computed tomograph at the same level as shown in in Figure 1A. Showing marked thickening of the gallbladder (gb) wall (small arrow) and enlargement of the common bile duct (large arrow).During the following weeks, the patient's condition slowly improved. Total bilirubin decreased to 2.2 mg/dL but hepatic enzyme and erythrocyte sedimentation rates remained elevated (AST, 131 U/L; ALT, 137 U/L; ESR, 60 mm/h). A bone marrow aspirate did not show the presence of malignant cells. Exploratory laparotomy was performed. There was infiltration of the hepatic hilum and gallbladder. The tumoral process had involved all the extrahepatic biliary tract. No other mass was found. An incisional biopsy of the gallbladder wall was performed and showed marked lymphocytic infiltration. Lymphoid nodules with germinative centers were seen. Immunohistochemistry performed on paraffin sections revealed that all cells expressed leucocyte common antigen and that a portion of them expressed either a T-cell marker (UCHL-1) or a B-cell marker (L-26). Immunophenotype studies by flow cytometry could not be performed because of specimen deterioration. The final report concluded that there was massive lymphoid hyperplasia without signs of lymphoma. Two weeks after admission, the patient felt better and the decision was made to follow the evolution of his disease. One month after biopsy, the boy again reported abdominal pain, pale stools, and dark urine. His total bilirubin was 2.0 mg/dL, and hepatic enzyme levels were similar to those measured in the previous month. No CT changes were reported. A laparotomy similar to the first and a cholecystectomy were performed. Macroscopically, the gallbladder was recognizable but its lumen was severely narrowed by a markedly thickened wall (up to 1.1 cm thick). The extrahepatic biliary tract was patent but also showed thickened walls. Microscopically, a diffuse lymphoproliferative process was infiltrating the walls of the gallbladder and the cystic duct (Fig. 3A). The tumor cells had round or slightly indented hyperchromatic nuclei with small nucleoli (Fig. 3B). The tumor-cell nuclei were smaller than those of the surrounding macrophages and mitoses were numerous. Few remnants of lymphoid nodules were found.FIG. 3.: Pathology studies. Microscopic examination reveals massive lymphomatous infiltration of the gallbladder wall (A). High-power magnification (40 ×) discloses multiple tumoral nucleated cells (B). Multiple mitoses are evident with higher enlargement (100 ×). Flow cytometry shows that cells expressed HLA-DR protein without CD3 protein (C) and that cells had CD19 surface protein without CD10 protein (D).Immunohistochemistry of paraffin sections revealed that, although all cells expressed leucocyte-common antigen, few expressed a T-cell marker (UCHL-1) or B-cell marker (L-26). Immunophenotype studies by flow cytometry showed that the proliferating cells expressed CD19, CD45, and human leukocyte antigen (HLA-DR) proteins but not CD10 and CD21 surface proteins or Kappa or Lambda chains (Fig. 3C and D). These results confirmed that a lymphoblastic lymphoma of the pre-B type developed in the biliary tract of this child. Extensive work-up failed to find any other localization of the tumor. The patient was started on chemotherapy with prednisone, vincristine, doxorubicine, and methotrexate. During 18 months of treatment, he was hospitalized only for chemotherapy and isolated fever; all clinical and radiological exams failed to show a relapse of the lymphoma. His bilirubin and hepatic enzyme levels returned to normal. DISCUSSION The patient described here was hospitalized because of cholestasis of unknown cause. In most cases, history, physical examination, simple blood tests, and ultrasonography will elucidate the cause (16). Intermittent jaundice associated with a slight elevation of liver enzymes, increased direct bilirubin, and gamma-glutamyl-transpeptidase (GGT) in children suggests extrahepatic obstruction. Radiologic studies are part of the basic evaluation in such cases. In our case, computed tomography revealed an enlarged common bile duct but did not differentiate between a dilated common bile duct lumen and an infiltrated wall with collapsed lumen. Ultrasound studies provided differential diagnosis by showing a narrow lumen with thickening of the wall of the main bile ducts. From an imaging standpoint, the differential diagnosis included primary sclerosing cholangitis, histiocytosis X, inflammatory pseudo-tumor, and lymphoma. Cholangiocarcinoma of the extrahepatic biliary tract is a mucus-secreting tumor with an inflammatory reaction that can mimic the radiologic images of sclerosing cholangitis. Adenocarcinoma or cholangiocarcinoma would have been considered a possible diagnosis in an adult but is rare in children. Without histologic studies, it is difficult to establish the true nature of the lesion. Takehara et al. (13) suggest that a homogenous hypoechoic mass in the lumen of the duct is more suggestive of lymphoma; unfortunately, because of the limited number of patients with that disease, this statement cannot be confirmed or refuted. Many authors have reported the relevance of endoscopic retrograde cholangiopancreatography to complete the investigation in these cases. Biliary tract lymphoma usually shows an irregular narrowed segment of the main bile duct followed by dilated intrahepatic bile ducts. This procedure would be of little help in differentiating the causes of the infiltrative process. Consequently, surgical biopsy is the diagnostic procedure of choice. A cholecystectomy is usually necessary to provide enough material for analysis. Because primary lymphoma of the extrahepatic biliary tract is uncommon, diagnosis of frozen sections may be difficult. The first recorded patients were initially diagnosed as having chronic nonspecific inflammation (8,11), which may be confused with an inflammatory pseudo-tumor. One patient was presumed to have a nonepithelial neoplasm before final pathologic studies revealed lymphoma (10). In the present case, intraoperative frozen sections were suspected for lymphoma twice, but the first biopsy was not specific enough to confirm the malignancy. The specimen was denatured because of nonoptimal preservation and delayed preparation of the material. The lack of reliable immunophenotype studies by flow cytometry and of immunologic investigations of paraffin sections and the presence of reactive lymphoid nodules prevented a firm diagnosis of lymphoma. Because of the recurrence of symptoms, cholecystectomy was indicated. Histological tissue examination and flow cytometry then confirmed the diagnosis of lymphoma. The identification of cell-surface proteins by flow cytometry allows for better characterization of lymphoid cells. During its differentiation from pluripotent stem cell to mature B cell, a lymphoid cell acquires and loses surface proteins. In the case reported, a tumoral process was suspected because the cells expressed all the same surface proteins. Expression of CD19, CD45, and HLA-DR proteins suggest that the cells are of the lymphoid pathway, but the absence of Kappa or Lambda chains confirms that they did not reach the mature B-lymphocyte stage. The absence of CD10 and CD21 surface proteins confirmed that the proliferating cells were from a pre–B-lymphoblastic lymphoma. B-cell lymphoma is the most common type of lymphoma affecting the digestive tract. In the 12 cases reported, all lymphoma types (non-Hodgkin or Hodgkin, B cell or T cell) were found to originate from the common bile duct. Only time will permit us to determine the lymphoma type most often originating from the biliary tract. The patient described in this paper responded well to chemotherapy. Eighteen months after beginning treatment, he seemed to be free of disease. This correlates well with previously recorded cases. If left untreated, primary non-Hodgkin lymphoma of the extrahepatic biliary tract has a bad prognosis; there was lymphoma recurrence in the four cases recorded where surgery was not immediately followed by chemotherapy (6,8,11,14). Of the four patients, only two survived after chemotherapy was started. Of the seven cases initially treated with surgery and chemotherapy (the present case and (5,7,9,10,13,15)), four were disease-free at the time of publication, one was lost to follow-up, and two died in the following months. One of the two patients to die was a man with AIDS who died of a meningeal lymphoma 10 months after initial surgery (7), and the other was a patient who died of pneumonia 4 months after surgery but showed infiltrative pancreatic lymphoma at autopsy (15). These are small numbers, but most cases of primary non-Hodgkin lymphoma of the extrahepatic biliary tract appear to respond well to chemotherapy treatment after initial surgery. Evaluation of this interesting pediatric case of intermittent jaundice illustrates the differential diagnosis of extrahepatic biliary-tract–wall infiltration. Final histologic studies confirmed that primary lymphoma of the bile duct must be considered in this kind of presentation, even in the absence of other signs of tumor. Because the diagnosis is difficult to establish with simple pathologic studies, more aggressive management should be proposed. Large surgical biopsy is necessary to organize rapid and satisfactory treatment.

Editor,—Similarly to adult pathology, human papillomavirus (HPV) infection is the most common sexually transmitted disease in adolescent girls, whose prevalence is 16% according to one US study.1 However, little or no HPV sequencing data from paediatric specimens are available. We used our two tier polymerase chain reaction (PCR) direct sequencing (PCR-DS) approach2 to study cervical biopsies from 44 adolescent Quebec girls (14–17 years old). They originated from various social and ethnic groups, as well as geographically distinct areas of Quebec. Written informed consent about the use of the specimens was obtained from the ethics committee of this institution. All biopsies were analysed for histological changes and presence of HPV specific DNA. Most of them (n = 36) were diagnosed as cervical intraepithelial neoplasia (CIN), seven as inflammatory changes, and one as …

Human papillomaviruses (HPV) are etiological agents of cervical cancer. In order to address clinical demand for HPV detection and sequence typing, mostly in pre-cancerous cervical lesions, we applied our two-tier PCR-direct sequencing (PCR-DS) approach based on the use of both MY09/MY11 and GP5 + /GP6 + sets of primers. We tested 691 pathological specimens, all of which were biopsies, 75% of which were diagnosed histologically as cervical intraepithelial neoplasia (CIN) grades I-III. In total, 484 samples (70%) tested HPV-positive, yielding 531 HPV sequences from 47 HPV types, including two novel types. Four most frequently found HPV types accounted for 52.9% of all isolates: HPV6, 16, 11, and 31 (21.5%, 20.0%, 7.0%, and 4.5%, respectively). Some interesting results are the following: all currently known high-risk HPV (14 types) and low-risk HPV (6 types) were detected; HPV18 was not the 1st or 2nd but rather the 4th-5th most frequent high-risk HPV type; the highest detection rate for HPV (86%) among samples suspected to be HPV-infected was found in the youngest age group (0-10 years old), including 70% (44/63) "genital" HPV types; HPV types of undetermined cervical cancer risk represented 19% and of the total HPV isolates but were strongly increased in co-infections (36.5% of all isolates). To our knowledge, this is the largest sequencing-based study of HPV. The HPV types of unknown cancer risk, representing the majority of the known HPV types, 27 of the 47 types detected in this study, are not likely to play a major role in cervical cancer because their prevalence in CIN-I, II, and III declines from 16% to 8% to 2.5%. The two-tier PCR-DS method provides greater sensitivity than cycle sequencing using only one pair of primers. It could be used in a simple laboratory setting for quick and reliable typing of known and novel HPV from clinical specimens with fine sequence precision. It could also be applied to anti-cancer vaccine development.

Autoimmune enteropathy (AIE) is an entity reported primarily in infancy, resulting in intractable diarrhea and associated with small bowel villous atrophy and the presence of circulating anti-enterocyte (AEA) antibodies. It is a multisystem disorder with a response, in many cases, to immunosuppressive therapy.

An in-house polymerase chain reaction direct sequencing (PCR-DS) approach for HPV detection and typing was developed, taking advantage of two widely used pairs of human papillomavirus (HPV)-specific PCR primers, MY09/MY11 and GP5/GP6, and 33P-labeled dideoxynucleotides. In this study, 105 pathological specimens were examined: 89% were diagnosed as cervical intraepithelial neoplasia (CIN) grade I-III, 76.2% were HPV-positive by PCR-DS. The PCR using GP5/GP6 (first tier) and MY09/MY11 primers (second tier for the GP5/GP6-negative samples) detected additional 15%-25% HPV-positive samples compared with each pair used separately. Direct sequencing was then used to type the HPV. A readout of a sequence as short as 34 nucleotides within a specific region in the L1 gene is sufficient to type known or novel sequences. Because of its high sensitivity and cost-effectiveness, the two-tier PCR-DS was adopted by the authors as the current method of choice for HPV diagnosis with ultimate sequence precision.