Proteomic analysis of mononuclear cells of patients with minimal-change nephrotic syndrome of childhood.

Background/Aims. Recently, peripheral blood mononuclear cell transcriptome analysis has identified genes that are upregulated in relapsing minimal-change nephrotic syndrome (MCNS). In order to investigate protein expression in peripheral blood mononuclear cells (PBMC) from relapsing MCNS patients, we performed proteomic comparisons of PBMC from patients with MCNS in relapse and controls. METHODS: PBMC from a total of 20 patients were analysed. PBMC were taken from five patients with relapsing MCNS, four in remission, five patients with other glomerular diseases and six controls. Two dimensional electrophoresis was performed and proteome patterns were compared. RESULTS: Automatic heuristic clustering analysis allowed us to pool correctly the gels from the MCNS patients in the relapse and in the control groups. Using hierarchical population matching, nine spots were found to be increased in PBMC from MCNS patients in relapse. Four spots were identified by mass spectrometry. Three of the four proteins identified (L-plastin, alpha-tropomyosin and annexin III) were cytoskeletal-associated proteins. Using western blot and immunochemistry, L-plastin and alpha-tropomyosin 3 concentrations were found to be enhanced in PBMC from MCNS patients in relapse. Conclusions. These data indicate that a specific proteomic profile characterizes PBMC from MCNS patients in relapse. Proteins involved in PBMC cytoskeletal rearrangement are increased in relapsing MCNS. We hypothesize that T-cell cytoskeletal rearrangement may play a role in the pathogenesis of MCNS by altering the expression of cell surface receptors and by modifying the interaction of these cells with glomerular cells.

Chorioretinal lacuna in the amniotic band syndrome.

The malformations in the amniotic band syndrome (ABS) are due to entrapment of fetal parts by fibrous band in the amniotic sac. Limbs are most commonly affected followed by craniofacial defects in one third of patients. Ocular defects include corneal leukomas and lid colobomas often contiguous with facial clefts, strabismus, hypertelorism, and microphthalmos. Unilateral chorioretinal defects or lacunae are rare findings in the ABS. We report a female infant with such a lacunar defect along with central nervous abnormalities, and discuss the differential diagnosis and the embryopathic implications.

PFAPA syndrome is not a sporadic disease.

OBJECTIVES: To determine whether PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) patients have a positive family history (FH) for recurrent fever syndromes. METHOD: For all patients with PFAPA seen in two paediatric rheumatology centres (Romandy, Switzerland and Bordeaux, France), parents were interviewed to record the FH for periodic fever. As controls, we interviewed a group of children without history of recurrent fever. RESULTS: We recruited 84 patients with PFAPA and 47 healthy children. The FH for recurrent fever (without an infectious cause and recurring for at least half a year) was positive in 38/84 (45%), and was positive for PFAPA (diagnosis confirmed by a physician) in 10/84 (12%) of the PFAPA patients. For 29 of the 38 patients with positive FH, the affected person was a sibling or a parent. None of the healthy children had a positive FH for recurrent fever or PFAPA. A positive FH for rheumatological diseases was seen in both groups of children. CONCLUSION: These data show that a significant percentage of PFAPA patients present a positive FH of recurrent fever and PFAPA. This familial susceptibility suggests a potential genetic origin for this syndrome.

Development and evaluation of a shaken baby syndrome prevention program.

OBJECTIVE: To evaluate parents' and nurses' opinions regarding the adequacy of an educational program on shaken baby syndrome: the Perinatal Shaken Baby Syndrome Prevention Program (PSBSPP). DESIGN: Qualitative and quantitative assessments in the form of interviews and questionnaires administered in French. SETTING: Two birthing institutions in Montréal, QC, Canada: a university hospital and a regional center. PARTICIPANTS: Two hundred and sixty-three parents (73.8% mothers, 26.2% fathers) received the intervention after the birth of their child, and 69 nurses administered it. METHODS: Parents' and nurses' assessments of the adequacy and relevance of the program and nurses' assessments of the training they received to administer the program were evaluated. RESULTS: Both parents and nurses supported this initiative. Most parents appreciated the usefulness of the information. Nurses believed the program was adequate, and their training to deliver the program was satisfactory. All participants reported that the program was highly relevant, especially for new parents. CONCLUSION: The Perinatal Shaken Baby Syndrome Prevention Program achieves the goals of (a) increasing parents' knowledge about infant crying, anger, and shaken baby syndrome and (b) helping parents identify coping strategies. The relevance of introducing the PSBSPP in all birthing institutions is supported. Future studies should focus on vulnerable and culturally diverse populations, and longitudinal follow-up could help determine if the PSBSPP reduces the incidence of shaken baby syndrome.

Focal dermal hypoplasia (goltz-gorlin syndrome): A new case with a novel variant in the PORCN gene (c.1250T>C:p.F417S) and unusual spinal anomaly.

Focal dermal hypoplasia (FDH; Goltz-Gorlin syndrome; OMIM 305600) is a disorder that features involvement of the skin, skeletal system, and eyes. It is caused by loss-of-function mutations in the PORCN gene. We report a young girl with FDH, microphthalmos associated with colobomatous orbital cyst, dural ectasia and cystic malformation of the spinal cord, and a de novo variant in PORCN. This association has not been previously reported, and based on these observations the phenotypic spectrum of FDH might be broader than previously appreciated. It would be prudent to alter the suggested surveillance for this rare disorder. © 2013 Wiley Periodicals, Inc.

Dépistage du syndrome des apnées du sommeil [Screening for sleep apnea syndrome]

Sleep apnea syndrome (SAS) consists of nocturnal snoring interrupted by obstructive apnea and of diurnal symptoms like hypersomnolence as a consequence of sleep fragmentation. Cardiovascular morbidity and mortality associated with this syndrome justify early detection and appropriate treatment. Polysomnography is still a frequently used method for early detection; however, several disadvantages like duration, discomfort and expense led to a search for alternatives. Since the beginning of the eighties, oximetry allows recording of nocturnal oxygen saturation of hemoglobin even at home. Nocturnal oximetry reveals O2-desaturation associated with apnea and thus permits often to diagnose or exclude SAS. Diagnosis of SAS is made when at least 20 desaturations per hour with an amplitude of at least 4% are recorded. On the other hand, normal nocturnal oximetry nearly excludes SAS. In those cases where nocturnal oximetry is not diagnostic, polysomnography remains the method of choice. Departing from published work, a model for SAS detection, based mainly on nocturnal oximetry, is proposed.

Analyses of a novel SCN5A mutation (C1850S): conduction vs. repolarization disorder hypotheses in the Brugada syndrome.

AIMS: Brugada syndrome (BrS) is characterized by arrhythmias leading to sudden cardiac death. BrS is caused, in part, by mutations in the SCN5A gene, which encodes the sodium channel alpha-subunit Na(v)1.5. Here, we aimed to characterize the biophysical properties and consequences of a novel BrS SCN5A mutation. METHODS AND RESULTS: SCN5A was screened for mutations in a male patient with type-1 BrS pattern ECG. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in HEK293 cells. Sodium currents (I(Na)) were analysed using the whole-cell patch-clamp technique at 37 degrees C. The electrophysiological effects of the mutation were simulated using the Luo-Rudy model, into which the transient outward current (I(to)) was incorporated. A new mutation (C1850S) was identified in the Na(v)1.5 C-terminal domain. In HEK293 cells, mutant I(Na) density was decreased by 62% at -20 mV. Inactivation of mutant I(Na) was accelerated in a voltage-dependent manner and the steady-state inactivation curve was shifted by 11.6 mV towards negative potentials. No change was observed regarding activation characteristics. Altogether, these biophysical alterations decreased the availability of I(Na). In the simulations, the I(to) density necessary to precipitate repolarization differed minimally between the two genotypes. In contrast, the mutation greatly affected conduction across a structural heterogeneity and precipitated conduction block. CONCLUSION: Our data confirm that mutations of the C-terminal domain of Na(v)1.5 alter the inactivation of the channel and support the notion that conduction alterations may play a significant role in the pathogenesis of BrS.

Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren's syndrome.

BAFF (BLyS, TALL-1, THANK, zTNF4) is a member of the TNF superfamily that specifically regulates B lymphocyte proliferation and survival. Mice transgenic (Tg) for BAFF develop an autoimmune condition similar to systemic lupus erythematosus. We now demonstrate that BAFF Tg mice, as they age, develop a secondary pathology reminiscent of Sjögren's syndrome (SS), which is manifested by severe sialadenitis, decreased saliva production, and destruction of submaxillary glands. In humans, SS also correlates with elevated levels of circulating BAFF, as well as a dramatic upregulation of BAFF expression in inflamed salivary glands. A likely explanation for disease in BAFF Tg mice is excessive survival signals to autoreactive B cells, possibly as they pass through a critical tolerance checkpoint while maturing in the spleen. The marginal zone (MZ) B cell compartment, one of the enlarged B cell subsets in the spleen of BAFF Tg mice, is a potential reservoir of autoreactive B cells. Interestingly, B cells with an MZ-like phenotype infiltrate the salivary glands of BAFF Tg mice, suggesting that cells of this compartment potentially participate in tissue damage in SS and possibly other autoimmune diseases. We conclude that altered B cell differentiation and tolerance induced by excess BAFF may be central to SS pathogenesis.

Early neurological impairment and severe anemia in a newborn with Pearson syndrome

BACKGROUND: Pearson marrow-pancreas syndrome (PS) is usually a fatal mitochondrial disease, mostly diagnosed during infancy or postmortem. PS is caused by the deletions or duplications of mitochondrial DNA (mtDNA). The tissue distribution and relative proportions of expressed abnormal mtDNA determine the phenotype and the clinical course. MATERIALS AND METHODS: We describe the case of a term baby boy who was diagnosed with PS early in the neonatal period due to severe aregenerative anemia and persistent lactic acidosis. RESULTS: His neurological examination was abnormal since birth. Brain magnetic resonance imaging (MRI) at term was abnormal, indicating that mitochondrial encephalopathy in PS can be already manifested in the neonatal period. To our knowledge, neonatal encephalopathy in PS has not been previously described. CONCLUSION: PS is a rare condition diagnosed in the newborn. It should be suspected in the presence of severe anemia and persistent lactic acidosis, and may manifest with early encephalopathy.

Superior vena cava syndrome caused by invasive epidermoid carcinoma.

Lung cancer is the most frequent cause of superior vena cava (SVC) syndrome. Malignant SVC syndrome is generally considered a contraindication to curative resection, although palliative bypasses are done for symptoms that do not respond to medical therapy. However, a majority of patients with such advanced disease die of complications caused by the primary tumor rather than distant metastasis. We present the case of one patient with lung cancer invading the mediastinal structures. Combined resection and replacement of the SVC with a segment of Dacron vascular graft was performed. Postoperative survival time was 24 months.

Correction of pectus excavatum combined with open heart surgery in a patient with Marfan's syndrome.

We report a patient with Marfan's syndrome and pectus excavatum who underwent open heart surgery with simultaneous correction of the sternal malformation. Permanent internal stabilization, achieved by bilateral overlapping of the bevelled ends of the lowest ribs and reinforced with sternal closure wires offered a maintained postoperative chest wall stability, avoided the potential postoperative complications of cardiac compression, and improved the aesthetic appearance of the anterior chest wall. The increased risk of bleeding due to extensive dissection was minimized by postponing the repair of pectus excavatum to when protamin is administered after termination of cardiopulmonary bypass.

Evidence for classification of c.1852_1853AA>GC in MLH1 as a neutral variant for Lynch syndrome

Background: Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala) variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS.Methods: The following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co-segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls). Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers.Results: Twenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%), seven were suspected of having hereditary CRC (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of microsatellite instability (2/17, 11.8%) were detected in tumours from p.Lys618Ala carriers, indicating that this variant does not play a role in functional inactivation of MLH1 in CRC patients.Conclusions: The p.Lys618Ala variant should be considered a neutral variant for LS. These findings have implications for the clinical management of CRC probands and their relatives.

Hypothalamus transcriptome profile suggests an anorexia-cachexia syndrome in the anx/anx mouse model

The anx/anx mouse displays poor appetite and lean appearance and is considered a good model for the study of anorexia nervosa. To identify new genes involved in feeding behavior and body weight regulation we performed an expression profiling in the hypothalamus of the anx/anx mice. Using commercial microarrays we detected 156 differentially expressed genes and validated 92 of those using TaqMan low-density arrays. The expression of a set of 87 candidate genes selected based on literature evidences was also quantified by TaqMan low-density arrays. Our results showed enrichment in deregulated genes involved in cell death, cell morphology and cancer as well as an alteration of several signaling circuits involved in energy balance including neuropeptide Y and melanocortin signaling. The expression profile along with the phenotype led us to conclude that anx/anx mice resemble the anorexia-cachexia syndrome typically observed in cancer, infection with human immunodeficiency virus or chronic diseases, rather than starvation, and that anx/anx mice could be considered a good model for the treatment and investigation of this condition.