Identification of the first homozygous intragenic deletion in the YY1AP1 gene in a consanguineous family: New insights into the phenotypic variability associated with Grange syndrome.

Grange syndrome (GRNG-MIM#135580) is a rare recessive disorder associating variable features including diffuse vascular stenosis, brachysyndactyly, osteopenia with increased bone fragility, cardiac malformations, and variable developmental delay. Since its first description in 1998, only 15 individuals from 10 families have been reported, carrying homozygous or compound heterozygous frameshift or nonsense variants in YY1AP1. In a patient with cutaneous and bone syndactyly and a hemorrhagic stroke at the age of 16 months, consistent with a clinical diagnosis of GRNG, we performed exome sequencing after negative array-CGH and congenital limb malformation panel results. Copy number variant analysis from exome data identified a homozygous intragenic out-of-frame deletion of 1.84 kb encompassing exons seven and eight of YY1AP1, confirming a molecular diagnosis of GRNG. Genetic counseling led to the identification of additional family members compatible with GRNG. Here, we provide new insights into the phenotypic variability associated with GRNG and highlight the utility of the detection of small copy number variants to identify the molecular causes of heterogeneous malformative genetic disorders.

[Fighting against unexplained sudden death]. / Mort subite, en quête d'une explication.

Sudden cardiac death, mostly related to ventricular arrhythmia, is a major public health issue, with still very poor survival at hospital discharge. Although coronary artery disease remains the leading cause, other etiologies should be systematically investigated. Exhaustive and standardized exploration is required to eventually offer specific therapeutics and management to the patient as well as his/her family members in case of inherited cardiac disease. Identification and establishing direct causality of the detected cardiac anomaly may remain challenging, underlying the need for a multidisciplinary and experimented team.

Pseudoxanthoma elasticum overlaps hereditary spastic paraplegia type 56.

PURPOSE: Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the ABCC6-negative patients. METHODS: First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients. RESULTS: 6.4% of ABCC6-negative PXE patients (n = 3) harboured biallelic pathogenic variants in CYP2U1. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. CYP2U1 missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE. CONCLUSION: CYP2U1 pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and CYP2U1 should be explored to explain their respective role and potential interaction in ectopic mineralization.

Antibiotic strategy in severe community-acquired pneumococcal pneumonia.

OBJECTIVE: The authors had for aim to make an inventory of antibiotic treatment for severe community-acquired Streptococcus pneumoniae pneumonia and compare local practices to the local and national guidelines. PATIENTS AND METHOD: An audit was conducted retrospectively in the Versailles hospital ICU between January 2006 and April 2009. Forty patients were included. RESULTS: Ninety-three percent had major risk factors for pneumonia. Ninety-eight percent were treated, with the usual empirical treatment (69%) or treatment active against Pseudomonas aeruginosa (31%). Eighty-five percent of empirical treatment complied with the French national guidelines issued by the SPILF and 49% with the local ICU protocol, more restrictive for the choice of the agent and dose. Early de-escalation to amoxicillin was applied to 41% of patients after obtaining results for pneumococcal and Legionella antigen and results of respiratory sample direct examination. For all patients, empirical treatment was reassessed according to culture results: 81% were prescribed amoxicillin. Evaluation showed that 92% of treatment complied with SPILF guidelines and 65% with the local ICU protocol that required adaptation of amoxicillin doses according to MICs; adaptation to severity and BMI was necessary for ten patients. Mortality remained high, at 37%, despite using antibiotics still effective against S. pneumoniae. CONCLUSIONS: This survey revealed a satisfactory adhesion to recommendations and prompt responsiveness of the team for adjustment of antibiotic therapy. The audit allowed updating the local ICU protocol.

False positive galactomannan Platelia due to piperacillin-tazobactam.

INTRODUCTION: Invasive aspergillosis is a serious disease, the lethality of which is important among hematology patients. Early diagnosis is crucial for treatment options and the prognosis. Detection of the antigen galactomannan is the most frequently used microbiological tools. But galactomannan detection may be falsely positive, and this false positivity has been associated with piperacillin-tazobactam treatment, the main antibiotic combination used in clinical hematology. OBJECTIVE: The purpose of our study, carried out from January 2009 to December 2010 at the Versailles hospital on in-patients with hematological disorders, was to evaluate the association between false galactomannan positivity and administration of piperacillin-tazobactam, and to study a possible variability of products issued by three manufacturers. PATIENTS AND METHOD: We noted that 207 patients were included (n=207), accounting for 69 false positive and 138 true negative results. The intrinsic galactomannan values in the study were sensitivity 100%, specificity 68%, positive and negative predictive values respectively 16%, 100%, and a likelihood positive and negative test at respectively 3.12, and 0. RESULTS: The statistical analysis did not determine any association between false positivity in galactomannan and piperacillin-tazobactam issued by two manufacturers (P=0.87 and P=0.94). But, there was a significant association between false galactomannan positivity and piperacillin-tazobactam issued by the third manufacturer (P=0.02). Four of the 25 batches issued by this manufacturer were tested and negative "in vitro" for galactomannan. DISCUSSION: This study results suggest that the association between false galactomannan positivity and piperacillin-tazobactam is not longer systematic, but can still prevail depending on the manufacturers. It also confirmed the positive contribution of testing piperacillin-tazobactam batches "in vitro" before using the antibiotic.

Quantitative microbiological risk assessment: principles applied to determining the comparative risk of salmonellosis from chicken products.

Ensuring microbiological safety requires identification of realistic hazards and the means of controlling them. The risk assessment framework proposed by Codex Alimentarius allows the impact of raw materials and processes to be appreciated, and the output can be used for risk management and communication. Mathematical models allow numerical information to be processed by a computer and interpreted to give quantitative or comparative risk assessments. In this example, models have been put together according to the Codex. Alimentarius principles, providing a quantitative risk assessment (QRA) of salmonellosis from frozen poultry products. This model-based QRA takes into account three types of information: occurrence and distribution of the agent, sensitivity of populations to infection (e.g., normal or susceptible), and the effect of cooking (in the factory or home) on concentration of the agent and hence risks of infection after product consumption. It only demonstrates the impact of a single-process step (heating) and the effect of changes in population sensitivity, raw material quality, and cooking regime on the final risk. The effects of growth and recontamination are not considered. To aid risk communication, the models have been visualized by means of displays and slider controls on a computer screen because effective communication is essential to encourage manufacturers and their product designers to assess the effect of changes in processing or materials on risk.

Development of thermal inactivation models for Salmonella enteritidis and Escherichia coli O157:H7 with temperature, pH and NaCl as controlling factors.

The thermal inactivation of Salmonella enteritidis phage type 4 and Escherichia coli O157:H7 as affected by temperature (54.5-64.5 degrees C), pH (4.2-9.6 with HCl or NaOH) and NaCl concentration (0.5-8.5% w/w) was studied. Cell suspensions in modified tryptone soya broth were heated in a submerged-coil heating apparatus and survivors were enumerated on tryptone soya agar incubated aerobically. For most thermal inactivation data there was a logarithmic decrease in the viable cell concentration over the initial 4-6 log10 reduction and D-values were fitted. In some cases, tailing of the survivor curves was observed with cells surviving longer than the D-values predicted. Models describing the effect of temperature, pH and NaCl concentration on the thermal inactivation of S. enteritidis and E. coli O157:H7 were produced. For both organisms, predicted z-values of 4.6-7.0 C degrees were obtained depending on conditions, with larger z-values at higher levels of NaCl. Optimum survival occurred between pH 5 and pH 7 and increasing acidity or alkalinity caused a decrease in the predicted D-values. At equivalent pH, acetic acid and lactic acid (at 0.5, 1 and 2% w/w) generally had a similar, or increased, lethal effect compared with HCl, whereas in most cases citric acid had a less lethal effect. For E. coli O157:H7, increasing NaCl concentration had a protective effect up to the maximum tested (8.5% w/w), while for S. enteritidis optimal survival at a NaCl concentration of 5-7% w/w was predicted. The models were validated in foods by comparing predictions with published data. Most (80%) of the predicted D-values from the S. enteritidis model were within the 95% confidence interval (within 2.45-fold of the published data) for different Salmonella serotypes in whole egg, egg albumen, egg yolk, beef and milk. Most (93%) of the predicted D-values from the E. coli O157:H7 model were larger than the limited published data for this organism in meat, poultry, milk and apple juice with 42% within the 95% confidence interval (within 2.05-fold of the published data). The D-value models were incorporated into Version 1, and subsequent versions, of the predictive microbiology software program, Food MicroModel.

The effect of temperature on the germination of single spores of Clostridium botulinum 62A.

Phase-contrast microscopy coupled with image analysis has been used to study the germination of single spores of Clostridium botulinum and to investigate the variation of germination lag of individual spores in a population (biovariability). The experiment was repeated at five different temperatures between 20 degrees C and 37 degrees C to look at the effect of temperature on the biovaribility of the spore germination. Data analysis shows that the germination lag distribution is skewed, with a tail, and that its shape is affected by the temperature. The origin of this biovariability is not exactly known, but could be due to a distribution of characteristics (e.g. permeabilities) or molecules (e.g. lytic enzymes) in the spore population. The method developed in this study will help us to describe and better understand the kinetics of spore germination and how this is influence by different environmental factors such as temperature and other factors that influence germination.

[Isolated mucosal ulcers disclosing idiopathic hypereosinophilic syndrome]. / Ulcérations muqueuses isolées révélatrices d'un syndrome hyperéosinophilique idiopathique.

INTRODUCTION: Idiopathic hypereosinophilic syndrome is an uncommon disease often associated with diverse non-specific skin manifestations. Mucosal ulcerations suggest a myeloproliferative from with poor prognosis due to possible progression to malignant hemopathy or visceral complications. CASE REPORT: A 28-year-old man presented idiopathic hypereosinophilia with isolated mucosal ulcerations involving the buccal and genital areas. Laboratory results (hematology, CD25) suggested a myeloproliferative form. Treatment with alpha interferon (18 months) led to regression of the mucosal lesions and a decrease in the markers of eosinophil toxicity. There was no visceral involvement. DISCUSSION: Immunosuppression with/without high-dose alpha interferon is usually used for the treatment of hypereosinophilic syndrome. In our case favorable outcome was obtained with lower doses of alpha interferon than those reported in the literature. There was objective decrease in eosinophil toxicity (regular counts of hypodense eosinophils, CD25 or interleukin 2 soluble receptor) and no progression (malignant hemopathy, mortal visceral involvement).

[Cutaneous manifestations of acromegaly: 4 cases]. / Signes cutanés de l'acromégalie: 4 observations.

INTRODUCTION: Some skin changes in acromegaly belong to the classical dysmorphic syndrome. Furthermore, other minor skin changes can be associated. OBSERVATIONS: We report 3 patients consulting in the department of Dermatology for various skin changes that have lead to the diagnosis of acromegaly. However these patients have also typical dysmorphic syndrome that they have failed to recognize. The fourth patient associated a cutaneous mastocytosis and acromegaly, as reported only once in literature. The evolution of the minor skin changes was parallel with the endocrinopathy. Moreover in one case, they have preceded the recurrence of the acromegaly. COMMENTS: Our observations demonstrate the importance of the minor skin changes that lead the patient to consult more than the dysmorphic syndrome. Moreover these changes that depend of growth hormone and other associated growth factors can be evolutive signs for endocrinopathy.

[Care charges and direct costs related to hospitalization of Senegalese children with cerebral malaria. Study of 76 cases in the Albert-Royer Hospital in Dakar in 1991-1992]. / Charge en soins et coûts directs liés à l'hospitalisation des neuropaludismes de l'enfant sénégalais. Etude de 76 cas à l'hôpital Albert-Royer de Dakar en 1991-1992.

To optimize the funds devoted to health care, and to objectively assess the tools used in monitoring patients with cerebral malaria, we determined two parameters, care charges and direct costs due to hospitalization. During this longitudinal study conducted at the Albert Royer Pediatric Hospital in Dakar from October 15, 1991 to October 15, 1992 with 76 cases, malaria represented 5.2% of the febrile cases and 3.4% of the hospitalized cases. The lethality rate was 3.4%. Clinical features were not correlated with care charges and thus were not good indicators of worker's labor. The average cost of a cerebral malaria hospitalization was estimated at 35,710 F CFA (In October 1992, 1 F CFA = 0.02 FF). This cost is very high depending the limited resources of the region. Rapid and proper treatment of malaria cases may lead to a significant reduction of costs.

Sleep apnoea syndrome secondary to rheumatoid arthritis.

A patient who developed severe sleepiness and sleep apnoea in association with adult acquired retrognathia and subluxation of the cervical spine at the level of C3-C4, both resulting from rheumatoid arthritis, is described. The possible causative factors of the association between sleep apnoea and rheumatoid arthritis include reduction of the size of the upper airway by temporomandibular joint destruction, brainstem compression due to rheumatoid arthritis affecting the cervical spine, sleep fragmentation, and drug effects.

[Right to left shunts in the adult]. / Les shunts droite-gauche de l'adulte.

Right to left shunts in the adult in their usual location are either intraarticular or intrapulmonary, and are often congenital. The acquired intrapulmonary shunt of the cirrhotic is now well defined by the hepatopulmonary syndrome. The major complication of right to left shunts are paradoxical pulmonary emboli which are often more severe than haemoptysis or chronic hypoxia. The diagnosis of intracardiac shunts as well as intrapulmonary shunts is now easier, thanks to transoesophageal ultrasound associated with contrast. Pulmonary angiography enables the treatment of arteriovenous fistula to be carried out by embolisation, and also avoids any surgery.

[Sero-epidemiological study in Mauritania (1985-1986): incidence of treponematosis, hepatitis B virus, HIV virus and viral hemorrhagic fevers]. / Etude séro-épidémiologique en Mauritanie (1985-1986): fréquence des tréponématoses, du virus de l'hépatite B, du virus VIH et des fièvres hémorragiques virales.

A serological serosurvey was made in different ethnic groups of Mauritania in 1985. A very high prevalence of hepatitis B markers was found with more than 20% of HBs antigen carriers. Treponema specific antibodies in low-age classes observed is a reflect of endemic syphilis. The seroprevalence of antibody against HIV and viral haemorrhagic fever viruses (Rift Valley fever, Crimean-Congo haemorrhagic fever and haemorrhagic fever with renal syndrome) was very low.

PIP: A serological survey in Mauritania in 1985-86 provided data on certain viral and bacterial markers whose frequency has been well established in countries neighboring this gateway between North Africa and subSaharan Africa. Blood samples from 1230 male blood donors and 983 pregnant women at the hospital in Nouakchott were analyzed for treponema infection, hepatitis B, HIV, and for antibodies to certain viruses causing hemorrhagic fever. Positive results for treponema specific antibodies using the Kline reaction were obtained in 76 of 2213 serums examined. High positive rates in young age groups reflect endemic nonvenereal treponematosis. 16 of 218 persons aged 10-19 tested positive compared to 10 of 593 aged 30-39 and 2 of 133 aged over 40. Observed differences between ethnic groups were highly significant. Infection rates were higher among males except among the Poulars. A very high prevalence of hepatitis B markers was found with more than 20% of hepatitis B surface antigen carriers among the 766 samples studied. 88.68% of the 813 subjects studied had been infected with the hepatitis B virus. The results suggest that nomadism, or the hygienic conditions of nomadism, favor contamination by the hepatitis B virus. 3 of the 510 samples examined were positive for HIV. Only 1 of the positive samples was from a Mauritanian, a 28-year-old male Poular. The other 2 positive results were obtained from foreigners temporarily residing at Nouakchott. The prevalence of antibodies against the viruses responsible for hemorrhagic fever was very low: 1/965 for the Crimee-Congo, 2/965 for the Rift Valley fever virus, and 3/965 for the Hantaan virus.

[Epidemiology of Pseudomonas aeruginosa in Mauritania: study of 239 strains of various origins]. / Epidémiologie de Pseudomonas aeruginosa en Mauritanie: étude de 239 souches d'origines diverses.

239 strains (173 from hospital infections, 20 from carriers, 46 from animal infections and environment) were studied with regard to their serogroups, biovars, phage-types and drug-resistance. 82.2% of all strains were typable by specific immune sera and distributed in 15 serogroups (0:1, 0:2, 0:3, 0:4, 0:5, 0:6, 0:7, 0:8, 0:9, 0:10, 0:11, 0:12, 0:13, 0:15, 0:16). Among them, 8 were ubiquitous (0:1, 0:3, 0:4, 0:5, 0:8, 0:9, 0:11 and 0:16) and found in hospital patients, carriers, animals and environment. Thirty-five 0:11 strains and four no agglutinable strains produced an orthonitrophenyl beta-d-galactopyranoside hydrolase (ONPG +). Among 183 strains typable by phages of the Lindberg phage-typing system, 96 different phage-types were recognized. The proportions of the strains untypable by phages were 8.6% for animal strains, 23.6% for hospital strains and 55% for strains from carriers. The frequency of the resistance to each of eleven tested antibiotics was as follows: carbenicillin: 48%, ticarcillin: 12.2%, azlocillin: 9.1%, cefotaxime: 22.8%, cefsulodin: 27.4%, ceftazidime: 0.5%, latamoxef: 6.2%, gentamycin: 12.2%, amikacin: 15.4%, tobramycin: 12.5%, norfloxacin: 0%. However, 18.7% of hospital strains, 65% from carriers and 92.5% of animal or environmental strains were susceptible to all of these antibiotics. These results are compared with those from a previous report on epidemiology of P. aeruginosa hospital infection in Ivory-Coast (Dosso, Vieu et al., Bull. Soc. Path. exot., 1987, 80, 19-27) and with the data of the scientific literature.

Effects of naftidrofuryl on cerebral hemodynamics, metabolism and function after a retracted ischaemia.

Unilateral microemboli were formed in the brains of Long Evans rats by means of an intracarotid injection of microspheres (50 mu). This embolization resulted in a decrease in blood flow, severe cerebral oedema and a modification of glucose uptake. Furthermore, these microemboli affected a conditioned avoidance response. Naftidrofuryl enabled a better recovery of the processes involved in the expression of acquisition. This has been related to a decrease in the development of oedema on one side and to a better glucose uptake on the other. These data demonstrated that naftidrofuryl influences the sequelae of rapidly regressive ischaemia.

Short-term memory and cerebral ischemia: pharmacological application.

Transient ischemia results in changes in the cerebral blood flow at the level of microinfarcts, enzymatic and metabolic changes and the development of a cerebral edema; all these disorders regress in the week following ischemia. Besides, the observed functional disorders disappear as the cerebral edema regresses. The brain functional activity is protected by the use of treatments which reduce the development of the cerebral edema and/or a quicker regression of the edema.

[Cerebral blood flow, metabolism and learning after a cerebral infarction in the rat (author's transl)]. / Débit cérébral, métabolisme et comportement a la suite d'un infarctus cérébral chez le rat.

Experimental microembolization of the rat brain has been used as a model for the production of cerebral microinfarction which resulted in a decrease in blood flow and secondary brain edema with changes in the oxidative metabolic pathways. The use of radioactive microspheres as embolizing agents allowed to determine the number of microinfarctions and their localization. In every microinfarct, oedema developed and it could be quantified by measuring the water percentage as soon as the fourth hour following the microembolization. The activity of oxygen-dependent enzymes was severely reduced in the ischemic area around which hyperemia was present. A quick decrease in the ATP and glucose levels and an increase in the lactate levels were observed, showing that the energetic metabolism was deviated towards the anaerobic pathway. On the fifth day following the microembolization, the oedema disappeared. The cellular metabolic activity and the cerebral blood flow almost returned to normal values within the same time. The simultaneously study of an avoidance response in a conditioned learning test showed a correlation between the reappearance of this response and the regression of the oedema.