[Epidemiological surveillance: family doctors' responsibility]. / Surveillance épidémiologique: une responsabilité du médecin de famille.

Epidemiological surveillance systems are essential and require efficient collaborations between family doctors and public health services. Such a system has to take into account the increase in the number of health problems to be studied. Information gathered at an individual level should imply decisions at a population level which in turn should impact on the individual patient. Epidemiological surveillance requires a well organized, representative and constantly revised system led by motivated, adequately trained doctors.

[The place of the clinic in primary case--the TOPIC study]. / Place de la clinique en médecine ambulatoire--les enseignements de l'etude TOPIC.

We know very little about the importance of history and physical examination compared to the importance of paraclinical tests in the diagnostic process in primary care. To answer this question, we examined prospectively 672 consecutive patients with chest pain in primary care. We recorded the timing and the clinical characteristics of the most frequent diagnosis. The resort to laboratory or other clinical tests and reference to specialist were influenced by: emergency consultation, potentially life-threatening aetiology, personal characteristics of the general practitioners' (GP) and patients' anxiety. GPs attributed the diagnosis to history and physical examination alone in 66% and to the association of history, physical examination and tests in 31% cases. This, clinical strategy remains the most important factor in the diagnostic process; even when they are insufficient, they allowed to generate hypotheses and guide investigations.

Chronic norovirus infection in primary immune deficiency disorders: an international case series.

OBJECTIVE: Predictive factors associated with clinical outcomes of chronic norovirus infection (CNI) in primary immunodeficiency diseases (PIDD) are lacking. METHOD: We sought to characterize CNI using a multi-institutional cohort of patients with PIDD and CNI using the Clinical Immunology Society's CIS-PIDD Listserv e-mail group. RESULTS: Thirty-four subjects (21 males and 13 females) were reported from centers across North America, Europe, and Asia. All subjects were receiving high doses (median IgG dose: 1200 mg/kg/month) of supplemental immunoglobulin therapy. Fifty-three percent had a complete absence of B cells (median B-cell count 0; range 0-139 cells/µL). Common Variable Immune Deficiency (CVID) subjects manifested a unique phenotype with B-cell lymphopenia, non O+ blood type, and villous atrophy (logistic regression model, P = 0.01). Five subjects died, all of whom had no evidence of villous atrophy. CONCLUSION: While Norovirus (NoV) is thought to replicate in B cells, in this PIDD cohort of CNI, B-cell lymphopenia was common, indicating that the presence of B lymphocytes is not essential for CNI.

Hematopoietic stem cell transplantation for primary immunodeficiency disease.

Hematopoietic stem cell transplantation is the definitive therapy for a variety of rare primary cellular immunodeficiency syndromes diagnosed in children. All primary immunodeficiencies benefit from early diagnosis and transplantation before the development of serious infections, which contribute to a significant increased risk of mortality following transplant. In the absence of a matched sibling, parental haplocompatible, matched unrelated donor and cord blood stem cells have all been utilized with varying degrees of success and immune reconstitution. The role of pretransplant conditioning in patients with SCID disease in terms of its effects upon T- and B-cell immune reconstitution and late effects is still under debate and will require further study.

Increasing mixed chimerism and the risk of graft loss in children undergoing allogeneic hematopoietic stem cell transplantation for non-malignant disorders.

We performed quantitative PCR-based serial chimerism testing of whole blood (WB) and CD3+ cells and retrospectively correlated the results of chimerism tests and the risk of graft loss in children undergoing transplant for non-malignant disorders. Twenty-four children were included in this study. All patients initially engrafted; subsequently, 12% lost the graft, 21% achieved complete donor chimerism and 67% had mixed chimerism (MC). Patients underwent delayed taper of cyclosporine (CsA) if they had MC. Overall survival was 87+/-7% (s.d.) at 5-years post transplant, and it was not affected by chimerism status. Both WB and CD3+ chimerism showed significant fluctuations with a peak in autologous cell signal occurring at a median of 7 months for WB and 2 months for CD3+ cells. Initial post transplant chimerism percentage in either WB or CD3+ lineage was not related to graft loss. Increasing MC to >30% host cells was seen in 33% of patients, and it was related to increased risk of graft loss, as previously published. However, 63% of children with increasing MC did not lose their graft. Additional studies of post transplant chimerism are required to improve our ability to accurately identify children at risk of graft loss following transplant for non-malignant disorders.

Demonstration by in situ hybridization of the zonal modulation of rat liver cytochrome P-450b and P-450e gene expression after phenobarbital.

The various physiological processes that constitute liver function are compartmentalized within the hepatic acinus. The molecular mechanisms modulating the development and maintenance of this hepatocyte heterogeneity have not been defined. The objective of this study was to determine whether transcriptional or posttranscriptional zonal modulation of cytochromes P-450b,e gene expression was responsible for the heterogeneous induction of the P-450 proteins, which is observed after phenobarbital (PB) administration. The exact localization in liver tissue of hepatocytes responding to PB with induction of either P-450b,e mRNA or proteins was established by in situ hybridization and by immunofluorescence, respectively. As demonstrated by quantitative assessment of autoradiographs of approximately 20 hepatocytes located between a terminal portal venule and a hepatic venule, PB induced the P-450b,e mRNA up to sixfold in the 12-15 hepatocytes located closer to the hepatic venules (zones 2 and 3). In contrast, there was only a twofold induction in the 4-6 hepatocytes surrounding the terminal portal venules (zone 1). Quantitative immunofluorescence using an MAb showed that the acinar distribution of PB-induced P-450b,e proteins was similar to that of the mRNA. This combined approach indicated that, most likely, an increased rate of transcription of cytochromes P-450b,e genes in hepatocytes of zones 2 and 3 concomitantly, with a relative lack of activation, or repression, of these genes in hepatocytes of zone 1, were responsible for the heterogeneous phenotype observed after PB administration. Therefore, modulation of gene expression among hepatocytes of the liver acinus is one mechanism by which the functional heterogeneity of hepatocytes is attained. Experiments in which the induction of cytochromes P-450b,e genes was studied after administration of either PB or para-hydroxyphenobarbital, a main hepatic metabolite of PB, suggested that the species involved in the inductive process is the parent PB molecule rather than para-hydroxyphenobarbital.

Pre-existing invasive fungal infection is not a contraindication for allogeneic HSCT for patients with hematologic malignancies: a CIBMTR study.

Patients with prior invasive fungal infection (IFI) increasingly proceed to allogeneic hematopoietic cell transplantation (HSCT). However, little is known about the impact of prior IFI on survival. Patients with pre-transplant IFI (cases; n=825) were compared with controls (n=10247). A subset analysis assessed outcomes in leukemia patients pre- and post 2001. Cases were older with lower performance status (KPS), more advanced disease, higher likelihood of AML and having received cord blood, reduced intensity conditioning, mold-active fungal prophylaxis and more recently transplanted. Aspergillus spp. and Candida spp. were the most commonly identified pathogens. 68% of patients had primarily pulmonary involvement. Univariate and multivariable analysis demonstrated inferior PFS and overall survival (OS) for cases. At 2 years, cases had higher mortality and shorter PFS with significant increases in non-relapse mortality (NRM) but no difference in relapse. One year probability of post-HSCT IFI was 24% (cases) and 17% (control, P<0.001). The predominant cause of death was underlying malignancy; infectious death was higher in cases (13% vs 9%). In the subset analysis, patients transplanted before 2001 had increased NRM with inferior OS and PFS compared with later cases. Pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT but significant survivorship was observed. Consequently, pre-transplant IFI should not be a contraindication to allogeneic HSCT in otherwise suitable candidates. Documented pre-transplant IFI is associated with lower PFS and OS after allogeneic HSCT. However, mortality post transplant is more influenced by advanced disease status than previous IFI. Pre-transplant IFI does not appear to be a contraindication to allogeneic HSCT.

Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors.

Inflammatory myofibroblastic tumor (IMT) is a relatively rare soft tissue tumor. The reactive versus neoplastic pathogenesis of this tumor is unresolved. We found clonal chromosome aberrations involving 2p23 upon metaphase analysis of two IMTs. Fluorescence in situ hybridization with a probe flanking the ALK gene at 2p23 demonstrated rearrangement of the probe in both of these cases and in a third case, and immunohistochemistry revealed ALK expression in all three cases. 2p22-24 involvement has been reported previously in four additional cases of IMT. We suggest that chromosomal rearrangements involving 2p23 near or within ALK are recurrent alterations in IMT and that ALK may have a novel role outside its previously recognized realm of lymphoid neoplasms.

The incidence, mortality and timing of Pneumocystis jiroveci pneumonia after hematopoietic cell transplantation: a CIBMTR analysis.

Pneumocystis jiroveci pneumonia (PJP) is associated with high morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Little is known about PJP infections after HSCT because of the rarity of disease given routine prophylaxis. We report the results of a Center for International Blood and Marrow Transplant Research study evaluating the incidence, timing, prophylaxis agents, risk factors and mortality of PJP after autologous (auto) and allogeneic (allo) HSCT. Between 1995 and 2005, 0.63% allo recipients and 0.28% auto recipients of first HSCT developed PJP. Cases occurred as early as 30 days to beyond a year after allo HSCT. A nested case cohort analysis with supplemental data (n=68 allo cases, n=111 allo controls) revealed that risk factors for PJP infection included lymphopenia and mismatch after HSCT. After allo or auto HSCT, overall survival was significantly poorer among cases vs controls (P=0.0004). After controlling for significant variables, the proportional hazards model revealed that PJP cases were 6.87 times more likely to die vs matched controls (P<0.0001). We conclude PJP infection is rare after HSCT but is associated with high mortality. Factors associated with GVHD and with poor immune reconstitution are among the risk factors for PJP and suggest that protracted prophylaxis for PJP in high-risk HSCT recipients may improve outcomes.

Risks and outcomes of invasive fungal infections in pediatric patients undergoing allogeneic hematopoietic cell transplantation.

Invasive fungal infections (IFI) are the leading cause of infectious mortality in adult patients undergoing hematopoietic cell transplantation (HCT) after myeloablative conditioning, but the extent of this problem in the pediatric population is unclear. We retrospectively examined risk factors for IFI among 120 consecutive pediatric patients undergoing allogeneic HCT at a single center. The incidence of proven or probable IFI in pediatric patients during the first year after allogeneic HCT was 13%, comparable to the rate reported in adult patients; however, unlike IFI in adult patients, the majority of IFI in children occurred within the first month after transplantation. The primary risk factors for IFI were duration of neutropenia, age greater than 10 years, transplant for severe aplastic anemia or Fanconi anemia, and high-dose corticosteroid administration for 10 days or longer. IFI were more likely to be successfully treated (42%, 5/12 patients) in pediatric HCT recipients when compared to previous reports of adult recipients. Nonrelapse mortality was estimated at 17% (20/120 patients) after allogeneic HCT, of which 35% (seven patients) were directly attributed to IFI. Thus, IFI is a significant cause of nonrelapse mortality in children undergoing allogeneic HCT and more effective strategies are needed to prevent and treat IFI.

Gene discovery and expression profiling in porcine Peyer's patch.

Peyer's patches of the intestinal mucosa are essential for host defense and immune regulation in the enteric system. To better understand molecular mechanisms of Peyer's patch function, we have screened for differentially expressed genes specific to Peyer's patch. cDNA libraries were created from normal Peyer's patch, immune stimulated Peyer's patch, and pooled cDNA subtracted with fibroblast RNA. From the subtracted library, 3687 expressed sequence tags (ESTs), representing 2414 unique nucleotide sequences, were isolated, identified by BLAST searches against public databases, and spotted onto a microarray for gene expression profiling. Approximately 30% of these ESTs BLAST to genes of unknown function and 20% have no known homology in the public databases (novel genes). Of the novel genes, 70% are expressed in normal immune tissues by microarray analysis, suggesting that at least 371 of the unidentified EST sequences from the subtracted library are novel porcine genes and can now be further characterized to determine their function in the porcine Peyer's patch. We surmise that the products of these genes participate in biochemical and cellular functions related to the unique immunological and gastroenterological functions of the small intestine. The BLAST and gene ontology information for each of the subtracted library EST sequences, the normal and immune stimulated libraries, and the microarray are all valuable resources that will facilitate further examination of the biological function of porcine Peyer's patch tissue.

Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies.

Clinical outcomes after primary graft failure (PGF) remain poor. Here we present a large retrospective analysis (n=23,272) which investigates means to prevent PGF and early detection of patients at high risk. In patients with hematologic malignancies, who underwent their first myeloablative allogeneic hematopoietic cell transplantation, PGF was reported in 1278 (5.5%), and there was a marked difference in PGFs using peripheral blood stem cell compared with bone marrow grafts (2.5 vs 7.3%; P<0.001). A fourfold increase of PGF was observed in myeloproliferative disorders compared with acute leukemia (P<0.001). Other risk factors for PGF included recipient age <30, HLA mismatch, male recipients of female donor grafts, ABO incompatibility, busulfan/cyclophosphamide conditioning and cryopreservation. In bone marrow transplants, total nucleated cell doses ⩽2.4 × 10(8) per kg were associated with PGF (odds ratio 1.39; P<0.001). The use of tacrolimus-based immunosuppression and granulocyte colony-stimulating factor were associated with decreased PGF risk. These data, allow clinicians to do more informed choices with respect to graft source, donor selection, conditioning and immunosuppressive regimens to reduce the risk of PGF. Moreover, a novel risk score determined on day 21 post transplant may provide the rationale for an early request for additional hematopoietic stem cells.

Quantitative electron microscopic analysis of the optic nerve of the turtle, Pseudemys.

It is estimated by means of electron microscopy that the optic nerve of the turtle Pseudemys scripta elegans contains 394,900 fibers of which approximately 80% are myelinated. The total fiber count agrees well with counts obtained from electron microscopic studies on other turtle species. There are, however, differences among these species in the percentage of myelinated fibers in the optic nerve. The axon diameter distribution of the myelinated fibers (excluding myelin) has a mode at 0.87 micrometer while that of the unmyelinated fibers has a mode at 0.42 micrometer. Both distributions are unimodal and are of a similar form in all areas of the nerve sampled. The total fiber count reported here agrees well with previous reports of ganglion cell counts in Pseudemys and the characteristics of the fiber distributions are comparable to those reported for nonreptilian vertebrates.

9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine: a new potent and selective antiherpes agent.

The synthesis of a new acyclic analogue of deoxyguanosine, 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG, 1), is described starting from epichlorohydrin via condensation of 2-O-(acetoxymethyl)-1,3-di-O-benzylglycerol (5) with N2,9-diacetylguanine (6). In vitro studies indicate that DHPG is a potent and broad-acting (herpes simplex virus types 1 and 2, cytomegalovirus, and Epstein-Barr virus) antiherpetic agent. In vivo studies indicate its lack of toxicity [LD50 (mice) = 1-2 g/kg, ip] and its superiority over acyclovir [oral ED50 = 7 (mg/kg)/day vs. 550 (mg/kg)/day in HSV-2 infected mice].

Synthesis and central nervous system properties of 2-[(alkoxycarbonyl)amino]-4(5)-phenyl-2-imidazolines.

A series of 2-[( alkoxycarbonyl )amino]-4(5)-phenyl-2-imidazolines was prepared and evaluated for central nervous system (CNS) effects (antidepressant, anticonvulsant, muscle relaxant, and depressant) in animal models. Some separation of those CNS activities was achieved through substitutions on the phenyl and imidazoline moieties. Halo-substituted phenyl compounds were among the most potent antidepressants in this series, while imidazole N-alkylation produced compounds with increased depressant effects (loss of righting reflex, mouse behavior). Comparison of in vitro and in vivo data for pairs of 2-[(methoxycarbonyl)amino]-4(5)-phenyl-2-imidazolines and their parent, 2-amino-4(5)-phenyl-2-imidazolines, suggests that the title compounds were prodrugs for the 2-amino-4(5)-phenyl-2-imidazolines in inhibition of norepinephrine reuptake.

Methyl 5(6)-phenylsulfinyl-2-benzimidazolecarbamate, a new, potent anthelmintic.

1. Human hepatic "acid" beta-galactosidase preparations, which had been purified approximately 250-fold, were examined for activities toward 4-methylumbelliferyl beta-galactosylceramide, lactosylceramide, galactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosyl-glucosylceramide(GM1-ganglioside) and galactosyl-N-acetylgalactosaminyl-galactosyl-glucosylceramide (asialo GM1-ganglioside). 2. The enzyme was active toward the synthetic substrate, GM1-ganglioside and asialo GM1-ganglioside but was inactive toward galactosylceramide. Under our assay conditions, optimized for lactosylceramidase II, the preparations were as active toward lactosylceramide as toward GM1-ganglioside or its asialo derivative. The apparent Km values for the three natural substrates were similar. When determined by the assay system of Wehger, D.A., Sattler, M., Clark, C. and McKelvey, H. (1974) Clin. Chim Acta 56, 199-206, lactosylceramide-cleaving activity was 0.2% of that determined by our assay system. This confirmed our previous suggestion that the Wenger assay system determines exclusively the activity of lactosylceramidase I, which is probably identical with galactosylceramide beta-galactosidase. 3. Crude sodium taurocholate was far more effective than pure taurocholate in stimulating hydrolysis of the three glycosphingolipids by the beta-galactosidase. However, crude taurocholate could largely be replaced by smaller amounts of sodium taurodeoxycholate, suggesting that the unique activating capacity of the crude taurocholate might be due to taurodeoxycholate present as the major impurity. 4. Cl- was generally stimulatory for hydrolysis of the natural glycosphingolipids by our enzyme preparation. Effects of additional oleic acid and Triton X-100 were generally minor in either direction. 5. When the enzyme preparation was diluted with water, activity toward the synthetic substrate declined rapidly while those toward the natural substrates were essentially stable. Activity toward the synthetic substrate remained much more stable when the enzyme was diluted with 0.1 M sodium citrate/phosphate buffer, pH 5.0. 6. These observations provide insight into the complex relationship among the human hepatic beta-galactosidases.

Anaplastic thyroid carcinoma: a 50-year experience at a single institution.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is among the most aggressive of human malignancies. However, there have been few large studies of histologically well-defined ATC. We report the results of a 50-year experience of this lethal malignancy. METHODS: We reviewed all cases of ATC managed in this institution between 1949 and 1999. One pathologist (J.R.G.) reviewed all pathologic material. Clinical details were obtained from medical records, and current status of all patients was determined. RESULTS: There were 134 cases, with a female-to-male ratio of 1.5:1 and a mean age of 67 years. Benign thyroid disease was present in 27 cases (20%) and well-differentiated thyroid carcinoma in 31 (23%). Sixty-two patients (46%) had distant metastases at diagnosis, and 98% of the tumors were locally invasive. Primary treatment was surgical for 96 patients (72%). Complete resection was achieved in 29 cases (30%), with "minimal residual disease" in 25. Neither extent of operation nor completeness of resection affected survival (P > .4). Postoperative radiotherapy gave slightly longer median survival (5 vs 3 months), which was not significant (P < .08). Multimodal therapy, including operation, chemotherapy, and radiotherapy, did not improve survival. CONCLUSIONS: The outlook for patients with ATC remains grim. Novel treatments for ATC are desperately needed.

Haploidentical related-donor hematopoietic cell transplantation in children using megadoses of CliniMACs-selected CD34(+) cells and a fixed CD3(+) dose.

We conducted a prospective phase II trial utilizing the CliniMACs system to perform CD34(+)-cell selection of PBSCs from haploidentical donors to evaluate engraftment and hematoimmunological reconstitution. In total, 21 children with hematological malignancies or nonmalignant conditions underwent conditioning with 1200 cGy TBI, thiotepa, fludarabine and Thymoglobulin. Patients received megadoses of CD34(+) cells (median: 22 × 10(6)/kg) with a fixed dose of 3 × 10(4)/kg CD3(+) cells/kg, and engraftment occurred in 90% with prompt recovery of neutrophils and platelets. Grade II acute GVHD (aGVHD) was seen in 32% (95% confidence interval (CI), 15-54%) of evaluable patients, there was no grade III-IV aGVHD, and chronic extensive GVHD was seen in 35% (95% CI, 17-59%) of patients. The estimated 2-year EFS was 62% (95% CI, 48-83%) with a median survivor follow-up of 49 months (range: 18-119 months). Patients with nonmalignant diseases had an estimated 2-year EFS of 100% (95% CI, 56-100%) and patients with malignancies in remission had an estimated 2-year EFS of 56% (95% CI, 22-89%). Megadose CD34(+) cells with a fixed CD3(+) cell dose from haploidentical related donors resulted in good outcomes for pediatric patients with nonmalignant diseases and those with malignant diseases transplanted in remission.