From intra- to extra-uterine: early phase design of a transfer to extra-uterine life support through medical simulation.

Introduction: Extra-uterine life support technology could provide a more physiologic alternative for the treatment of extremely premature infants, as it allows further fetal growth and development ex utero. Animal studies have been carried out which involved placing fetuses in a liquid-filled incubator, with oxygen supplied through an oxygenator connected to the umbilical vessels. Hence, by delaying lung exposure to air, further lung development and maturation can take place. This medical intervention requires adjustments to current obstetric procedures to maintain liquid-filled lungs through a so-called transfer procedure. Methods: Our objective was to develop obstetric device prototypes that allow clinicians to simulate this birth procedure to safely transfer the infant from the mother's uterus to an extra-uterine life support system. To facilitate a user-centered design, implementation of medical simulation during early phase design of the prototype development was used. First, the requirements for the procedure and devices were established, by reviewing the literature and through interviewing direct stakeholders. The initial transfer device prototypes were tested on maternal and fetal manikins in participatory simulations with clinicians. Results & discussion: Through analysis of recordings of the simulations, the prototypes were evaluated on effectiveness, safety and usability with latent conditions being identified and improved. This medical simulation-based design process resulted in the development of a set of surgical prototypes and allowed for knowledge building on obstetric care in an extra-uterine life support context.

Simulation-based development: shaping clinical procedures for extra-uterine life support technology.

BACKGROUND: Research into Artificial Placenta and Artificial Womb (APAW) technology for extremely premature infants (born < 28 weeks of gestation) is currently being conducted in animal studies and shows promising results. Because of the unprecedented nature of a potential treatment and the high-risk and low incidence of occurrence, translation to the human condition is a complex task. Consequently, the obstetric procedure, the act of transferring the infant from the pregnant woman to the APAW system, has not yet been established for human patients. The use of simulation-based user-centered development allows for a safe environment in which protocols and devices can be conceptualized and tested. Our aim is to use participatory design principles in a simulation context, to gain and integrate the user perspectives in the early design phase of a protocol for this novel procedure. METHODS: Simulation protocols and prototypes were developed using an iterative participatory design approach; usability testing, including general and task-specific feedback, was obtained from participants with clinical expertise from a range of disciplines. The procedure made use of fetal and maternal manikins and included animations and protocol task cards. RESULTS: Physical simulation with the active participation of clinicians led to the diffusion of tacit knowledge and an iteratively formed shared understanding of the requirements and values that needed to be implemented in the procedure. At each sequel, participant input was translated into simulation protocols and design adjustments. CONCLUSION: This work demonstrates that simulation-based participatory design can aid in shaping the future of clinical procedure and product development and rehearsing future implementation with healthcare professionals.

Clinical aspects of umbilical cord cannulation during transfer from the uterus to a liquid-based perinatal life support system for extremely premature infants a qualitative generic study.

A liquid-based perinatal life support system (PLS) for extremely premature infants (born before 28 week of gestational age) envisions a connection between the infant's native umbilical cord and an artificial placenta system through cannulation. This system mimics a natural mothers' womb to achieve better organ maturations. The objective of this study is to gain insight into the clinical focus points of umbilical cord cannulation and how cannulation should be addressed in extremely premature infants during the transfer from the uterus to an in-utero simulating liquid-based PLS system. We performed an explorative qualitative study. Twelve medical specialists with knowledge of vessel cannulation participated. We collected data through twelve interviews and two focus group discussions. Data were analyzed using inductive content and constant comparison analysis via open and axial coding. Results were derived on the following topics: (1) cannulation technique, (2) cannula fixation, (3) local and systemic anticoagulation, and (4) vasospasm. A side-entry technique is preferred as this may decrease wall damage, stabilizes the vessel better and ensures continuous blood flow. Sutures, especially via an automatic microsurgery instrument, are favored above glue, stents, or balloons as these may be firmer and faster. Medication possibilities for both vasospasm and anticoagulation should function locally since there were uncertainties regarding the systemic effects. According to the findings of this research, the needed umbilical cord cannulation method should include minimal wall damage, improved vascular stability, blood flow maintenance, a strong fixation connection, and local anticoagulation effect.

Molecular characterization and delineation of subtle deletions in de novo "balanced" chromosomal rearrangements.

To test the hypothesis that the phenotypic abnormalities seen in cases with apparently balanced chromosomal rearrangements are the result of the presence of cryptic deletions or duplications of chromosomal material near the breakpoints, we analyzed three cases with apparently balanced chromosomal rearrangements and phenotypic abnormalities. We characterized the breakpoints in these cases by using microsatellite analysis by polymerase chain reaction and fluorescence in situ hybridization analysis of yeast artificial chromosome clones selected from the breakpoint regions. Molecular characterization of the translocation breakpoint in patient 1 [46,XY,t(2;6)(p22.2;q23.1)] showed the presence of a 4- to 6-Mb cryptic deletion between markers D6S412 and D6S1705 near the 6q23.1 breakpoint. Molecular characterization of the proximal inversion 7q22.1 breakpoint in patient 2 [46,XY,inv(7)(q22.1q32.1)] revealed the presence of a 4-Mb cryptic deletion between D7S651 and D7S515 markers. No deletion or duplication of chromosomal material was found near the breakpoints in patient 3 [46,XX,t(2;6)(q33.1;p12.2)]. Our study suggests that a systematic molecular study of breakpoints should be carried out in cases with apparently balanced chromosomal rearrangements and phenotypic abnormalities, because cryptic deletions near the breakpoints may explain the phenotypic abnormalities in these cases.

Parental origin of De Novo chromosome 9 deletions in del(9p) syndrome.

Parental origin of de novo deletions in the short arm of chromosome 9 in patients with a clinical diagnosis of del(9p) syndrome was assessed in 13 patients using polymerase chain reaction (PCR) analysis of highly polymorphic dinucleotide repeat microsatellite markers located in the putative deleted region. The deletion was found to be of paternal origin in 9 cases and of maternal origin in the remaining 4 cases, suggesting that the molecular event resulting in the deletion occurs in both male and female gametogenesis and that genomic imprinting does not appear to play a role in the pathogenesis of del(9p) syndrome.

Chromosome abnormalities in B cell chronic lymphocytic leukemia and their clinical correlations.

Cytogenetic analysis was successfully performed on 31 of 40 patients with chronic B cell leukemia. Clonal abnormalities were seen in 16 patients using various culture methods. Fourteen of these had unstimulated cultures established of which 13 had the clonal abnormality. Trisomy 12 was observed in seven patients while a 14q32 translocation was present in four. Race, age, hemoglobin, WBC, percentage of lymphocytes and prolymphocytes in BM and PB, platelets, Smig, lymph node, spleen, liver, pattern of bone marrow infiltration, therapy free interval, and overall survival were all compared. Significant correlations between the presence of clonal abnormalities and prior therapy (p less than 0.005) and an increase in prolymphocytes in bone marrow (p = 0.05) and/or peripheral blood (p = 0.0014) were observed.

Neuroleptic malignant syndrome complicating closed head injury.

Lethargy, hyperpyrexia, tremor, and rigidity associated with leukocytosis and elevation of the creatine kinase level occurred in a patient with a closed head injury who was being treated with haloperidol for control of agitation. This constellation of symptoms, known as the neuroleptic malignant syndrome (NMS), partially improved when the neuroleptic medication was stopped, but complete resolution of the syndrome did not occur until the patient was treated with bromocriptine. Because haloperidol is the most widely used medication for the agitation that develops in patients with significant closed head injuries, neurosurgeons should be aware of the NMS. The NMS is caused by neuroleptic medications and may initially present with unexplained hyperpyrexia, leukocytosis, and elevated creatine kinase levels. Halting the neuroleptic, supportive care, and the use of dantrolene sodium and bromocriptine are the treatment modalities of choice for this syndrome, which has a mortality rate of 20 to 30% and may be linked to malignant hyperthermia.

Prognostic implications of karyotype and morphology in patients with non-Hodgkin's lymphoma.

Clonal chromosome abnormalities were observed in 30 patients with non-Hodgkin's lymphoma; the type of lymphoma was characterized on the basis of the International Working Formulation. The 30 patients were classified into five groups according to the chromosome abnormality. There were 8 patients with t(14;18), 3 with t(8;14), 7 with a translocation to the long arm of chromosome 3 (a 3q+ chromosome), 5 with near-tetraploidy, and 7 with other abnormalities. Among the 8 patients with t(14;18), 5 had follicular small cleaved-cell lymphoma (FSC), I had follicular mixed cell lymphoma (FM), and 2 had diffuse large-cell lymphoma (DL); the diagnosis in these 2 patients was based on extranodal tissue. All 3 patients with t(8;14) had DL and B-cell markers. Except for 1 patient, all those with a 3q+ chromosome had DL; 4 of those who were tested had B-cell or pre-B-cell markers. Four of the 5 patients with near-tetraploidy had follicular mixed-cell lymphoma, and 2 of the 7 patients with other abnormalities had T-cell lymphoma. Thus, patients with a t(8;14), a 14q+ chromosome, or a 3q+ chromosome all tend to have diffuse large-cell lymphoma, usually of the non-cleaved type. On the other hand, our data suggest that patients with FSC generally have a t(14;18) whereas those with follicular and diffuse mixed small cleaved cells and large noncleaved cells have a different pattern with modal chromosome numbers in the tetraploid range. We added 17 previously reported patients to the 30 presented here and correlated the karyotype with survival. The 6 patients with near-tetraploidy had the longest median survival, 69 months, the 15 patients with t(14;18) had the next longest, 48 months. The 4 patients with t(8;14) had the shortest survival, 12 months, and the 9 with other abnormalities had the next shortest, 17 months. Intermediate survivals of 27 and 30 months were observed in patients with a 14q+ or a 3q+ chromosome, respectively. The median survival of these various categories differs and our data, thus, indicate that the karyotypic pattern of the malignant cell may be a significant independent prognostic feature influencing the survival of patients with non-Hodgkin's lymphoma.

Nonrandom chromosome abnormalities in angioimmunoblastic lymphadenopathy.

Cytogenetic and pathologic studies were performed on six patients with angioimmunoblastic lymphadenopathy (AILD). All six had diffuse lymphadenopathy; five had fever, four had weight loss, and four had a diffuse erythematous rash. All patients except one had a polyclonal elevation of immunoglobulin. All patients had diagnostic findings in lymph node (LN) and bone marrow (BM) biopsies. Two patients died of progressive AILD; one patient died after transformation of AILC to immunoblastic sarcoma (IBS); one patient died of gastrointestinal bleeding of unknown cause. The remaining two patients, who have achieved complete remission with intensive chemotherapy, are alive 20 and 8 mo after the diagnosis; one of these had AILD and the other, both AILD and IBS. Despite diagnostic BM biopsy findings, none of the patients had chromosome abnormalities in their BM cells. In studying LN cels of 5 patients, however, we found chromosome abnormalities in each; clonal abnormalities were detected in two, both clonal and nonclonal abnormalities in two, and only nonclonal single-cell abnormalities in one. An extra chromosome 3, seen in four patients, was clonal in two and nonclonal in the two others. Cells with +5, +15, +19, +21, +22 were seen in two patients. All patients had 50% or more normal dividing cells in their LN. The mosaicism of unrelated abnormal cells in their LN. The mosaicism of unrelated abnormal karyotypes that was seen in four patients suggests that this malignant tumor is not necessarily monoclonal in its early stages, but that one clone may be selected and predominate in the late stage. Because nonrandom acquired clonal chromosome abnormalities are a consistent feature of malignancies, our data suggest that AILD may be a malignant disease despite its original description as a benign proliferative process. Therefore, it may require aggressive chemotherapy.

Evidence for shared idiotypy expressed by the IgM, IgG, and IgA serum proteins of a patient with a complex multiple paraprotein disorder.

The results of a comparative idiotypic analysis of multiple Ig paraproteins isolated from the serum of an individual patient, Ca, with Sjögren's syndrome and Waldenström's macroglobulinemia are reported. At initial presentation, Ca serum was found to contain two major paraproteins, an IgMkappa and an IgGkappa, together with a small elevation in the level of IgA protein. The patient's clinical course was characterized by dramatic and opposing changes in the respective serum levels of the IgMkappa and IgGkappa paraproteins over an extended time period that coincided in part with received chemotherapy. Idiotypic antigenic analysis of the IgMkappa and IgGkappa paraproteins revealed that the two monotypic proteins shared identical idiotypic determinants. The Ca IgA serum fraction, specifically isolated by an immunoabsorbent and free of any IgG and IgM, was shown to possess idiotypic determinants identical to the IgG and IgM proteins. In extensive tests of specificity, the idiotypic determinants shared by Ca IgM, IgG, and IgA proteins were not present in large excesses of heterologous IgM and IgG, nor on Ig molecules contained in a large number of normal and myeloma sera.

[Epidemiology of C57 black/6M mouse strain: statistical findings in a control population]. / Epidémiologie de la souris C 57 black/6 M: données actuarielles d'une population témoin.

Non-linearity in age specific gompertzian rates regression versus age was observed in actuarial analysis of all causes of death, tumor incidence and tumor/tumor-host index in 503 male and 497 female control C57 Black/6M mice. The overall tumor incidence averaged 66.7% in males and 84.4% in females during a maximum lifespan of 1,300 days. In males as well as in females, time related incidence peaks were identified for lymphocytic lympho-sarcomas, reticulum cell sarcomas, histiocytic type and reticulum cell sarcomas of reticular type.