Integrin α4-positive human trophoblast progenitors: functional characterization and transcriptional regulation.

STUDY QUESTION: What are the functional characteristics and transcriptional regulators of human trophoblast progenitor cells (TBPCs)? SUMMARY ANSWER: TBPC lines established from the human smooth chorion by cell sorting for integrin α4 expressed markers of stemness and trophoblast (TB) stage-specific antigens, invaded Matrigel substrates and contributed to the cytotrophoblasts (CTBs) layer of smooth chorion explants with high-mobility group protein HMGI-C (HMGA2) and transcription factor GATA-4 (GATA4) controlling their progenitor state and TB identity. WHAT IS KNOWN ALREADY: Previously, we reported the derivation of TBPC lines by trypsinization of colonies that formed in cultures of chorionic mesenchyme cells that were treated with an activin nodal inhibitor. Microarray analyses showed that, among integrins, α4 was most highly expressed, and identified HMGA2 and GATA4 as potential transcriptional regulators. STUDY DESIGN, SIZE, DURATION: The aim of this study was to streamline TBPC derivation across gestation. High-cell surface expression of integrin α4 enabled the use of a fluorescence-activated cell sorter (FACS) approach for TBPC isolation from the human smooth chorion (n = 6 lines). To confirm their TBPC identity, we profiled their expression of stemness and TB markers, and growth factor receptors. At a functional level, we assayed their invasive capacity (n = 3) and tropism for the CTB layer of the smooth chorion (n = 3). At a molecular level, we studied the roles of HMGA2 and GATA4. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Cells were enzymatically disassociated from the human smooth chorion across gestation. FACS was used to isolate the integrin α4-positive population. In total, we established six TBPC lines, two per trimester. Their identity was determined by immunolocalization of a suite of antigens. Function was assessed via Matrigel invasion and co-culture with explants of the human smooth chorion. An siRNA approach was used to down-regulate HMGA2 and GATA4 expression and the results were confirmed by immunoblotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses. The endpoints analyzed included proliferation, as determined by 5-bromo-2'-deoxyuridine (BrDU) incorporation, and the expression of stage-specific antigens and hormones, as determined by qRT-PCR and immunostaining approaches. MAIN RESULTS AND THE ROLE OF CHANCE: As with the original cell lines, the progenitors expressed a combination of human embryonic stem cell and TB markers. Upon differentiation, they primarily formed CTBs, which were capable of Matrigel invasion. Co-culture of the cells with smooth chorion explants enabled their migration through the mesenchyme after which they intercalated within the chorionic CTB layer. Down-regulation of HMGA2 showed that this DNA-binding protein governed their self-renewal. Both HMGA2 and GATA4 had pleitropic effects on the cells' progenitor state and TB identity. LIMITATIONS, REASONS FOR CAUTION: This study supported our hypothesis that TBPCs from the chorionic mesenchyme can contribute to the subpopulation of CTBs that reside in the smooth chorion. In the absence of in vivo data, which is difficult to obtain in humans, the results have the limitations common to all in vitro studies. WIDER IMPLICATIONS OF THE FINDINGS: The accepted view is that progenitors reside among the villous CTB subpopulation. Here, we show that TBPCs also reside in the mesenchymal layer of the smooth chorion throughout gestation. We theorize that they can contribute to the CTB layer in this region. This phenomenon may be particularly important in pathological situations when CTBs of the smooth chorion might provide a functional reserve for CTBs of the placenta proper. STUDY FUNDING/COMPETING INTERESTS: Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award P50HD055764. O.G., N.L., K.O., A.P., T.G.-G., M.K., A.B., M.G. have nothing to disclose. S.J.F. received licensing fees and royalties from SeraCare Life Sciences for trisomic TBPC lines that were derived according to the methods described in this manuscript. TRIAL REGISTRATION NUMBER: N/A.

Precursors of CD3+CD4+CD8+ cells in the human thymus are defined by expression of CD34. Delineation of early events in human thymic development.

Studies of the most immature T cell progenitors in the human thymus have been hampered by the lack of markers and assays that define these cells. In this report we used a novel human fetal thymic organ culture system to determine the potential of T cell precursors isolated from human postnatal thymus, to differentiate into CD3+ thymocytes, and to investigate early stages of human T cell development. It was found that thymocytes that lack the markers CD3, CD4, and CD8 (triple negative [TN]) can differentiate in an allogeneic organotypic thymic culture. The capacity of TN thymocytes to differentiate was exclusively confined to the CD34+ population. CD34- TN thymocytes failed to differentiate in this system. In contrast, cloned lines of CD3- thymocytes could only be established from CD34- TN thymocytes. Five subsets of CD3- thymocytes were found with the following phenotype: CD1-TN, CD1+TN, CD1+CD4+CD8-, CD1+CD4+CD8 alpha+ beta-, and CD1+CD4+CD8 alpha beta+. These subpopulations expressed decreasing levels of CD34. The CD1-CD3- population expressed the highest levels of CD34 supporting the notion that this population is the most immature T cell precursor in the thymus, whereas the CD1+CD4+CD8 alpha+ beta+ which did not express CD34 seems to be the most mature of these CD3- populations. This notion is supported by the observations that CD34+ cells isolated from fetal liver, which differentiated into T cells in a FTOC, developed into CD3+ cells via CD1- and CD4+CD8- intermediates. Based on these data, we present a model of early stages in human intrathymic development.

A role for interleukin 4 in the differentiation of mature T cell receptor gamma/delta + cells from human intrathymic T cell precursors.

We have analyzed the effect of human recombinant interleukin 4 (rIL-4) on the growth and differentiation of human intrathymic pre-T cells (CD7+2+1-3-4-8-). We describe that this population of T cell precursors proliferates in response to rIL-4 (in the absence of mitogens or other stimulatory signals) in a dose-dependent way. The IL-4-induced proliferation is independent of the IL-2 pathway, as it cannot be inhibited with an anti-IL-2 receptor alpha chain antibody. In our culture conditions, rIL-4 also promotes the differentiation of pre-T cells into phenotypically mature T cells. Although both CD3/T cell receptor (TCR)-alpha/beta + and CD3-gamma/delta + T cells were obtained, the preferential differentiation into TCR-gamma/delta + cells was a consistent finding. These results suggest that, in addition to IL-2, IL-4 plays a critical role in promoting growth and differentiation of intrathymic T cell precursors at early stages of T cell development.

Involvement of the interleukin 2 pathway in the rearrangement and expression of both alpha/beta and gamma/delta T cell receptor genes in human T cell precursors.

In this report, we have undertaken the phenotypic, functional and molecular characterization of a minor (less than 5%) subpopulation of adult thymocytes regarded as the earliest intrathymic T-cell precursors. Pro-T cells were immunoselected and shown to express different hematopoietic cell markers (CD45, CD38, CD7, CD5) and some activation-related molecules (4F2, Tr, HLA class II), but lack conventional T cell antigens (CD2-1-3-4-8-). TCR-gamma RNA messages are already expressed at this early ontogenic stage, while alpha and beta chain TCR genes remain in germline configuration. In vitro analyses of the growth requirements of pro-T cells demonstrated the involvement of the IL-2 pathway in promoting their proliferation and differentiation into CD3+ CD4+ or CD8+ mature thymocytes. Moreover, during the IL-2-mediated maturation process rearrangements and expression of both alpha and beta chain TCR genes occurred, and resulted in the acquisition of alpha/beta as well as gamma/delta (either disulphide-linked or non-disulphide-linked) heterodimeric TCR among the pro-T cell progeny.

Lymphoid and myeloid differentiation of fetal liver CD34+lineage- cells in human thymic organ culture.

In this article, we report that the human fetal thymus contains CD34bright cells (< 0.01% of total thymocytes) with a phenotype that resembles that of multipotent hematopoietic progenitors in the fetal bone marrow. CD34bright thymocytes were CD33-/dull and were negative for CD38, CD2, and CD5 as well as for the lineage markers CD3, CD4, and CD8 (T cells), CD19 and CD20 (B cells), CD56 (NK cells), glycophorin (erythrocytes), and CD14 (monocytes). In addition, total CD34+ lineage negative (lin-) thymocytes contained a low number of primitive myeloid progenitor cells, thus suggesting that the different hematopoietic lineages present in the thymus may be derived from primitive hematopoietic progenitor cells seeding the thymus. To investigate whether the thymus is permissive for the development of non-T cells, human fetal organ culture (FTOC) assays were performed by microinjecting sorted CD34+lin- fetal liver cells into fragments of HLA-mismatched fetal thymus. Sequential phenotypic analysis of the FTOC-derived progeny of CD34+lin- cells indicated that the differentiation into T cells was preceded by a wave of myeloid differentiation into CD14+CD11b+CD4dull cells. Donor-derived B cells (CD19+CD20+) were also generated, which produced immunoglobulins (IgG and IgM) when cultured under appropriate conditions, as well as functional CD56+CD3- NK cells, which efficiently killed K562 target cells in cytotoxicity assays. These results demonstrate that the microinjection of fetal liver hematopoietic progenitors into fetal thymic organ fragments results in multilineage differentiation in vitro.

[Contingency plan for the intensive care services for the COVID-19 pandemic]. / Plan de contingencia para los servicios de medicina intensiva frente a la pandemia COVID-19.

In January 2020, the Chinese authorities identified a new virus of the Coronaviridae family as the cause of several cases of pneumonia of unknown aetiology. The outbreak was initially confined to Wuhan City, but then spread outside Chinese borders. On 31 January 2020, the first case was declared in Spain. On 11 March 2020, The World Health Organization (WHO) declared the coronavirus outbreak a pandemic. On 16 March 2020, there were 139 countries affected. In this situation, the Scientific Societies SEMICYUC and SEEIUC have decided to draw up this Contingency Plan to guide the response of the Intensive Care Services. The objectives of this plan are to estimate the magnitude of the problem and identify the necessary human and material resources. This is to provide the Spanish Intensive Medicine Services with a tool to programme optimal response strategies.

Contingency Plan for the Intensive Care Services for the COVID-19 pandemic. / Plan de contingencia para los servicios de medicina intensiva frente a la pandemia COVID-19.

In January 2020, the Chinese authorities identified a new virus of the Coronaviridae family as the cause of several cases of pneumonia of unknown aetiology. The outbreak was initially confined to Wuhan City, but then spread outside Chinese borders. On 31 January 2020, the first case was declared in Spain. On 11 March 2020, The World Health Organization (WHO) declared the coronavirus outbreak a pandemic. On 16 March 2020, there were 139 countries affected. In this situation, the Scientific Societies SEMICYUC and SEEIUC, have decided to draw up this Contingency Plan to guide the response of the Intensive Care Services. The objectives of this plan are to estimate the magnitude of the problem and identify the necessary human and material resources. This is to provide the Spanish Intensive Medicine Services with a tool to programme optimal response strategies.

Role of CD95/Fas and its ligand in the regulation of the growth of human CD34(++)CD38(-) fetal liver cells.

The functional significance of CD95/Fas expressed by candidate hematopoietic stem cells (HSCs) from human fetal liver was studied by testing the effect of agonistic anti-CD95 monoclonal antibody (mAb) CH-11 and soluble CD95 ligand (sCD95L) on the growth of CD34(++)CD38(-)lineage cells in vitro. Candidate fetal HSCs exhibited a dose-dependent proliferative response to CH-11 as well as to sCD95L when combined with kit ligand (KL) + interleukin 3 (IL-3) under serum-deprived culture conditions. CH-11 mAb increased, in a synergistic fashion, the number of myeloid colony-forming unit culture (CFU-C) generated by candidate HSCs in liquid cultures with the cytokine combinations KL + IL-3, KL + granulocytemacrophage colony-stimulating factor, and KL + IL-6. CH-11 mAb and sCD95L also enhanced erythropoiesis supported by KL + IL-3 + erythropoietin (Epo). Furthermore, sCD95L was able to increase the number of megakaryocytes, granulocytes, and CD34- cells generated in the presence of KL + IL-3 + Epo + thrombopoietin. An analysis performed using Western blotting revealed that the membrane-bound CD95L (mCD95L) was expressed by both immature (total CD34+/++) and mature (CD34-) hematopoietic lin(-) FL cells. Among the CD34(++)lin(-)cells, both the freshly isolated CD38+ and CD38 subsets as well as CD95+ and CD95- cells constitutively expressed mCD95L, demonstrating that the CD95/CD95L system represents a paracrine and potentially autocrine regulator of early hematopoiesis. To study the role of the endogenously produced CD95L, we determined the effects of a neutralizing anti-CD95L NOK-1 on the growth of candidate HSCs. By blocking the endogenous CD95L with NOK-1 mAb, we observed an increase in CFU-C generated by candidate HSCs. We conclude that the endogenous CD95L has an inhibitory effect on fetal candidate HSCs, which can be blocked by sCD95L and CH-11 mAb.

Differential effects of interleukin-3, interleukin-7, interleukin 15, and granulocyte-macrophage colony-stimulating factor in the generation of natural killer and B cells from primitive human fetal liver progenitors.

The regulatory roles of a number of early-acting growth factors on the generation of natural killer (NK) cells and B cells from primitive progenitors were studied. Experiments focused on the contributions of granulocyte-macrophage colony-stimulates factor (GM-CSF) and interleukin-3 (IL-3) to the regulation of the early events of lymphopoiesis.Two progenitor populations isolated from human fetal liver were studied, CD38(-)CD34(++)lineage(-) (Lin(-)) cells (candidate hematopoietic stem cells [HSCs]) and the more mature CD38(+)CD34(++)Lin(-) cells. The effects of different cytokines on the generation of CD56(+)CD3(-) NK cells and CD19(+) B cells were studied in serum-deprived cultures in the absence of stroma.NK cells generated in vitro were able to kill NK-sensitive target cells, expressed NK-associated marker CD161 (NKR-P1A), but exhibited little or no expression of CD2, CD8, CD16, CD94/NKG2A, or killer cell inhibitory receptors (KIRs). Among the cytokine combinations tested, kit ligand (KL) and IL-15 provided the best conditions for generating CD56(+) NK cells from CD38(+)CD34(++)Lin(-) cells. However, either flk-2/flt3 ligand (FL), GM-CSF, IL-3, or IL-7 could partially substitute KL. All of these cytokines also supported the growth of NK-cell progenitors from candidate HSC, with the combination of IL-15, KL, GM-CSF, and FL generating the greatest number of CD56(+) cells. B cells were generated from both progenitor populations in response to the combined effects of KL, FL, and IL-7. Both B and NK cells were generated with the further addition of IL-15 to these cultures. The in vitro generated B cells were CD10(+), CD19(+), HLA-DR(+), HLA-DQ(+), and some were CD20(+), but no cytoplasmic or surface immunoglobulin M expression was observed. In contrast with NK lymphopoiesis, GM-CSF, IL-3, and IL-15 had no effect on the generation of B cells from CD38(-)CD34(++)Lin(-) cells, and GM-CSF inhibited B-cell generation from CD38(+)CD34(++)Lin(-) progenitors. These findings indicate a differential regulation of NK and B lymphopoiesis beginning in the early stages of hematopoiesis as exemplified by the distinctive roles of IL-7, IL-15, GM-CSF, and IL-3.

Plan de contingencia para los servicios de medicina intensiva frente a la pandemia COVID-19 / Contingency plan for the intensive care services for the COVID-19 pandemic

En enero de 2020 China identificó un nuevo virus de la familia de los Coronaviridae como causante de varios casos de neumonía de origen desconocido. Inicialmente confinado a la ciudad de Wuhan, se extendió posteriormente fuera de las fronteras chinas. En España, el primer caso se declaró el 31 de enero de 2020. El 11 de marzo, la Organización Mundial de la Salud declaró el brote de coronavirus como pandemia. El 16 de marzo había 139 países afectados. Ante esta situación, las Sociedades Científicas SEMICYUC y SEEIUC han decidido la elaboración de este plan de contingencia para dar respuesta a las necesidades que conllevará esta nueva enfermedad. Se pretende estimar la magnitud del problema e identificar las necesidades asistenciales, de recursos humanos y materiales, de manera que los servicios de medicina intensiva del país tengan una herramienta que les permita una planificación óptima y realista con que responder a la pandemia

In January 2020, the Chinese authorities identified a new virus of the Coronaviridae family as the cause of several cases of pneumonia of unknown aetiology. The outbreak was initially confined to Wuhan City, but then spread outside Chinese borders. On 31 January 2020, the first case was declared in Spain. On 11 March 2020, The World Health Organization (WHO) declared the coronavirus outbreak a pandemic. On 16 March 2020, there were 139 countries affected. In this situation, the Scientific Societies SEMICYUC and SEEIUC, have decided to draw up this Contingency Plan to guide the response of the Intensive Care Services. The objectives of this plan are to estimate the magnitude of the problem and identify the necessary human and material resources. This is to provide the Spanish Intensive Medicine Services with a tool to programme optimal response strategies

Plan de contingencia para los servicios de medicina intensiva frente a la pandemia COVID-19 / Contingency Plan for the Intensive Care Services for the COVID-19 pandemic

En enero de 2020 China identificó un nuevo virus de la familia de los Coronaviridae como causante de varios casos de neumonía de origen desconocido. Inicialmente confinado a la ciudad de Wuhan, se extendió posteriormente fuera de las fronteras chinas. En España, el primer caso se declaró el 31 de enero de 2020. El 11 de marzo, la Organización Mundial de la Salud declaró el brote de coronavirus como pandemia. El 16 de marzo había 139 países afectados. Ante esta situación, las Sociedades Científicas SEMICYUC y SEEIUC han decidido la elaboración de este plan de contingencia para dar respuesta a las necesidades que conllevará esta nueva enfermedad. Se pretende estimar la magnitud del problema e identificar las necesidades asistenciales, de recursos humanos y materiales, de manera que los servicios de medicina intensiva del país tengan una herramienta que les permita una planificación óptima y realista con que responder a la pandemia

In January 2020, the Chinese authorities identified a new virus of the Coronaviridae family as the cause of several cases of pneumonia of unknown aetiology. The outbreak was initially confined to Wuhan City, but then spread outside Chinese borders. On 31 January 2020, the first case was declared in Spain. On 11 March 2020, The World Health Organization (WHO) declared the coronavirus outbreak a pandemic. On 16 March 2020, there were 139 countries affected. In this situation, the Scientific Societies SEMICYUC and SEEIUC, have decided to draw up this Contingency Plan to guide the response of the Intensive Care Services. The objectives of this plan are to estimate the magnitude of the problem and identify the necessary human and material resources. This is to provide the Spanish Intensive Medicine Services with a tool to programme optimal response strategies

Mid-trimester fetal livers are a rich source of CD34+/++ cells for transplantation.

Human fetal livers (FL), between 16 and 24 weeks of gestation, were studied for their potential as a source of hematopoietic stem cells for prenatal and postnatal transplantation. In this report we give a quantitative evaluation of human FL as a source of candidate stem cells, and develop a protocol for the isolation of these cells free of microbial contaminants and almost free of mature T cells. Human FLs contained a median 1.9 x 10(9) viable cells and a mean of 1.3 x 10(8) CD34+/++ cells (range 1.1 x 10(7) to 4.7 x 10(8)). Regardless of gestational age, no significant differences were apparent in the numbers of total progenitors or in the numbers of candidate stem cells (CD34++ CD38- and CD34++CD4+), suggesting that the expansion in the liver of the early compartments of hematopoietic progenitors reaches a plateau after the sixteenth week of gestation. Colony-forming units culture (CFU-C) were found to range from 4.1 x 10(6) to 2.5 x 10(7) per FL. Positive selection of FL CD34++ cells was achieved using the Baxter Isolex 50 device. An average purity of 74% and yield of 29% of CD34+/++ cells was achieved. T cells were depleted by 99.95%, resulting in a mean of 6.5 x 10(3) T cells per processed liver. Analysis of candidate stem cell populations and primitive colony-forming cells (CFC) suggested a preferential enrichment of these cells over the total population of CD34+/++ cells. Processed CD34+/++cells were found to be sterile. In conclusion, purification of FL progenitors between 16 and 24 weeks of gestation results in a large number of early progenitors suitable for in utero and possibly post-natal transplantation.

Transplantation of a fetus with paternal Thy-1(+)CD34(+)cells for chronic granulomatous disease.

A fetus diagnosed with X-linked chronic granulomatous disease was transplanted with Thy-1(+)CD34(+) cells of paternal origin. The transplant was performed at 14 weeks gestation by ultrasound guided injection into the peritoneal cavity. The fetus was delivered at 38 weeks gestation after an otherwise uneventful pregnancy. Umbilical cord blood was collected and used to determine the level of peripheral blood chimerism as well as levels of functional engrafted cells. Flow cytometry was used to detect donor leukocytes identified as HLA-A2(-)B7(+) cells, whereas recipient cells were identified as HLA-A2(+)B7(-) cells. No evidence of donor cell engraftment above a level of 0.01% was found. PCR was used to detect HLA-DRB1*15(+) donor cells among the recipient's HLA-DRB1*15(-) cells, but no engraftment was seen with a sensitivity of 1:1000. The presence of functional, donor-derived neutrophils was assessed by flow cytometry using two different fluorescent dyes that measure reactive oxygen species generated by the phagocyte NADPH oxidase. No evidence of paternal-derived functional neutrophils above a level of 0.15% was observed. Peripheral blood and bone marrow samples were collected at 6 months of age. Neither sample showed engraftment by HLA typing using both flow cytometry and PCR. Functional phagocytes were also not observed. Furthermore, no indication of immunological tolerance specific for the donor cells was indicated by a mixed lymphocyte reaction assay performed at 6 months of age. While there appears to be no engraftment of the donor stem cells, the transplant caused no harm to the fetus and the child was healthy at 6 months of age. Analyses of fetal tissues, obtained from elective abortions, revealed that CD3(+) T cells and CD56(+)CD3(-) NK cells are present in the liver at 8 weeks gestation and in the blood by 9 weeks gestation. The presence of these lymphocytes may contribute to the lack of donor cell engraftment in the human fetus.

Tracing the expression of CD7 and other antigens during T- and myeloid-cell differentiation in the human fetal liver and thymus.

During the last decade, the function/s of the cell membrane CD7 antigen have been investigated in human mature T and NK cells, showing the direct involvement of this molecule in multiple effector functions related with activation, proliferation, production of cytokines and modification of adhesion properties. The CD7 glycoprotein is not only expressed by mature lymphoid cells, but also by early hematopoietic progenitors and several types of leukemias, suggesting a role of CD7 during hematopoiesis. However, the function of CD7 in the early stages of hematopoietic development has not yet been elucidated. CD7 has been classically considered the earliest T-cell specific marker. This assumption was based on data indicating the presence of CD45+CD7+CD3-CD4-CD8- cells in the human embryonic/fetal liver at the gestational age at which the thymic rudiment is colonized by T-cell progenitors. In the present article, we review recent results obtained by several groups concerning the expression of CD7 and various other cell surface antigens by T-, B- and myeloid-cell progenitors generated in the adult bone marrow and fetal liver. In addition, we present an hypothetical model of hematopoiesis in the fetal liver and thymus.

Progress in the ex vivo expansion of hematopoietic progenitors.

In this review we describe how studies on the cytokine-stimulated growth of murine bone marrow (BM) progenitors have lead to the observations that large increases in progenitor numbers can be achieved in short-term cytokine-stimulated liquid cultures. Transplantation of these ex vivo expanded murine BM cells was shown to decrease the number of BM cells required to confer radioprotection and to increase the recovery rate of both myeloid and erythroid peripheral blood cells. The ex vivo expansion of murine BM cells does not however, markedly diminish stem cells capable of long-term hematopoietic reconstitution. Investigations on the expansion of human BM, peripheral blood, umbilical cord blood and fetal hematopoietic progenitors have demonstrated that clinically useful increases in progenitor numbers from these tissues are possible. Thus, ex vivo progenitor expansion may soon be of use in transplantation protocols to accelerate hematopoietic reconstitution and in gene therapy protocols if hematopoietic stem cells can be maintained during ex vivo culture.

Spinal metastatic disease: analysis of factors determining functional prognosis and the choice of treatment.

The authors surveyed 31 surgical and radiotherapy series comprising over 2300 patients with spinal metastases to determine the influence of factors such as tumor biology and topography, pretreatment neurological status, the presence of a myelographic block, the progression rate of symptoms, and the general medical condition of the patient on both the functional prognosis and the choice of treatment. Both life expectancy and the functional results after therapy are mainly dependent on tumor biology, which in turn determines radiosensitivity. The remaining factors seem to have only complementary predictive power. Because radiotherapy has been found to be as effective as operation plus radiotherapy in the management of the majority of patients with spinal metastases, it is very important to improve the selection of surgical candidates (less than 42% of the total cases) to prevent unnecessary surgery-related morbidity and mortality. Factors considered important in the selection of therapy are the location of the tumor within the spinal canal, the neurological status at the time of treatment, and the systemic condition of the patient.

Intermittent exophthalmos studied with computerized tomography. Report of two cases.

Two cases of intermittent exophthalmos are reported. In both instances, cerebral angiography and orbital venography failed to outline the lesion, which was clearly demonstrated with the aid of computerized tomography. An orbital varix was seen to be the cause of proptosis in one surgically verified case, whereas in the other this same diagnosis was suspected on the basis of the clinicoradiological findings. The etiology, clinical manifestations, and management of orbital varix are briefly discussed.

Normal computerized tomography scans in severe head injury. Prognostic and clinical management implications.

The authors analyze the clinical course of 46 severely head-injured patients who had completely normal computerized tomography (CT) scans through the immediate posttraumatic period (1 to 7 days after trauma). These patients represent 10.2% of a consecutive series of 448 cases of severe head injuries and two-thirds of the cases showing a normal CT scan on admission (the other one-third of the cases developed new pathology). The usual course in these 46 patients after the initial coma was toward progressive neurological improvement, and 35 patients (76%) achieved a functional level of survival. Nine patients (19.5%) remained comatose for several weeks and developed severe disability. There were two fatalities due to medical complications. The final outcome was more closely related to the duration of coma (the longer the duration the worse the result) than to the initial Glasgow Coma Scale (GCS) score. In fact, 26% of the patients in the lower GCS score ranges (3 to 4 points) made a good recovery and 46% developed moderate disability only. These findings indicate that the grim prognostic significance of deep posttraumatic coma is tempered in the presence of a normal scan. However, the absence of CT abnormalities in severely head-injured patients cannot be equated with a good prognosis because in one-fifth of the cases serious permanent disability develops. Sustained elevation of the intracranial pressure (ICP) was not seen in these patients, indicating that ICP monitoring may be omitted in cases with a normal scan. However, since one-third of the patients with a normal admission scan developed new pathology within the first few days of injury, a strategy for control scanning is recommended. Control CT scans performed more than 6 months after injury showed a significantly higher incidence of brain atrophy in patients developing permanent disability than in those who made a good recovery.

Outcome from severe head injury related to the type of intracranial lesion. A computerized tomography study.

The influence of the type of intracranial lesion on the final outcome in a consecutive series of 277 severely head-injured patients was analyzed. Patients were studied with computerized tomography (CT) and underwent continuous measurement of intracranial pressure. They received identical treatment according to a standardized protocol. Outcome of patients with either epidural hematoma (38 cases), subdural hematoma (56 cases), brain contusion (87 cases), or diffuse brain damage (96 cases) was rather heterogeneous, and serial CT scanning allowed the authors to outline eight consistent anatomical patterns in the whole series which have stronger prognostic significance than the four major lesion categories mentioned above. Patients with pure extracerebral hematoma (19 cases), single brain contusion (45 cases), general brain swelling (41 cases), and normal CT scans (28 cases) had a significantly better outcome than patients developing acute hemispheric swelling after operation for a large extracerebral hematoma (27 cases), patients with multiple brain contusion, either unilateral or bilateral (74 cases), and patients with diffuse axonal injury (43 cases). These anatomical patterns are interesting because, in addition to having clinical and physiopathological significance, they provide useful prognostic information and facilitate improved therapeutic decision-making in severely head-injured patients.

Intraventricular hemorrhage in severe head injury.

A series of 30 patients suffering posttraumatic intraventricular hemorrhage (IVH) after closed head injury is reviewed. Clotted blood and a mixture of blood and cerebrospinal fluid could be distinguished by computerized tomography (CT). Posttraumatic IVH was associated with diffuse brain lesions in most cases; intracerebral lesions with contusion, and subdural hematomas coexisted with posttraumatic IVH in eight and four instances, respectively. In two more cases, no CT abnormality other than IVH was noted. All patients in this series were in deep coma at the time of CT examination, and only seven survived. The early clinical findings, the site of ventricular hematoma, and the final outcome are analyzed.