Biomedical subjects
M Levin
Publications and source records attributed to M Levin.
Avoidable deficiencies in the delivery of health care to children with meningococcal disease.
OBJECTIVES: It is apparent that delays and inadequate or inappropriate management occur frequently and may contribute to the continued high mortality seen in meningococcal disease. An attempt has been made to define the major sources of delay or inappropriate treatment. METHODS: A prospective, descriptive study of children with meningococcal disease referred to a tertiary centre paediatric intensive care and infectious disease unit. Definitions of optimal care were established at three stages: parental; general practitioner (GP)/accident and emergency (A&E) department; and hospital. Duration of symptoms and management were recorded from direct questioning of parents and carers, and from hospital records. RESULTS: 54 consecutive children with meningococcal disease were recruited to the study. Delayed parental recognition occurred in 16 children. GPs correctly diagnosed 19 of 35 children. Delay of 2.5-21 hours occurred in those who were incorrectly diagnosed. Two of 15 children who presented to the A&E department with specific features were incorrectly diagnosed. Hospital treatment was suboptimal in 71%. Shock was not recognised or treated in 50%, 20% of children had unnecessary lumbar punctures. Time from illness onset to treatment was longer in fatal disease (median 18.3, range 8-24 hours), compared with survivors (median 12, range 2-48 hours; p < 0.01, Mann-Whitney U test). CONCLUSION: Suboptimal treatment in meningococcal disease is due to failure of parents, GPs, and hospital doctors to recognise specific features of the illness. Improvement by public education and better training of clinicians in recognition, resuscitation, and stabilisation of seriously ill children.
Acute oliguric renal failure associated with unilateral renal embolism: a successful treatment with iloprost.
A 66-year-old woman presented with acute-onset rapid atrial fibrillation and right upper quadrant pain which had appeared 24 h prior to admission. The patient also manifested acute oliguric renal failure (serum creatinine 6.9 mg/dl). Selective renal angiography revealed total occlusion of the right renal artery with normal visualization of the left kidney vasculature. The patient was treated with intra-arterial urokinase and intravenous heparin, with no response. Intravenous administration of the prostacyclin analogue, iloprost, resulted in rapid resolution (within hours) of the oliguric acute renal failure, in spite of the continuing presence of a nonfunctioning right kidney. We conclude that the etiology of the acute renal insult in this patient is probably related to unilateral renal arterial embolization accompanied by arterial spasm of the unaffected kidney. The contralateral vasospasm can be reversed by iloprost, which then leads to a rapid recovery from acute renal failure. We are unaware of prior reports documenting the beneficial effect of iloprost in a clinical setting as described here.
CSF and MRI findings in patients with acute herpes zoster.
OBJECTIVE: To explore MRI and CSF findings in patients with herpes zoster (HZ) and to correlate the findings with clinical manifestations of the disease. METHODS: Fifty immunocompetent patients (mean age, 59 years; range, 17 to 84 years) with HZ of fewer than 18 days duration participated. None had clinical signs of meningeal irritation, encephalitis, or myelitis. In 42 patients (84%), the symptoms constituted pain and rash only. Six patients (12%) had motor paresis, and three patients (6%) had ocular complications. One to three CSF samples were obtained from 46 patients (the first sampling taken 1 to 18 days from onset of rash), and 16 patients (all with either trigeminal or cervical HZ) underwent MRI of the brain. The clinical follow-up continued at least 3 months. RESULTS: CSF was abnormal in 28/46 patients (61%): pleocytosis (range, 5 to 1,440 microL) was detected in 21, elevated protein concentration in 12, varicella zoster virus (VZV) DNA in 10, and immunoglobulin G antibody to VZV in 10. These changes were more common in patients with acute complications, although they did not predict development of postherpetic neuralgia (PHN). In 9/16 patients (56%), MRI lesions attributable to HZ were seen in the brainstem and cervical cord. At 3 months, 5/9 patients (56%) with abnormal MRI had PHN, whereas none of the 7 patients with no HZ-related lesions on MRI had any remaining pain. CONCLUSIONS: Subclinical extension of viral inflammation into the CNS occurs commonly in HZ. This finding may have implications for treatment of HZ and prevention of various associated complications.
A comparative analysis of integrating visual representations with haptic displays.
As further advances in visual display technologies and force feedback devices are integrated in virtual systems, questions remain: What level of reality does the system provide to the user? Is the environment convincing enough to engage the user and to maximize transfer? Are the visual and haptic displays fully integrated to provide seamless operation in the simulated environment? Does the system provide not only the ability to navigate through a simulated environment, but also realistic interaction with instrumentation and structures? We report on our advances in developing a virtual simulation system for training in functional endoscopic sinus surgery (FESS). Specifically, we will present work on subject trials exploring the realism provided by integrated visual and haptic displays, and compare and contrast surface vs. volume representation for presenting realistic models of the anatomy for surgical interaction.
Review and consideration of coagulopathies.
Blood components bring nutrients to the tissues, remove wastes, provide defenses against microorganisms and foreign bodies, and retain sufficient fluidity to keep the system functioning properly. Coagulation factors are also present in the blood as part of a sensitive system that stems the flow of blood from a wound and maintains homeostasis. These factors include anuclear platelets that originate from megakaryocytes in the bone marrow, as well as soluble factors in precursor form, and calcium ion. Faults in single or multiple parts of this system, which can be determined in the patient's history, may result in bleeding problems that may be clinically relevant. Clarification of coagulation defects requires cooperation with a hematologist before medication that affects the coagulation system is prescribed or before any procedures that may result in bleeding are undertaken.
The roles of activin and follistatin signaling in chick gastrulation.
Activin, a TGF-beta family member, and follistatin, an activin antagonist, encode signaling proteins which have been implicated in fundamental events in early vertebrate embryogenesis, such as mesoderm and neural tissue induction, and axial patterning. In this study I examine the roles of activin and follistatin in gastrulation in the chick. Activin betaB is found to be expressed at the base of the primitive streak prior to its formation, consistent with a role in streak induction. Follistatin has a more complex and dynamic expression in Hensen's node, and exhibits a left-right (LR) asymmetry. Antagonizing endogenous activin by ectopic application of follistatin protein causes the partial dissolution of the primitive streak and node, both morphologically and as assayed by loss of expression of molecular markers. This suggests that activin is necessary for the maintenance of streak morphology, and that follistatin may be involved in termination of the anterior progress of streak growth or in suppression of supernumerary streaks. Cell ingression through the node following follistatin application is normal, suggesting that it does not depend on the pit-like morphology of the wild-type node. Finally, follistatin temporally extends the asymmetric pattern of expression of HNF3-beta, this, as well as the stronger right-sided expression of follistatin, suggests a possible role in LR patterning.
Bone marrow biopsy and blood culture in evaluating HIV patients.
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Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guérin infection and a sibling with clinical tuberculosis.
Complete interferon-gamma receptor 1 (IFNgammaR1) deficiency has been identified previously as a cause of fatal bacillus Calmette-Guérin (BCG) infection with lepromatoid granulomas, and of disseminated nontuberculous mycobacterial (NTM) infection in children who had not been inoculated with BCG. We report here a kindred with partial IFNgammaR1 deficiency: one child afflicted by disseminated BCG infection with tuberculoid granulomas, and a sibling, who had not been inoculated previously with BCG, with clinical tuberculosis. Both responded to antimicrobials and are currently well without prophylactic therapy. Impaired response to IFN-gamma was documented in B cells by signal transducer and activator of transcription 1 nuclear translocation, in fibroblasts by cell surface HLA class II induction, and in monocytes by cell surface CD64 induction and TNF-alpha secretion. Whereas cells from healthy children responded to even low IFN-gamma concentrations (10 IU/ml), and cells from a child with complete IFNgammaR1 deficiency did not respond to even high IFN-gamma concentrations (10,000 IU/ml), cells from the two siblings did not respond to low or intermediate concentrations, yet responded to high IFN-gamma concentrations. A homozygous missense IFNgR1 mutation was identified, and its pathogenic role was ascertained by molecular complementation. Thus, whereas complete IFNgammaR1 deficiency in previously identified kindreds caused fatal lepromatoid BCG infection and disseminated NTM infection, partial IFNgammaR1 deficiency in this kindred caused curable tuberculoid BCG infection and clinical tuberculosis.
Abandoning empirical antibiotics for febrile children.
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Left/right patterning signals and the independent regulation of different aspects of situs in the chick embryo.
Recently, a pathway of genes which are part of a cascade regulating the side on which the heart forms during chick development was characterized (M. Levin et al., 1995, Cell 82, 1-20). Here we extend these previous studies, showing that manipulation of at least one member of the cascade, Sonic hedgehog (Shh), can affect the situs of embryonic rotation and of the gut, in addition to the heart. Bilateral expression of Shh, which is normally found exclusively on the left, does not result in left isomerism (a bilaterally symmetrical embryo having two left sides) nor in a complete situs inversus phenotype. Instead, misexpression of Shh on the right side of the node, which in turn leads to bilateral nodal expression, produces a heterotaxia-like condition, where different aspects of laterality are determined independently. Heart situs has previously been shown to be altered by ectopic Shh and activin. However, the most downstream gene identified in the LR pathway, nodal, had not been functionally linked to heart laterality. We show that ectopic (right-sided) nodal expression is able to affect heart situs, suggesting that the randomization of heart laterality observed in Shh and activin misexpression experiments is a result of changes in nodal expression and that nodal is likely to regulate heart situs endogenously. The first defined asymmetric signal in the left-right patterning pathway is Shh, which is initially expressed throughout Hensen's node but becomes restricted to the left side at stage 4(+). It has been hypothesized that the restriction of Shh expression may be due to repression by an upstream activin-like factor. The involvement of such an activin-like factor on the right side of Hensen's node was suggested because ectopic activin protein is able to repress Shh on the left side of the node, as well as to induce ectopic expression of a normally right-sided marker, the activin receptor cAct-RIIa. Here we provide further evidence in favor of this model. We find that a member of this family, Activin betaB, is indeed expressed asymmetrically, only on the right side of Hensen's node, at the correct time for it to be the endogenous asymmetric activin signal. Furthermore, we show that application of follistatin-loaded beads eliminates the asymmetry in Shh expression, consistent with an inhibition of an endogenous member of the activin-BMP superfamily. This combined with the previous data on exogenous activin supports the model that Activin betaB functions in the chick embryo to initiate Shh asymmetry. While these data extend our understanding of the early signals which establish left-right asymmetry, they leave unanswered the interesting question of how the bilateral symmetry of the embryo is initially broken to define a consistent left-right axis. Analysis of spontaneous chick twins suggests that, whatever the molecular mechanism, left-right patterning is unlikely to be due to a blastodermal prepattern but rather is initiated in a streak-autonomous manner.
ECMO for refractory cardiorespiratory failure due to meningococcal disease.
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Association of mutations in mannose binding protein gene with childhood infection in consecutive hospital series.
OBJECTIVE: To determine the extent to which mutations in the mannose binding protein gene predispose to childhood infection. DESIGN: Clinical details and genotype of mannose binding protein determined in consecutive children attending a paediatric department. SETTING: Inner city hospital paediatric service in London. SUBJECTS: 617 children attending hospital between October 1993 and August 1995. MAIN OUTCOME MEASURE: Infection as the cause for attendance or admission in relation to mutations in the mannose binding protein gene. RESULTS: The prevalence of mutations in the mannose binding protein gene in children with infection (146/345) was about twice that in children without infection (64/272) (P < 0.0001). Increased susceptibility to infection was found in both heterozygotic and homozygotic children. 13 out of 17 children homozygotic for variant alleles presented with strikingly severe infections, including 6 with septicaemia. CONCLUSIONS: The findings suggest that mutations in the mannose binding protein gene are an important risk factor for infections in children. Screening for such mutations should be included in the investigation of severe or frequent infections.
Genetic influence on cytokine production in meningococcal disease.
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Detection of fibronectin expression by human endothelial cells using a enzyme-linked immunosorbent assay (ELISA): enzymatic degradation by activated plasminogen.
An enzyme-linked immunosorbent assay (ELISA) has been developed to measure cellular fibronectin (cFN) in association with human umbilical vein endothelial cells (HUVEC) in culture. The expression of a number of functional domains on the cFN molecule was demonstrated using three specific murine monoclonal antibodies. This system was found to be sensitive, detecting as little as 0.156 microg/ml of cFN, and required only 1.3 x 10(5) cells per well confluent cells per experimental condition. This allowed multiple experiments to be performed on one batch of endothelial cells. cFN was detected on both viable and methanol fixed endothelial cells without significant non-specific antibody binding. The utility of this experimental model was studied by exploring the effect of urokinase activated plasminogen, a potent protease, on the expression of cFN and its functional domains.
Comments on "Special report: recommendations for safe current limits for electrocardiographs'.
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Unravelling the genetic basis of susceptibility to mycobacterial infection.
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Applied DC magnetic fields cause alterations in the time of cell divisions and developmental abnormalities in early sea urchin embryos.
Most work on magnetic field effects focuses on AC fields. The present study demonstrates that exposure to medium-strength (10 mT-0.1 T) static magnetic fields can alter the early embryonic development of two species of sea urchin embryos. Batches of fertilized eggs from two species of urchin were exposed to fields produced by permanent magnets. Samples of the continuous cultures were scored for the timing of the first two cell divisions, time of hatching, and incidence of exogastrulation. It was found that static fields delay the onset of mitosis in both species by an amount dependent on the exposure timing relative to fertilization. The exposure time that caused the maximum effect differed between the two species. Thirty millitesla fields, but not 15 mT fields, caused an eightfold increase in the incidence of exogastrulation in Lytechinus pictus, whereas neither of these fields produced exogastrulation in Strongylocentrotus purpuratus.