Training in infectious diseases--looking to the future.
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Communicable Diseases↗
Biomedical subjects
J Cohen
Publications and source records attributed to J Cohen.
Role of Ca2+in the replication and pathogenesis of rotavirus and other viral infections.
Ca2+ plays a key role in many pathological processes, including viral infections. Rotavirus, the major etiological agent of viral gastroenteritis in children and young animals, provides a useful model to study a number of Ca2+ dependent virus-cell interactions. Rotavirus entry, activation of transcription, morphogenesis, cell lysis, particle release, and the distant action of viral proteins are Ca2+ dependent processes. In the extracellular medium, Ca2+ stabilizes the structure of the viral capsid. During entry into the cell the low cytoplasmic Ca2+ concentration induced the solubilization of the outer protein layer of the capsid and transcriptase activation. Viral protein synthesis modifies Ca2+ homeostasis which, in turn, favours viral morphogenesis and induces cell death. The generation of diarrhea is a multifactorial process involving Ca2+ dependent secretory processes of mediators and water and electrolytes, as well as the induction of cell death in the different cell types that compose the intestinal epithelium. The discovery of the non-structural viral protein NSP4 as a viral enterotoxin and the possible participation of the enteric nervous system in the pathogenesis of diarrhea represent significant advances in its understanding. Ca2+ also plays a role in the replication cycles and pathogenesis of other viral diseases such as poliovirus, Coxsackie virus, cytomegalovirus, vaccinia and measles virus and HIV.
Animals↗
The paracetamol absorption test: a useful addition to the enteral nutrition algorithm?
BACKGROUND: Enteral nutrition in critically ill patients given via the nasogastric route is often decreased or stopped because of large gastric residual volumes. AIM: To assess the effect of continuing enteral nutrition in patients with an elevated gastric residual volume but normal gastric emptying by the paracetamol absorption test. METHODS: The paracetamol absorption test was performed on all patients receiving enteral nutrition via a nasogastric tube who had a residual volume (assessed every 8 hours) of >150 ml or more than twice the hourly infusion rate. Patients were then divided into 2 groups according to the result of the test: Group 1 (n=8), normal gastric emptying; and Group II (n=24), abnormal gastric emptying. Group I continued to receive enteral nutrition. In Group II feeding was interrupted in 18 patients and prokinetic agents administered, while a subgroup of six patients continued to receive enteral nutrition without prokinetic agents. All patients were followed for evidence of delayed gastric emptying and aspiration. RESULTS: Residual volumes were similarly elevated in both groups (p=0.25). Enteral nutrition was continued in Group I with no adverse effects. Prokinetic agents allowed enteral nutrition to be resumed in 88% of the 18 Group II patients. Enteral nutrition in the subgroup had to be stopped because of persistently elevated residual volumes. CONCLUSION: The paracetamol absorption test may be normal in patients with relatively high gastric residual volumes. These patients may continue to receive enteral nutrition.
Acetaminophen↗
Reproducibility and complications in gene searches: linkage on chromosome 6, heterogeneity, association, and maternal inheritance in juvenile myoclonic epilepsy.
Evidence for genetic influences in epilepsy is strong, but reports identifying specific chromosomal origins of those influences conflict. One early study reported that human leukocyte antigen (HLA) markers were genetically linked to juvenile myoclonic epilepsy (JME); this was confirmed in a later study. Other reports did not find linkage to HLA markers. One found evidence of linkage to markers on chromosome 15, another to markers on chromosome 6, centromeric to HLA. We identified families through a patient with JME and genotyped markers throughout chromosome 6. Linkage analysis assuming equal male-female recombination probabilities showed evidence for linkage (LOD score 2.5), but at a high recombination fraction (theta), suggesting heterogeneity. When linkage analysis was redone to allow independent male-female thetas, the LOD score was significantly higher (4.2) at a male-female theta of.5,.01. Although the overall pattern of LOD scores with respect to male-female theta could not be explained solely by heterogeneity, the presence of heterogeneity and predominantly maternal inheritance of JME might explain it. By analyzing loci between HLA-DP and HLA-DR and stratifying the families on the basis of evidence for or against linkage, we were able to show evidence of heterogeneity within JME and to propose a marker associated with the linked form. These data also suggest that JME may be predominantly maternally inherited and that the HLA-linked form is more likely to occur in families of European origin.
Alleles↗
Kallikrein-kinin system activation in streptococcal toxic shock syndrome.
A retrospective analysis of 7 patients with streptococcal toxic shock revealed isolated prolongation of the activated partial thromboplastin time, which returned to normal during recovery. Levels of factor XII were reduced in 2 patients who had single factor assays performed, consistent with activation of the kallikrein-kinin system. We speculate that bradykinin release following activation of the kallikrein-kinin system in streptococcal toxic shock may underlie the features of pain, capillary leaking, and severe hypotension characteristic of this syndrome.
Bradykinin↗
Cleavage anomalies in early human embryos and survival after prolonged culture in-vitro.
This study examines the relationship between common morphological anomalies of cleaving embryos and their ability to form apparently normal blastocysts in vitro. The impact of cleavage rate, fragmentation, and multinucleation on compaction, cavitation, along with inner cell mass and trophectoderm formation has been assessed. The study population consisted of 102 patients who elected or were selected to have a day 5 embryo transfer. Clinical pregnancy and implantation rates were 66.7 and 49% respectively. Slow and fast cleavage had a significant negative association with normal blastocyst formation. Only 13.8% (67/484) of embryos with <7 cells and 27.5% (25/91) of those with >9 cells on day 3 formed blastocysts with apparently normal morphology, compared to 41.9% (252/602) with 7-9 cells on day 3 (P < 0.001). Fragmentation had a negative impact on normal blastocyst formation. Embryos with >15% fragmentation formed normal blastocysts at a significantly lower rate (46/279; 16.5%) than embryos with 0-15% fragmentation (311/935; 33.3%) (P < 0. 001). Furthermore, the pattern of fragmentation was associated with blastocyst formation. Type IV fragmentation led to a significant reduction in blastocyst formation (25/170 or 14.7%), compared to types I, II and III which performed much better (38.6, 32.9 and 32.4% respectively). Only 15.9% (22/138) of embryos with one or more multinucleate cells on day 2 and/or 3 formed normal blastocysts compared with 31.9% (335/1051) (P < 0.001) of those without multinucleation. Collectively, the data suggest that cleavage anomalies, some of which do not preclude development after short-term culture, may reduce the developmental competence of embryos after prolonged culture.
Blastocyst↗
Public perception on infertility and its treatment: an international survey. The Bertarelli Foundation Scientific Board.
The first large survey on the public perception of infertility and its treatment was conducted in six European countries, the USA and Australia. A representative sample of 8194 adults was polled, using standard validated methodology. The results obtained highlighted the following major aspects: (i) infertility is perceived as a disease by less than half of the people surveyed (38%), in contrast to the accepted medical opinion; (ii) awareness about the definition and incidence of infertility is relatively low, despite the fact that half of the people polled claimed to know someone affected by infertility; (iii) close to 90% of the adults surveyed knew about in-vitro fertilization (IVF), but less than one-quarter of them knew about the chances of success of this assisted reproductive technology; and (iv) when confronted with the knowledge that the cost of three IVF cycles is roughly equivalent to the cost of a hip replacement (a commonly reimbursed procedure), a large majority (70%) of the individuals interviewed agreed that IVF should be reimbursable.
Adult↗
Spontaneous and artificial changes in human ooplasmic mitochondria.
Our research has focused on promoting the development of compromised embryos by transferring presumably normal ooplasm, including mitochondria, to oocytes during intracytoplasmic insemination. Because of the enigma of mitochondrial heteroplasmy, the mixing of populations of oocyte cytoplasm has provoked considerable debate. We are currently investigating oocyte mitochondrial (mt) DNA mutations and the effects of ooplasmic transplantation on mitochondrial inheritance and mitochondrial functionality. Ageing human oocytes could accumulate mtDNA deletions, which might lead to detrimental development. Elimination of abnormal, rearranged mtDNA, such that the offspring inherit only normal mitochondria, is postulated to occur by a mtDNA 'bottleneck'. Among compromised human oocytes (n = 74) and early embryos (n = 137), investigations have shown the occurrence of deltamtDNA4977, the so-called common deletion, to be 33% among oocytes and 8% among embryos. Using a nested polymerase chain reaction (PCR) strategy of long followed by short PCR, another 23 novel mtDNA rearrangements were found: various rearrangements were present in 51% of the oocytes (n = 295) and 32% of early embryos (n = 197). The difference in the percentage of mtDNA rearrangements between oocytes and embryos was significant (P < 0.0001) and implies that there could be a process of selection as fertilized oocytes become embryos. There was no significant relationship between the percentage of human oocytes or embryos that contained mtDNA rearrangements and age. The first series of ooplasmic transfers have been performed in women with repeated implantation failure associated with slow and morphologically abnormal development of their embryos. In a total of 23 attempts in 21 women, eight healthy babies have been born and other pregnancies are ongoing. By examining the donor and recipient blood samples it is possible to distinguish differences in their mtDNA fingerprint. A small proportion of donor mitochondrial DNA was detected in samples with the following frequencies: embryos (six out of 13), amniocytes (one out of four), placenta (two out of four), and fetal cord blood (two out of four). Ooplasmic transfer can thus result in sustained mtDNA heteroplasmy representing both the donor and recipient.
Aging↗
The genetic revolution in artificial reproduction: a view of the future.
With the completion of the human genome project, micro-array technology offers the potential to open up a whole new vista in assisted reproduction. In the next 10-20 years we will be able to screen each human embryo for all numerical chromosomal abnormalities as well as many genetic diseases. Micro-array analysis may permit the screening of multiple alleles for monogenetic diseases and polygenic diseases, including diabetes, hypertension and schizophrenia. In the near future, it may be possible to assess an individual's genetic predisposition for cardiovascular disease, all types of cancer and infectious diseases. In the distant future, it may even be possible to screen for any genetic trait, e.g. stature, baldness, obesity, hair colour, skin colour or even IQ. Although it is still uncertain what molecular genetic tools may be available, we can be sure that some of these trends will have major consequences on the future of assisted reproduction and society at large.
Chromosome Aberrations↗
Quantification of mRNA in single oocytes and embryos by real-time rapid cycle fluorescence monitored RT-PCR.
Deciphering the complex series of regulatory events that occur during early development depends partly on the ability to accurately quantify stage-specific mRNA species. However, the paucity of biological material coupled with the lack of sensitivity and/or reproducibility of the currently available quantitative methods had been severe limitations on single cell analysis. Rapid cycle DNA amplification is a highly sensitive technique for amplification of specific DNA sequences. With the addition of fluorescence probes, it is possible to monitor the log-linear phase of amplification during which the most useful quantitative data is obtained. Unknown concentrations are extrapolated from standards co-amplified producing a standard curve. Furthermore, micro volume capabilities allow for the analysis of minute samples. Consequently, this approach is ideally suited to the needs of the clinical IVF laboratory. Rapid fluorescence monitored cycling was used to examine expression levels of the housekeeping genes beta-actin and hypoxanthine guanine phosphorlbosyltransferase in individual murine/human oocytes and/or embryos. Results obtained compared favourably with those attained by others and followed the predicted temporal patterns of expression. Once informative reproductive molecular markers are identified by micro-array analysis, minimally invasive techniques can be developed to biopsy cytoplasm and/or polar bodies for clinical evaluation using rapid fluorescence monitored reverse transcription-polymerase chain reaction methods.
Actins↗
The Global Burden of Disease Study: a useful projection of future global health?
One major conclusion of the Global Burden of Disease Study (GBDS) is that the global burden of disease will not change significantly from 1990 to 2020, in developed regions, developing regions or as a whole. Using the disability-adjusted life year (DALY), the Study estimates the burden as a result of 107 diseases, accidents and their disabling sequelae, disaggregated with respect to cause, sex, age and geographical region. The basic data used to construct estimates are sparse, and the DALY as a tool has received many criticisms. It obscures the distribution of disease and its impact in terms of handicap, and includes several social and economic value judgements. This weakens its power as a guide for the rational allocation of health resources at any point in time. Does it have use in guiding future planning and preventive action? At a global level, exceeding ecological capacity primarily through relative overpopulation is likely to be the greatest threat to overall health, yet overpopulation is not considered as a risk factor in itself. This reflects the understanding of health as an issue of the individual rather than the community. Together with the productivity-orientated weighting of DALYs, the Study appears to be more concerned with cost-effectiveness of health interventions rather than their equity. This underlies the reservations of the World Health Organization regarding the Study's use as a rational tool in health policy.
Cost of Illness↗
Linking nursing care interventions with client outcomes: a community-based application of an outcomes model.
This article describes a conceptual model that provides an organizing framework for assessing client outcomes in community-based settings. The "Outcomes Model for Community-Based Settings" (OMCBS) examines the relationships among structure, process, and outcomes juxtaposed to the dimensions of client, provider, and setting including sample measures for each variable. OMCBS incorporates the Omaha System including its comprehensive list of client health problems, nursing interventions, and an outcome rating scale assessing client knowledge, behavior, and health status to standardize nursing care and client outcomes. The OMCBS provides a strategy to evaluate the effectiveness of nursing interventions for clients in a variety of milieus.
Community Health Nursing↗
Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: time for a reevaluation.
Definitions for sepsis, septic shock, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) were developed by consensus conferences with the goal of achieving standardization of terminology and improved homogeneity of patient populations in clinical studies. Although such definitions have been useful in epidemiologic investigations, the criteria specified by the consensus conferences are broad and insufficiently specific to address the problem of heterogeneous mechanisms leading to clinical syndromes. An important challenge is to progress from clinical syndromes, as presently defined, to more specific entities that are delineated by alterations in specific immunologic or biochemical pathways. Such mechanistic definitions will provide more homogeneous groups of patients who can be identified at early stages of their clinical course. This approach encourages focused investigation of pathways leading to organ system dysfunction and death and, also, provides an efficient framework for the development of new therapies useful in critically ill patients.
Animals↗
Meningococcal disease as a model to evaluate novel anti-sepsis strategies.
OBJECTIVE: To consider the appropriateness of meningococcemia as a clinical entity for the evaluation of anti-endotoxin agents. DATA SOURCES: English language published literature concerning meningococcemia, sepsis, and endotoxin. STUDY SELECTION: The purpose of this work is to consider some of the practical and scientific issues that arise in designing clinical trials to evaluate anti-endotoxin agents. A selected review of recently published articles was undertaken. DATA EXTRACTION AND SYNTHESIS: Relevant literature has been cited to support factual statements in the text. CONCLUSION: Meningococcemia as a paradigm of endotoxin-mediated Gram-negative sepsis has many advantages. It is a homogeneous population, and it represents a single, measurable, bacterial target that is unequivocally implicated in the pathogenesis of the disease. However, it is an uncommon disease that may develop so quickly that attempts to intervene may be too late to have an effect. There is considerable morbidity, but how best to measure the outcome and the extent to which the results can be extrapolated to adult populations with sepsis secondary to nosocomial infection remain unclear.
Adult↗
Roundtable I: relationships between coagulation and inflammatory processes.
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Blood Coagulation↗
Contact activation in shock caused by invasive group A Streptococcus pyogenes.
OBJECTIVES: The aim of this study was to characterize abnormalities of coagulation in mice with experimental, invasive group A, streptococcal shock, in an attempt to explain the prolongation of the activated partial thromboplastin time identified in patients with streptococcal toxic shock syndrome. DESIGN: A longitudinal descriptive animal model study of coagulation times and single coagulation factors in mice infected with Streptococcus pyogenes. This was followed by an experimental study to determine whether streptococci or streptococcal products could activate the human contact system in vitro. SETTING: University infectious diseases and hemostasis molecular biology laboratories. SUBJECTS: CD1 outbred mice. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Coagulation times, single factor assays, and bradykinin assays were conducted on murine plasma at different times after streptococcal infection and compared with uninfected mice. In experiments in which streptococcal products were co-incubated with human plasma, we compared coagulation times, single factor assays, and activities against a range of chromogenic substrates with control plasma. In a murine model of streptococcal necrotizing fasciitis, the activated partial thromboplastin times were significantly prolonged in infected mice compared with controls, whereas prothrombin times were normal, suggesting an isolated abnormality of the intrinsic pathway. Bleeding was not seen. Prolongation of activated partial thromboplastin time was associated with reduced factor XII and prekallikrein, whereas levels of factors VIII, IX, XI, and high molecular weight kininogen were elevated. In vitro studies suggested that streptococcal supernatants can activate prekallikrein, in addition to causing plasminogen activation through the action of streptokinase. CONCLUSIONS: Prolongation of activated partial thromboplastin time in streptococcal toxic shock syndrome is associated with activation of the contact system, possibly contributing to the profound shock associated with streptococcal toxic shock syndrome.
Animals↗
A retrospective analysis of temporomandibular joint reconstruction with free fibula microvascular flap.
OBJECTIVES: The temporomandibular joint is occasionally encountered in extirpative surgery of the head and neck. It presents a difficult management issue. Little has been reported on functional outcomes after resection and reconstruction of the temporomandibular joint. DESIGN: A retrospective analysis consisting of chart reviews and phone interviews was performed on 17 patients who underwent fibular free flap reconstruction of the temporomandibular joint from 1993 to 1998. RESULTS: Mean follow-up in surviving patients (10) was 41.3 months. Mean age of the group was 62; male-to-female ratio was 11:6. Average hospital stay was 11.6 days. Four patients had no radiation therapy, 2 had preoperative and 11 had postoperative treatment. Five patients had one osteotomy, seven had two, one had three, and one had four. Ten patients could chew, one could not, and none were recorded for the remaining. Diet consisted of regular food for two patients, soft food for seven, full liquids for four, and tube feeds for four. Cosmesis was judged as excellent by eight patients, acceptable by two, and unacceptable by two. Five patients did not describe cosmesis. Most patients stated that bony contour was excellent, but that the soft tissue defect was noticeable. Speech was judged as intelligible by seven and moderately understandable by one. Nine patients did not describe speech. Two patients had postoperative displacement of the fibular head out of the fossa. CONCLUSION: Primary reconstruction of the temporomandibular joint with microvascular fibular flaps is a viable and effective means of restoring function. The majority of patients are able to resume oral feeds, obtain excellent or pleasing cosmetic results, and maintain intelligible speech.
Female↗
Randomized trial of four vs. seven days of ceftriaxone treatment for bacterial meningitis in children with rapid initial recovery.
BACKGROUND: Seven days or more of antimicrobial treatment is the standard for bacterial meningitis, although third generation cephalosporins are usually able to sterilize cerebrospinal fluid within 24 h. The limited experience from shorter regimens in children is encouraging, and we hypothesized that in rapidly recovering patients older than 3 months of age it would pose no risk for adverse outcome. METHODS: Strict clinical and laboratory criteria were used to define rapid initial recovery, in which case ceftriaxone therapy was either stopped after 4 days (4 injections) in children born on even dates (N = 53) or continued for 7 days in patients born on odd dates (N = 47). Outcomes were compared on Day 7 of hospitalization and at 1 to 3 months after discharge. RESULTS: On Day 7 no differences (P > 0.05 for each criteria) were observed between the 4-day and the 7-day groups regarding fever, clinical signs or serum C-reactive protein concentration. At the follow-up visit 1 to 3 months after discharge the 4-day group had fewer sequelae than the 7-day group (0% vs. 5% neurologic sequelae, P = 0.39 and 3% vs. 9% hearing loss, P = 0.49, respectively). One child in the 4-day group who had fully recovered was subsequently readmitted 53 days after the first hospitalization with recurrent Haemophilus influenzae meningitis. CONCLUSIONS: Four days of ceftriaxone therapy proved to be a safe alternative in patients with rapid initial recovery from bacterial meningitis. A 4-day course of treatment is particularly beneficial for countries with limited resources.
Ceftriaxone↗