Sudden unexpected unexplained death in infants

Summary Gross and histologic findings at autopsy in 32 cases of sudden unexpected unexplained death (SUUD) in infants were compared with autopsy findings in (1) 7 cases in which alarming clinical symptoms had been observed but no cause of death was found pathologically (morphologically unexplained death, MUD) and (2) 74 cases in which the cause of death was clearly established [8 cases of sudden unexpected explained death (SUED) and 66 control cases]. Laryngotracheitis was found most often in SUUD cases but did not differ histologically from the upper respiratory infections in the other categories. Other infections in SUUD which may be considered primary were bronchitis, focal pancreatitis, and mild pyelonephritis. Similar lesions were also found in control cases in which death was due to unrelated causes. The history in some SUUD and MUD cases and the morphologic changes in the spleen, thyroid gland, and adrenal gland indicated that unexpected unexplained death may occur at any time during the course of an upper respiratory or other type of infection. Our findings suggest that 2 factors have to combine to initiate the lethal episode: (1) an infection, usually of the upper respiratory tract, and (2) a predisposing condition or a trigger mechanism such as irritating skin lesions, trauma, or pain. The final common pathway appeared to be independent of the underlying disease. The characteristic findings of the terminal episode — hemorrhagic pulmonary edema and petechial hemorrhages — may also be part of a known fatal disease such as encephalitis or sepsis.

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Plötzlicher, unerwarteter und ungeklärter Tod im SäuglingsalterEine vergleichende klinisch-pathologische Studie

Zusammenfassung Makroskopische und mikroskopische Autopsiebefunde von 32 plötzlichen, unerwarteten und ungeklärten Todesfällen im Säuglingsalter (SUUD, Krippentod). werden verglichen mit 1. 7 Fällen, bei denen sich morphologisch keine Todesursache fand, obwohl alarmierende klinische Symptome beobachtet worden waren (MUD, morphologisch ungeklärter Tod) und 2. 74 Fällen, bei denen die Todesursache autoptisch gesichert war [8 Kinder dieser Gruppe waren plötzlich und unerwartet gestorben (SUED), und 66 Kinder mit schweren klinischen Symptomen dienten als Kontrollen].Laryngotracheitis war am häufigsten bei Krippentod (SUUD). Histologisch fanden sich keine Unterschiede zu den Infektionen der oberen Atemwege in den anderen Gruppen. Bronchitis, herdförmige Pankreatitis und geringgradige Pyelonephritis kamen ebenfalls als Primärinfektionen in Frage. Ähnliche Befunde wurden jedoch auch in Kontrollfällen mit anderer Todesursache erhoben.Der Krippentod (SUUD) kann wahrscheinlich zu jeder beliebigen Zeit im Ablauf einer Infektion, besonders der oberen Atemwege, auftreten. Dafürd srechen die klinischen Vorgeschichten einiger Krippentodesfälle (SUUD) sowie einiger Fälle von morphologisch ungeklärtem Tod (MUD) und außerdem morphologische Veränderungen in der Milz, der Schilddrüse und der Nebennierenrinde.Nach unseren Befunden müssen 2 Faktoren zusammentreffen, um den Krippentod auszulösen: 1. eine Infektion, gewöhnlich der oberen Atemwege, und 2. eine Disposition, z. B. als Folge einer Frühgeburt, oder Auslösemechanismen wie irritierende Hautschäden, Trauma oder Schmerz. Der Todesmechanismus scheint unabhängig von der auslösenden Krankheit zu sein. Die typischen Befunde des Endstadiums, hämorrhagisches Lungenödem und petechiale Schleimhautblutungen, finden sich auch bei tödlichen Krankheiten bekannter Ursache, wie Encephalitis oder Sepsis.

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This investigation was supported in part by Research Grant GM-14231 from the National Institutes of Health, Public Health Service.     

Patient-control association study of substance P-related genes in unipolar and bipolar affective disorders

In the search of genes potentially implicated in the aetiology of affective disorders (AD), SUBSTANCE P (SP) pathway is receiving increased interest. SP receptor antagonists, such as MK-869 and L-759274, have been shown to have antidepressant effect. Results from preclinical and human studies implicate SP and its pathway in the pathophysiology of mood disorders. We investigated a possible association between 20 single nucleotide polymorphisms (SNPS) among four SP-related genes and unipolar and bipolar ad (UPAD and BPAD) in a first sample of 92 UPAD patients and 92 control individuals and in a replication sample of 92 UPAD patients and 92 control individuals. An additional sample of 113 BPAD patients has also been ascertained. Our results showed a significant association between the angiotensin-converting enzyme gene (ACE1) and UPAD in our first sample, but not in the replication sample. No significant evidence of association was found in other SP-related genes. We did not find any association in the BPAD sample. When pooling first and replication UPAD samples, an association was found between ACE1 and a subgroup of patients remaining depressed after an adequate antidepressant treatment. In conclusion, our findings do not support a major contribution of SP-related genes in UPAD and BPAD, but provides some evidence of an ace influence in treatment response to antidepressants.     

Effects of the mGluR2/3 agonist LY354740 on computerized tasks of attention and working memory in marmoset monkeys

Rationale LY354740 is a recently developed metabotropic glutamatergic receptor 2 and 3 (mGluR2/3) agonist. A high density of mGluR2 has been reported in terminal fields of the perforant path in rodents and humans, suggesting its involvement in cognitive functions mediated by the temporal lobe, including memory. A small number of in vivo studies in rodents have assessed the effects of LY354740 on memory tasks, reporting the induction of impaired memory for spatial orientation in a water maze task and for delayed match and non-match to position in an operant version of these tasks.Objective In the present primate study, we used radioautography to describe the distribution and intensity of ³H-LY354740 binding in the hippocampal formation of the common marmoset monkey (Callithrix jacchus) relative to the rat. In the major, in vivo part of the study, the effects of systemic LY354740 on computerized tasks of attention and memory were investigated.Methods Adult common marmosets were trained to perform a five-choice serial reaction time (5-CSRT) task and a concurrent delayed match-to-position (CDMP) task from the Cambridge Neuropsychological Automated test Battery (CANTAB). Filter tests of LY354740 effects on motor dexterity and motivation for reward revealed high inter-individual variation in sensitivity; therefore, on the 5-CSRT, subjects were tested at a dose range of 3–10 mg/kg, and on the CDMP, subjects were tested at 1–3 or 3–10 mg/kg.Results Radioautography revealed a relatively low level of ³H-LY354740 binding in the marmoset hippocampal formation compared to the rat. Despite low binding, LY354740 reduced sustained-attention accuracy in the 5-CSRT, and reduced accuracy in two stages of the CDMP.Conclusions The current study provides novel evidence for the importance of mGluR2/3 in the regulation of primate cognitive functioning.     

Bioglue: a review of the use of this new surgical adhesive in thoracic surgery

BACKGROUND: Alveolar air leaks and broncho-pleural fistulae after thoracic surgical procedures contribute significantly to hospital morbidity and mortality. BioGlue has offered the thoracic surgeon an alternative to the products presently used to reduce the incidence of these complications. This retrospective study reviews our experience with this new adhesive. METHODS: Forty patients upon whom BioGlue was used were identified through operation records. Pre-, intra- and postoperative data were collected to establish use, indications and outcome. RESULTS: The predominant underlying pathology was malignancy. In 32 patients BioGlue was used during the primary procedure while in the remaining eight, persistent air- or lymph-leak led to a further procedure requiring the use of glue. The indications for BioGlue use were alveolar air leak (36), broncho-pleural fistula (2) and lymph leak (2). There was one death. In 35 out of 36 patients with alveolar air leak, BioGlue controlled the leak at the site of application. CONCLUSIONS: Our results in this particular patient group indicate that BioGlue is a reliable adjunct in the reduction of alveolar air leaks. Although further studies are necessary to establish the role of BioGlue in thoracic surgery in comparison to other sealants, these initial results are promising.     

Distribution and effects of polymorphic RANTES gene alleles in HIV/HCV coinfection -- a prospective cross-sectional study

AIM: Chemokines and their receptors are crucial for immune responses in HCV and HIV infection. RANTES gene polymorphisms lead to altered gene expression and influence the natural course of HIV infection. Therefore, these mutations may also affect the course of HIV/HCV coinfection. METHODS: We determined allele frequencies of RANTES-403 (G→A), RANTES-28 (C→G) and RANTES-IN1.1 (T→C) polymorphisms using real-time PCR and hybridization probes in patients with HIV (n = 85), HCV (n = 112), HIV/HCV coinfection (n = 121), and 109 healthy controls. Furthermore, HIV and HCV loads as well as CD4+ and CD8+ cell counts were compared between different RANTES genotypes. RESULTS: Frequencies of RANTES-403 A, RANTES-28 G and RANTES-IN1.1 C alleles were higher in HIV infected patients than in healthy controls (-403: 28.2% vs 15.1%, P = 0.002; -28: 5.4% vs 2.8%, not significant; IN1.1: 19.0% vs 11.0%, P = 0.038). In HIV/HCV coinfected patients, these RANTES alleles were less frequent than in patients with HIV infection alone (15.4% P = 0.002; 1.7%; P = 0.048; 12.0%; not significant). Frequencies of these alleles were not significantly different between HIV/HCV positive patients, HCV positive patients and healthy controls. CONCLUSION: All three RANTES polymorphisms showed increased frequencies of the variant allele exclusively in patients with HIV monoinfection. The finding that the frequencies of these alleles remained unaltered in HIV/HCV coinfected patients suggests that HCV coinfection interferes with selection processes associated with these alleles in HIV infection.     

Evaluation by monte carlo simulation of the pharmacokinetics of two doses of meropenem administered intermittently or as a continuous infusion in healthy volunteers

Meropenem is a broad-spectrum carbapenem antibacterial agent. In order to optimize levels in plasma relative to the MICs, the ideal dose level and dosage regimen need to be determined. The pharmacokinetics of meropenem were studied in two groups, each comprising eight healthy volunteers who received the following doses: 500 mg as an intravenous infusion over 30 min three times a day (t.i.d.) versus a 250-mg loading dose followed by a 1,500 mg continuous infusion over 24 h for group A and 1,000 mg as an intravenous infusion over 30 min t.i.d. versus a 500-mg loading dose followed by a 3,000-mg continuous infusion over 24 h for group B. Meropenem concentrations in plasma and urine were determined by liquid chromatography-mass spectrometry/mass spectrometry and high-performance liquid chromatography with UV detection, respectively. Pharmacokinetic calculations were done by use of a two-compartment open model, and the data were extrapolated by Monte Carlo simulations for 10,000 simulated subjects for pharmacodynamic evaluation. There were no significant differences in total clearance and renal clearance between group A and group B or between the intermittent treatment and the continuous infusion. The analyses of the probability of target attainment by MIC for the high- and low-dose continuous infusions were robust up to MICs of 4 mg/liter and 2 mg/liter, respectively. The corresponding values for intermittent infusions were only 0.5 mg/liter and 0.25 mg/liter. When these observations were correlated with MICs obtained from the MYSTIC database, intermittent infusion results in adequate activity against two of the most common nosocomially acquired pathogens, Klebsiella pneumoniae and Enterobacter cloacae. However, against Pseudomonas aeruginosa, the evaluation shows a clear advantage of high-dose therapy administered as a continuous infusion. We believe that in the empirical therapy situation, the continuous-infusion mode of administration is most worth the extra efforts. We conclude that clinical trials for evaluation of the continuous infusions of meropenem in critically ill patients are warranted.     

The potential for Toll-like receptors to collaborate with other innate immune receptors

Cells of the innate immune system express a large repertoire of germ-line encoded cell-surface glycoprotein receptors including Toll-like receptors (TLRs). TLRs recognize conserved motifs on microbes and induce inflammatory signals. Evidence suggests that individual members of the TLR family or other non-TLR surface antigens either physically or functionally interact with each other and cumulative effects of these interactions instruct the nature and outcome of the immune response to a particular pathogen.     

Cultures of ovarian surface epithelium from women with and without a hereditary predisposition to develop female adnexal carcinoma

AIM: Conflicting evidence exists on whether in vivo morphological characteristics can distinguish Ovarian Surface Epithelium (OSE) of ovaries obtained from women with and without a predisposition to develop female adnexal (ovarian and fallopian tube) carcinoma. This study aims to detect differences in growth potential and morphology that are maintained or specifically expressed in vitro. STUDY DESIGN: Ovarian surfaces were scraped to retrieve OSE cells from 56 women at hereditary high risk for female adnexal carcinoma, of whom 33 are BRCA1 and four are BRCA2 mutation carriers (Predisposed OSE, POSE) and from 26 women without such risk (Non Predisposed OSE, NPOSE). Number of passages and total cell yield until last passage, as well as morphology was compared between both groups. To confirm morphology, the expression of epithelial, mesothelial, and fibroblast markers was assessed. RESULTS: Both POSE and NPOSE cultures displayed similar growth potential and morphology. The expression of epithelial markers cyto-keratins 7 and 8 was similar between both groups. Only in cultures in which cells did not uniformly exhibit these markers, the percentage of cells expressing these markers was significantly lower at last passage when compared to the initial culture. In these latter cultures, cells that were morphologically indistinguishable from fibroblasts were observed. Mesothelial marker calretinin was expressed in 75% of cells of both POSE and NPOSE cultures and correlates with cyto-keratins 7 and 8 expression. CA 125 expression was equally low in POSE and NPOSE cultures (4.3%). Fibroblast markers FSM and vimentin were expressed in 100% and collagen IV was expressed in 16% of cells in all cultures. CONCLUSION: OSE cells derived from women with a hereditary predisposition to develop female adnexal cancer possess similar in vitro characteristics as OSE from women without this predisposition. On basis of our results, it seems advisable to study only 100% cyto-keratins 7 and 8 positive OSE cultures, since contamination of fibroblasts in some primary OSE cultures cannot be ruled out.     

Dual reporter system to dissect cis- and trans-effects influencing the mutation rate in a hypermutating cell line

Activation induced cytidine deaminase (AID) plays a key role in the induction of somatic hypermutation and class switching in the immunoglobulin genes of B-lymphocytes. AID expression by itself is sufficient to induce a GC-basepair biased mutator phenotype in lymphoid and non-lymphoid cell lines. Nevertheless a network of cis-regulatory elements and additional trans-factor proteins seems to govern the molecular mechanism of somatic hypermutation. To address the nature of mutation rate changes observed in the hypermutating pre-B cell line 18–81, we extended our previously described green fluorescent protein (GFP) reversion-system. Introducing an additional mutation reporter transgene enables us to discriminate between cis- and trans-factor caused alterations in the mutator phenotype. We show here that in cell line 18–81 the mutation rate declines upon prolonged periods of cell culture. The gradual loss of the mutator phenotype in cell line 18–81 is due to the downregulation of endogenous AID expression and can be reconstituted by overexpression of human AID protein. A correlation between AID mRNA levels and mutation rates is evident and even small changes in AID expression levels cause a significant effect on the mutability of the reporter transgenes.