Epidemiological impact of a large number of false negative SARS-CoV-2 test results in South West England during September and October 2021.

During September and October 2021, a substantial number of Polymerase Chain Reaction (PCR) tests in England processed at a single laboratory were incorrectly reported as negative. We estimate the number of false negative test results issued and investigate the epidemiological impact of this incident. We estimate the number of COVID-19 cases that would have been reported had the sensitivity of the laboratory test procedure not dropped for the period 2 September to 12 October. In addition, by making comparisons between the most affected local areas and comparator populations, we estimate the number of additional infections, cases, hospitalisations and deaths that could have occurred as a result of increased transmission due to false negative test results.We estimate that around 39,000 tests may have been false negatives during this period and, as a direct result of this incident, the most affected areas in the South-West of England could have experienced between 6000 and 34,000 additional reportable cases, with a central estimate of around 24,000 additional reportable cases. Using modelled relationships between key variables, we estimate that this central estimate could have translated to approximately 55,000 additional infections.Each false negative likely led to around 1.5 additional infections. The incident is likely to have had a measurable impact on cases and infections in the affected areas in the South-West of England. IMPACT STATEMENT: These results indicate the significant negative impact of incorrect testing on COVID outcomes; and make a substantial contribution to understanding the impact of testing systems and the need to ensure high accuracy in testing and reporting of results.

Impacts of a perinatal exposure to manganese coupled with maternal stress in rats: Learning, memory and attentional function in exposed offspring.

The developmental effects of chemicals that co-occur in vulnerable populations with elevated psychological stress are of increasing concern to the public. To investigate these concerns, we developed a rodent model of co-occurring perinatal manipulations and conducted a series of cognitive assessments in male and female offspring. Manganese (Mn), a neurodevelopmental toxicant when exceeding physiological requirements, was delivered in the drinking water (0, 2, or 4 mg Mn/mL) of rats from gestational day (GD) 7 to postnatal day (PND) 22. A variable perinatal stress paradigm was applied to half of the animals from GD13 to PND9. Novel object recognition (NOR), Morris water maze (MWM), differential reinforcement of low-rates procedure (DRL) and cued and uncued choice reaction time (CRT) tests were used to assess cognitive functions in offspring. Mn (4 mg/mL) and stress impaired NOR in adolescent males but facilitated NOR performance in females. However, when stress and Mn were combined these effects were attenuated in both sexes. During training for the DRL, Mn (2 mg/mL) facilitated, while stress impaired, lever press learning in both sexes. Few effects related to the treatments were found on DRL or MWM. During cued CRT, Mn (2 and 4 mg/mL) and stress reduced accuracy in males, while stress and Mn (2 mg/mL) increased anticipatory responding and slowed decision time in both sexes. Stress combined with Mn (2 mg/mL) improved cued accuracy and decision time, and Mn attenuated the effect of stress on anticipatory responding in both sexes. Stress slowed female movement time but when combined with Mn (4 mg/mL) the effect of stress was attenuated. During uncued CRT, except for decision time (which replicated effects observed with the cued task), no other effects of Mn or its combination with stress occurred. Females remained negatively affected by stress in most uncued CRT performance measures, while stressed improved male uncued accuracy. Taken together these data do not support increased cognitive impairment produced by Mn when combined with stress. However, the effects of perinatal stress alone, on these cognitive functions may hinder the detection of effects due to chemical exposures and underscores the need to consider the psychological health and wellbeing of the mother and her environment in risk assessment for developmental neurotoxicity of chemicals.

Standard treatment of female patients with breast cancer decreases substantially for women aged 70 years and older: a German clinical cohort study.

BACKGROUND: Standard treatment of patients with breast cancer decreases with age and older persons are mostly excluded from clinical trials. We hypothesized that non-adherence to treatment guidelines occurs for women aged > or =70 years and changes overall survival (OAS) and disease-free survival (DFS). PATIENTS AND METHODS: We enrolled 1922 women aged > or =50 years with histologically confirmed invasive breast cancer treated at the University of Ulm from 1992 to 2005. Adherence to guidelines and effects on OAS and DFS for women aged > or =70 years was compared with that for younger women (50-69 years). RESULTS: Women >70 years less often received recommended breast-conserving therapy (70-79 years: 74%-83%; >79 years: 54%) than women aged < or =69 years (93%). Non-adherence to the guidelines on radiotherapy (<70 years: 9%; 70-79 years: 14%-27%; >79 years: 60%) and chemotherapy (<70 years: 33%; 70-79 years: 54%-77%; > 79 years: 98%) increased with age. Omission of radiotherapy significantly decreased OAS [< or =69 years: hazard ratio (HR) = 3.29; P <0.0001; > or =70 years: HR = 1.89; P = 0.0005] and DFS (< or =69 years: HR = 3.45; P <0.0001; > or =70 years: HR = 2.14; P <0.0001). OAS and DFS did not differ significantly for adherence to surgery, chemotherapy, or endocrine therapy. CONCLUSION: Our study confirms that substandard treatment increases considerably with age. Omission of radiotherapy had the greatest impact on OAS and DFS in the elderly population.

Molecular mechanisms of ovarian hyperstimulation syndrome: paracrine reduction of endothelial claudin 5 by hCG in vitro is associated with increased endothelial permeability.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of ovarian stimulation associated with severe vascular hyperpermeability. Primary co-cultures of human luteinized granulosa cells (LGCs) and human umbilical vein endothelial cells (HUVECs) were used as a model of steroidgenic/endothelial cell interaction in OHSS. METHODS: hCG and the vascular endothelial growth factor (VEGF) inhibitor, Flt-1Fc, were added to co-cultures of LGCs and HUVECs separated by a micropore membrane. Endothelial permeability to labeled bovine serum albumin was measured and the expression of the endothelial cell-specific adhesion protein claudin 5 was investigated using immunocytochemistry and western blotting. RESULTS: The addition of hCG increased HUVEC permeability in the presence of LGCs (P < 0.05). hCG increased VEGF concentrations in both chambers of the co-culture system (P < 0.05). The increased permeability in the presence of LGCs and hCG was inhibited when VEGF was blocked by Flt-1Fc (P < 0.05). Endothelial membrane claudin 5 protein was reduced in the presence of hCG and LGCs, as measured by immunocytochemistry (P < 0.05) and western blotting (P < 0.05) and this reduction was inhibited by Flt-1Fc. hCG had no direct effects on endothelial cell claudin 5. CONCLUSIONS: For OHSS, this novel paradigm suggests that hCG can increase endothelial permeability by up-regulating VEGF in LGCs which causes reduction in endothelial claudin 5 expression.

Regulation of endothelial proliferation by the renin-angiotensin system in human umbilical vein endothelial cells.

This study was performed in order to evaluate the role of angiotensin II in physiological angiogenesis. Human umbilical vein endothelial cells (HUVEC) were stained for angiotensin II type 1 receptor (AGTR1) immunocytochemically and for gene expression of renin-angiotensin system (RAS) components. The regulation of the angiogenesis-associated genes vascular endothelial growth factor (VEGF) and angiopoietins (ANGPT1 and ANGPT2) were studied using quantitative RT-PCR. Furthermore, we examined the effect of angiotensin II on the proliferation of HUVEC using Ki-67 as well as BrdU immunocytochemistry and investigated whether the administration of the AGTR1 blocker candesartan or the VEGF antagonist FLT1-Fc could suppress the observed angiotensin II-dependent proangiogenic effect. AGTR1 was expressed in HUVEC and the administration of angiotensin II significantly increased the gene expression of VEGF and decreased the gene expression of ANGPT1. Since the expression of ANGPT2 was not affected significantly the ratio of ANGPT1/ANGPT2 was decreased. In addition, a significantly increased endothelial cell proliferation was observed after stimulation with angiotensin II, which was suppressed by the simultaneous administration of candesartan or the VEGF antagonist FLT1-Fc. These results indicate the potential capacity of angiotensin II in influencing angiogenesis by the regulation of angiogenesis-associated genes via AGTR1. Since VEGF blockade opposed the effect of angiotensin II on cell proliferation, it is hypothesised that VEGF mediates the angiotensin II-dependent effect in concert with the changes in angiopoietin expression. This is the first report of the RAS on the regulation of angiogenesis-associated genes in physiology.

Potential role of Renin-Angiotensin-system for tumor angiogenesis in receptor negative breast cancer.

OBJECTIVE: This study examined the potential role of Angiotensin II for the regulation of angiogenesis associated genes in receptor positive and negative human breast cancer. METHODS: Expression of different Renin-Angiotensin system (RAS) components in human breast cancer tissue was investigated using immunofluorescence, and in a receptor positive (MCF-7) and receptor negative (MDA-MB 468) breast cancer cell line by performing immunocytochemistry and RT-PCR. Both cell lines were stimulated with Angiotensin II and Angiotensin II receptor type 1 (At(1)R) blocker Candesartan, and gene expression of vascular endothelial growth factor (VEGF), Angiopoietin 1 and 2 (Ang-1 and Ang-2), tissue inhibitor of matrix metalloproteinases 1 (TIMP-1), and hypoxia inducible transcription factor 2alpha (HIF-2alpha) were quantified by TaqMan-Real-Time PCR analysis. RESULTS: RAS components, Angiotensinogen, Renin, Angiotensin I-converting enzyme (ACE), and At(1)R and At(2)R were expressed in hormone-receptor negative and positive human breast cancer tissue as well as in MDA-MB 468 and in MCF-7 human breast cancer cells. In addition, we found expression of VEGF, Ang-1, TIMP-1, and HIF-2alpha in both cell lines. However, only in receptor negative MDA-MB 468 cells, did Angiotensin II significantly increase gene expression of VEGF, HIF-2alpha, and TIMP-1. This effect was completely inhibited by Candesartan. CONCLUSION: In conclusion, it is hypothesized that Angiotensin II may be involved in regulation of tumor angiogenesis especially in receptor negative breast cancer by regulation of angiogenesis associated genes via At(1)R. These findings are the first evidence for targeting tumor angiogenesis by inhibition of At(1)R in receptor negative human breast cancer cells and may lead to new therapeutical anticancer strategies based upon inhibition of At(1)R.

Regulation of tight junction proteins occludin and claudin 5 in the primate ovary during the ovulatory cycle and after inhibition of vascular endothelial growth factor.

Ovarian follicular and corpus luteum development, including angiogenesis, are characterized by cell-cell rearrangements that may require dynamic changes in cell-cell adhesion. The present study investigates the expression of tight junction proteins occludin and claudin 5 during follicular and luteal development in the primate ovary and after inhibition of vascular endothelial growth factor (VEGF) by VEGF trap treatment. Occludin was localized to the plasma membrane of granulosa cells. During follicular development occludin staining decreased significantly (P < 0.05) and disappeared completely by the ovulatory stage. After inhibition of VEGF, occludin staining was significantly (P < 0.05) higher in the granulosa of secondary and tertiary follicles compared with controls. Claudin 5 was exclusively localized to the theca vasculature. A significant (P < 0.05) increase in staining was detected from the pre-antral to the antral and ovulatory stage. However, dual staining with CD31 revealed that within the theca endothelium the amount of claudin 5 remained constant during follicular development. Treatment with VEGF trap throughout the follicular phase revealed a lack of claudin 5 staining in the theca interna but no difference was observed in the remaining theca externa vasculature. In the corpus luteum, claudin 5 was also localized in the vasculature. Treatment with VEGF trap in the mid-luteal phase resulted in a significant increase in staining (P < 0.05). These results led us to hypothesize that tight junctions are involved in regulation of follicular growth, antrum transition and follicular angiogenesis which is compromised by VEGF inhibition. VEGF may influence luteal vascular permeability by regulation of the endothelial specific tight junction protein claudin 5.

Induction of aryl hydrocarbon hydroxylase and forestomach tumors ben benzo(a)pyrene.

While papillomatous tumors developed in the forestomach of female Ha/ICR mice after a 12-week chronic feeding period of benzo(a)pyrene (BP), no tumors developed in the glandular portion of stomach or in the lung or liver. Among all tissues examined, the forestomach showed the greatest increase of aryl hydrocarbon hydroxylase (AHH) activity following acute or chronic administration of BP. Single acute doses of BP induced AHH activity in forestomach, glandular stomach, lung, and small intestine, but not in the kidney and liver of these animals. Similarly, after chronic administration of BP, AHH activity was inducible in the forestomach, glandular stomach, and lung, but again not in the liver. Although the formation of tumors is associated with greater inducibility of AHH activity in the forestomach after BP administration, the relationship between tissue inducibility of AHH activity and susceptibility to BP carcinogenesis is still not clear. Further studies regarding the formation of specific carcinogenic epoxides of BP in itssues both susceptible (e.g., forestomach) and resistant to BP carcinogenesis would more clearly define the relationship between AHH inducibility and BP carcinogenesis.

Challenges of Longevity: Safety of Vaginal and Laparoscopic Urogynecological Procedures in Septuagenarians and Older Patients.

Introduction. Pelvic organ prolapse (POP) and urinary incontinence (UI) have increasing prevalence in the elderly population. The aim of this study was to compare the comorbidities of these procedures between <70 y/o and ≥70 y/o patients. Materials and Methods. In our retrospective study over a period of 2.5 years, 407 patients had received an urogynecological procedure. All patients with POP were treated by reconstructive surgery. Complications were reported using the standardized classification of Clavien-Dindo (CD). The study can be assigned to stage 2b Exploration IDEAL (Idea, Development, Exploration, Assessment, Long-term study)-system of surgical innovation. Results. Operation time, blood loss, and intraoperative complications have not been more frequent in the elderly, whereas hospital stay was significantly longer in ≥70 y/o patients. Regarding postoperative complications, we noticed that ≥70 y/o patients had an almost threefold risk to develop mild early postoperative complications compared to younger patients (OR: 2.86; 95% CI: 1.76-4.66). On the contrary, major complications were not more frequent. No case of life-threatening complication or the need for blood transfusion was reported. Conclusion. After urogynecological procedures, septuagenarians and older patients are more likely to develop mild postoperative complications but not more intraoperative or severe postoperative complications compared to younger patients.

Diagnostic Methods of Ectopic Pregnancy and Early Pregnancy Loss: a Review of the Literature.

This review article presents recent evidence on early pregnancy loss and ectopic pregnancy. In the light of recent evidence, the ß-hCG discriminatory zone may be extended in clinically stable cases without evidence of bleeding. A possible cut-off is 4300 mIU/ml, which corresponds to when a sonographer should detect an intrauterine pregnancy. Embryonic demise can be confirmed when a transvaginal ultrasound finding shows no heartbeat in an embryo of more than 7 mm CRL, no embryo in a gestational sac having a mean sac diameter of more than 25 mm, or no appearance of an embryo within 7-10 days after the primary examination. These are considered definitive signs of embryonic demise. Suggestive signs of embryonic demise require closer monitoring of the pregnancy.

Parental effects in Plantago lanceolata L. III. Measuring parental temperature effects in the field.

To determine the evolutionary importance of parental environmental effects in natural populations, we must begin to measure the magnitude of these effects in the field. For this reason, we conducted a combined growth chamber-field experiment to measure parental temperature effects in Plantago lanceolata. We grew in the field offspring of controlled crosses of chamber-grown parents subjected to six temperature treatments. Each treatment was characterized by a unique combination of maternal prezygotic (prior to fertilization), paternal prezygotic, and postzygotic (during fertilization and seed set) temperatures. Offspring were followed for three years to measure the effects of treatment on several life-history traits and population growth rate, our estimate of fitness. Parental treatment influenced germination, growth, and reproduction of newborns, but not survival or reproduction of offspring at least one year old. High postzygotic temperature significantly increased germination and leaf area at 17 weeks by approximately 35% and 2%, respectively. Probability of flowering and spike production in the newborn age class showed significant parental genotype x parental treatment interactions. High postzygotic temperature increased offspring fitness by approximately 50%. The strongest contributors to fitness were germination and probability of flowering and spike production of newborns. A comparison of our data with previously collected data for chambergrown offspring shows that the influence of parental environment on offspring phenotype is weaker but still biologically meaningful in the field. The results provide evidence that parental environment influences offspring fitness in natural populations of P. lanceolata and does so by affecting the life-history traits most strongly contributing to fitness. The data suggest that from the perspective of offspring fitness, natural selection favors parents that flower later in the flowering season in the North Carolina Piedmont when it is warmer. Genotypic-specific differences in response of offspring reproductive traits to parental environment suggest that parental environmental effects can influence the rate of evolutionary change in P. lanceolata.

Sulfation-dependent down-regulation of interferon-gamma-induced major histocompatibility complex class I and II and intercellular adhesion molecule-1 expression on tubular and endothelial cells by glycosaminoglycans.

BACKGROUND: Previously, it has been demonstrated that heparin inhibits major histocompatibility complex (MHC) class II and intercellular adhesion molecule-1 (ICAM-1) expression on interferon-gamma (IFN-gamma)-stimulated human umbilical vein endothelial cells (HUVECs). Inasmuch as proximal tubular epithelial cells (PTECs) are prime targets in acute renal allograft rejection, we investigated whether there is a difference in the ability of heparin to influence MHC and ICAM-1 expression on PTECs as compared to HUVECs. We also studied whether the degree of sulfation of heparin is of relevance for the binding to IFN-gamma and inhibition of MHC and ICAM-1 expression after IFN-gamma stimulation. METHODS: Cultured HUVECs and PTECs were stimulated with IFN-gamma for 72 hr in the presence or absence of various heparinoids. MHC and ICAM-1 expression were thereafter determined by fluorescence-activated cell sorting. RESULTS: Heparin was able to inhibit the up-regulation of MHC and ICAM-1 in a dose-dependent fashion on both IFN-gamma-stimulated HUVECs and PTECs. In PTEC cultures, higher concentrations of heparin were required for the inhibition of MHC class I. Heparin and supersulfated glycosaminoglycans (GAGs) were able to bind to IFN-gamma, whereas N-desulfated N-acetylated GAGs with a low amount of sulfate were not. Inhibition of cell-bound heparan sulfate proteoglycan sulfation with NaClO3 resulted in an impaired MHC and ICAM-1 expression after IFN-gamma stimulation. CONCLUSION: We postulate that IFN-gamma binds to cell-bound heparan sulfate proteoglycan in a sulfation-dependent fashion. This binding may facilitate the interaction of IFN-gamma with its receptor. Supersulfated GAGs with low anti-coagulant activity could be used therapeutically to decrease MHC and ICAM-1 expression on organ grafts.

Treatment of chronic renal allograft rejection in rats with a low-molecular-weight heparin (reviparin).

BACKGROUND: Low-molecular-weight heparin (LMWH) has been shown to prolong survival of rat cardiac allografts independently from immunosuppressive treatment. Furthermore, long-term treatment reduces the development of chronic graft vascular disease after experimental heart transplantation. The aim of the present study was to determine whether treatment with the LMWH reviparin has a beneficial effect on chronic rejection in a rat renal allograft model. METHODS: Kidneys of Fisher (F344) rats were transplanted into unilaterally nephrectomized Lewis (LEW) recipients. LEW-->LEW isografts served as controls. Animals were treated with cyclosporine (5 mg/kg/d) for the first 10 days. Nephrectomy of the remaining kidney was performed after 10 days. Allografted animals were treated either with reviparin (2 mg/kg/d subcutaneously) for 24 weeks (Allo-24), from week 12 to 24 (Allo-12), or with vehicle for 24 weeks. Proteinuria was determined at regular intervals. Kidneys were harvested after 24 weeks for histomorphological and immunohistochemical evaluation. RESULTS: No major bleeding complications were observed in reviparin-treated animals. Proteinuria was significantly reduced in allografted animals both by early as well as by late-onset treatment with reviparin. Transplant glomerulopathy was diminished in Allo-24 and in Allo-12 groups compared to vehicle-treated animals, whereas tubulointerstitial inflammation was influenced only in animals immediately treated with reviparin. Immunohistochemical studies demonstrated a marked reduction of renal monocyte and T-cell infiltration as well as expression of MHC II by treatment with reviparin. CONCLUSIONS: Treatment with the LMWH reviparin significantly improved chronic renal allograft rejection in the F344-to-LEW rat model, both after early and late start of therapy. Although the exact mechanisms of this beneficial effect remain unclear, our data offer a potential new therapeutical approach for prevention of chronic allograft nephropathy.

Antithrombotic efficacy in a rat model of the low molecular weight heparin, reviparin sodium, administered by the oral route.

Previous studies in rats show that unfractionated heparin and the low molecular weight heparin logiparin have a dose-dependent antithrombotic effect and are found in endothelium and plasma when administered orally. Objectives of the present study were to determine if similar evidence of absorption could be observed with oral reviparin sodium. Thrombosis incidence was determined 4 h after application of 10% formalin in methanol to the exposed jugular vein. A dose-dependent antithrombotic effect was observed when 0.01 to 7.5 mg/kg (20 rats/group) was administered by stomach tube immediately following thrombus initiation. Thrombotic incidence was also significantly reduced when 0.025 mg/kg was given 4 and 2 h prior to, immediately after, and 2 and 3 h following thrombus initiation. Reviparin was recovered from endothelium and plasma in trace amounts at all doses. At 0.025 mg/kg, peak aortic endothelial reviparin concentrations were found at 1 and 2 h and peak plasma anti-Xa activity was detected at 2 h. Trace amounts of plasma TFPI were found only at 8 h after administration. Dose-dependent antithrombotic activity and recovery from endothelium and plasma support the hypothesis that orally administered reviparin sodium is absorbed.

Airborne and rescue point-of-care testing.

The prehospital environment has not been studied for point-of-care testing. Therefore, the authors' helicopter program evaluated the performance of the i-STAT Portable Clinical Analyzer, a rapid point-of-care, hand-held instrument. The primary aim of the study was to determine if the i-STAT Portable Clinical Analyzer could be used in the field to assess patient status in flight, and to allow the flight crew to intervene immediately, thus delivering a more stable patient to the emergency room. Imprecision and initial split-sample comparative studies with the Portable Clinical Analyzer were completed in the hospital satellite laboratory and clinical chemistry laboratory. Comparison studies were performed on patient samples drawn and analyzed in the helicopter and subsequently analyzed in the satellite and clinical chemistry laboratories. The only significant differences observed were with glucose. The glucose discrepancies were probably due to the time delay between collection of the specimen in the helicopter and subsequent analysis in the laboratory. Following this initial validation, the i-STAT Portable Clinical Analyzer was used on 81 patients transported by the flight crew. The tests performed in the helicopter include sodium, potassium, glucose, and hematocrit/hemoglobin concentrations. Fifteen (18.5%) of the patients were treated with transfusions, glucose, or insulin based on the Portable Clinical Analyzer results. Other identified needs include blood gas analysis (in process) and use of point-of-care testing in the fixed-wing environment.

DDT-induced tremor in rats: effects of pharmacological agents.

Rats given a tremorigenic dose of DDT (75 mg/kg, PO) were treated with pharmacological agents either 30 min prior to DDT or 1-2 h prior to testing at the time of peak effect (12 h postdosing). The administration of mephenesin (a centrally acting muscle relaxant) or Dilantin (an anticonvulsant) prior to DDT significantly attenuated tremor. Pretreatment with pizotifen (a serotonergic receptor antagonist) had no significant effect on tremor. Administration of the same agents 1-2 h prior to measurement had minimal effects. Trihexyphenidyl (a muscarinic cholinergic receptor antagonist) exacerbated the tremor produced by DDT. These data suggest that cholinergic neurotransmitter systems may be involved in DDT-induced tremor. That DDT-induced tremor was significantly attenuated by mephenesin and Dilantin is in accord with the conclusion that DDT-induced tremor is a manifestation of repetitive discharge due to interference with ionic conductance.

Pharmacological modification of tremor and enhanced acoustic startle by chlordecone and p,p'-DDT.

Pretreatment of rats with phenoxybenzamine (5 mg/kg; SC), an alpha adrenergic antagonist, decreased the peak tremor power and startle magnitude of rats subsequently given DDT (75 mg/kg; PO) or chlordecone (60 mg/kg; IP), without having a significant effect on control animals. Pretreatment with an intracerebroventricular injection of calcium (3.75 microM in 5 microliters NaCl) decreased the peak tremor power due to subsequently administered DDT, while increasing the tremor response in rats later dosed with chlordecone. The effects of phenoxybenzamine are postulated to be due to a blockade of an excitatory influence of the adrenergic system. Calcium may decrease DDT-induced tremor by acting as a neuronal stabilizer. Potentiation of the tremorigenic effect of chlordecone by calcium may be due to increased levels of intracellular calcium, resulting in augmented release of neurotransmitters in chlordecone-exposed animals.

Pharmacological modification of DDT-induced tremor and hyperthermia in rats: distributional factors.

Pretreatment of rats with hydantoin (75 mg/kg, PO, an anticonvulsant), trihexyphenidyl (10 mg/kg, SC, a muscarinic cholinergic antagonist), or piperonyl butoxide (500 mg/kg, PO, a metabolic inhibitor) had no effect on the whole blood or brain tissue levels of orally administered DDT (75 mg/kg) or its metabolites DDD and DDE. Hydantoin and piperonyl butoxide decreased DDT-induced tremor and hyperthermia due to DDT when measured 12 h after DDT exposure, while trihexyphenidyl augmented some components of DDT-induced tremor. Additional experiments found that pretreatment with piperonyl butoxide increased tremor due to permethrin exposure (120 mg/kg, PO), while having no effect on tremor due to chlordecone administration (60 mg/kg, IP). Pretreatment with ellipticine (30 mg/kg, IP, a metabolic inhibitor) also decreased tremor 12 h after DDT exposure. The effects of piperonyl butoxide and ellipticine on DDT-induced tremor are postulated to occur through direct actions of these compounds on nerve or muscle tissue. Hydantoin-induced attenuation of DDT-induced neurotoxicity may be due to the ability of hydantoin to block repetitive firing of nerves by binding to the inactivation gates of sodium.

Safety and efficacy of propofol with EDTA when used for sedation of surgical intensive care unit patients.

OBJECTIVE: To compare propofol with disodium edetate (EDTA) and propofol without EDTAwhen used for the sedation of critically ill surgical intensive care unit (ICU) patients. DESIGN: Prospective, randomised, multicentre trial. PATIENTS: A total of 122 surgical ICU patients who required intubation and mechanical ventilation. INTERVENTIONS: Patients were randomised to receive either propofol or propofol plus EDTA (propofol EDTA) by continuous infusion for sedation. MEASUREMENTS AND RESULTS: The addition of EDTA to propofol had no effect on calcium or magnesium homeostasis, renal function, haemodynamic function, or efficacy when used for the sedation of surgical patients in the ICU. The most common adverse events were hypotension, atrial fibrillation, and hypocalcaemia. In this trial, a greater number of serious adverse events and adverse events leading to withdrawal occurred in the propofol group relative to the propofol EDTA group. There was a significantly lower crude mortality rate at 7 and 28 days for the propofol EDTA group compared with the propofol group. There were no statistically significant differences between groups with respect to depth of sedation. CONCLUSION: The propofol EDTA formulation had no effect on calcium or magnesium homeostasis, renal function, or sedation efficacy compared with propofol alone when used for sedation in critically ill surgical ICU patients. There was a significant decrease in mortality in the propofol EDTA group compared with the propofol group. Further investigations are needed to validate this survival benefit and elucidate a possible mechanism.

Effect of interferon gamma on infection-related death in patients with severe injuries. A randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the efficacy of interferon gamma in reducing infection and death in patients sustaining severe injury. DESIGN: Multicenter, randomized, double-blind, placebo-controlled trial with observation for 60 days and until discharge for patients with major infection on day 60. SETTING: Nine university-affiliated level 1 trauma centers. PATIENTS: Four hundred sixteen patients with severe injuries, assessed by Injury Severity Score and degree of contamination. INTERVENTION: Recombinant human interferon gamma, 100 micrograms, was administered subcutaneously once daily for 21 days (or until patient discharge if prior to 21 days) as an adjunct to standard antibiotic and supportive therapy. MAIN OUTCOME MEASURES: Incidence of major infection, death related to infection, and death. RESULTS: Infection rates were similar in both treatment groups; however, patients treated with interferon gamma experienced fewer deaths related to infection (seven [3%] vs 18 [9%]; P = .008) and fewer overall deaths (21 [10%] vs 30 [14%]; P = .17). While 12 early deaths (days 1 through 7) occurred in each treatment group, late death occurred in 18 placebo-treated patients and nine in interferon gamma-treated patients. The results were dominated by findings at one center, which had the highest enrollment and higher infection and death rates. Statistical analysis did not eliminate the possibility of an unidentified imbalance between arms as an explanation for the results. CONCLUSION: Further evaluation is required to determine the validity of the observed reduction in infection-related deaths in patients treated with interferon gamma.