Her family members are called home from abroad due to the severit

Her family members are called home from abroad due to the severity of the situation. She is discharged with GDC-0199 chemical structure the newborn 14 days after delivery.

She is never informed about the fact that she is treated with off-label medication. The family is not informed about their right to complain to the National Patient Complaint System and they are not informed about the possibility to seek compensation for the poor outcome (damaged uterus and a child with lifelong disability) from the Patient Complaint System [4] and [5]. Furthermore these cases (mother and baby) were not reported as an adverse incident report. After a public debate in 2012 on unreported side effects to misoprostol this family brought their case to the Patient Compensation Association and the child received a substantial economic compensation. The Patient Compensations Association stated that it was highly probable that misoprostol was the cause for these adverse events. Misoprostol is a prostaglandin E1 analog and very efficient uterotonic buy Dorsomorphin drug [1]. The US Food and Drug Administration (FDA) has listed a range of side effects such as hyperstimulation, uterine tetany, meconium-stained amniotic fluid, uterine rupture,

maternal shock, maternal death, fetal bradycardia and fetal death [6]. Though both mother and child survived, this parturition included hyperstimulation, uterine rupture, meconium-stained amniotic fluid, life-threatening maternal hemorrhage, fetal bradycardia and threatening fetal death. This woman previously had an uncomplicated vaginal delivery, and her current pregnancy was uneventful. It is highly unlikely to experience a uterine rupture in birth without a previously scarred uterus [7]. However high parity, malpresentation or placental abruption are predisposing factors [7], [8] and [9]. External force to the maternal abdomen (i.e. Kristeller-maneuver, vacuum- or forceps assisted birth) can, in rare cases, cause rupture of an unscarred uterus [7], [8] and [9]. None of these factors were present in this case. 25 μg misoprostol used vaginally is the recommended dose according Etomidate to the Cochrane

review [3]. Prostaglandins and other uterotonic agents can cause uterine rupture [7], [8], [9] and [10]. Several studies have found misoprostol more prone to hyperstimulation with fetal heart rate changes, meconium stained amniotic liquid and uterine rupture than other uterotonic agents [3] and [11] and reports on uterine rupture on previously unscarred uterus after misoprostol induction has been reported [12], [13], [14], [15], [16] and [17]. This birth was induced by misoprostol and thus not spontaneous. The woman experienced frequent contractions (5 in 10 min), which suggests hyperstimulation. The rapid progress of labor, her cervix dilated from 3–4 cm to 9 cm within 25 min and the fast decent of the fetal head from pelvic brim to below the ischial spines ads further to this argument.

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During the 6-month follow-up, at least one SAE was reported by 2

During the 6-month follow-up, at least one SAE was reported by 2.8% (35/1272) of the QIV selleck chemical group, and 1.4% (3/213) and 3.2% (7/218) of the TIV-Vic and TIV-Yam groups, respectively (Supplementary Table 1). None of the SAEs were considered

to be vaccine related. This Phase III, randomized, double-blind study of healthy adults aged ≥18 years showed that QIV was immunologically superior versus TIV for the alternate-lineage B strain, and was non-inferior for the influenza strains shared in the QIV and TIVs. HI antibody responses were also shown to be consistent between three lots of QIV, thus demonstrating manufacturing consistency of the candidate vaccine. Our results show that in people aged ≥18 years, QIV offers improved immunogenicity against the additional B strain without affecting antibody responses to existing strains compared with conventional TIVs; therefore, our study supports a switch

from conventional TIV to QIV with the aim of improving protection against influenza B disease. The immunogenicity and safety findings reported for this QIV which was manufactured in Canada are Gemcitabine consistent with a previous report of an inactivated QIV produced by the same company using a different process at facilities in Germany [16]. The results add to the growing evidence in both children and adults which shows that live attenuated and inactivated QIVs provide similar immune responses against shared vaccine strains versus TIV with added protection against the additional B strain [12], [13], unless [14], [15], [16] and [17]. We showed that each of the vaccines elicited strong

HI antibody responses against the A/H1N1 and A/H3N2 vaccine strains, and against B/Brisbane/60/2008 (Victoria) and/or against B/Florida/4/2006 (Yamagata). SCRs and SPRs against each vaccine strain were considered to be high, and immune responses were slightly stronger against influenza A than influenza B strains with QIV and both TIVs. The persistence of antibody responses was assessed six months after vaccination in a sub-cohort of subjects, and whereas immune responses decreased at 6 months in each vaccine group relative to those measured at day 21 after vaccination, they remain notably increased above baseline levels. In the QIV group, antibody persistence at 6 months appeared to be more robust against the influenza B strains with SPRs of 94.9% and 99.6% against B/Victoria and B/Yamagata, respectively, compared with SPRs of 66.5% and 64.6% against A/H1N1 and A/H3N2, respectively. Antibody levels were decreased against the influenza A strains at 6 months post-vaccination, and the clinical significance of this is uncertain. Descriptive analyses were also performed to further assess the immunogenicity of QIV according to age. The median age was 50.0 years (18–91 years) overall, with an equal distribution of subjects aged 18–64 years versus ≥65 years in each group.

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The composition of this adjuvant mimics bacterial DNA and so acts

The composition of this adjuvant mimics bacterial DNA and so acts to stimulate the immune system through the TLR9 pathway [20], [21], [22] and [23]. The CpG ODN, is being used in at least one registered FDA monitored clinical trial, but has not yet been approved by the FDA for use in conjunction with a specific vaccine [21]. We found that the presence

of CpG inside the spheres had a significant positive effect on the immune response (Fig. 2a, P = 0.0002). In addition, although previously published findings [24] and [25] showed increased CTL responses when MPLA was placed in the microsphere, we observed strong CTL responses only when MPLA was included in the carrier solution to rehydrate the microspheres for injection ( Fig. 2b, P = 0.0002). We believe MPLA in the carrier solution acts to stimulate the tissue macrophages in the area where transformation to dendritic cells takes place, selleckchem after which phagocytosis and antigen presentation occur. We found that presence of epitope inside the sphere was also critical. In particular, free epitope, even when combined with CpG and MPLA but without the presence of spheres produced essentially no immune response compared to the formulation using the PLGA loaded microspheres for the OVA ( Fig. 2c, P = 0.0015) and for the

VSV epitope ( Fig. 2d, P = 0.0002). We evaluated the dose response to inoculation with 11 μM microspheres loaded with 1%, 10% and 100% of maximum epitope for the OVA and VSV epitopes. The OVA epitope Histone Methyltransferase inhibitor dose response showed a plateau beginning at the lowest level with no statistically significant difference between the 1% and 100% loaded levels ( Fig. 3a, P = 0.25), whereas the VSV epitope showed a statistically significant increase in immune response with increasing loaded concentration at the loading levels tested ( Fig. 3b, P < 0.0001). Also, the difference in immune responses to OVA and VSV both at 1% loading were not statistically significant (P = 0.45), whereas

the difference in responses to OVA and VSV both at 100% were statistically significant (P = 0.0013). We next evaluated the immune response exhibited from two epitopes delivered simultaneously by putting the two epitopes in the same microsphere, with a concentration of OVA and VSV both below at 1% of maximum concentration. We used these concentrations because, as just mentioned, they produced immune responses of similar strength with single-epitope loadings. We administered these spheres in a total amount equal to the amount used previously, with CpG in the spheres and MPLA in the carrier solution. The immune response to OVA in the presence of VSV was not significantly different from the response to OVA in the sphere by itself ( Fig. 4a, P = 0.15), whereas the immune response to VSV in the presence of OVA was slightly greater than the response to VSV in the sphere by itself ( Fig. 4b, P = 0.045).

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Availability of affordable, efficacious vaccines holds promise bu

Availability of affordable, efficacious vaccines holds promise but challenges policy makers to assess critically the burden of disease and the anticipated impact in the local conditions. We review the mortality, morbidity and economic burden of rotavirus diarrhea in India in the context of improving child survival and health access, and present estimates of morbidity associated with rotavirus diarrhea from the follow up of five observational cohorts that were offered access to healthcare without fees. This, we drug discovery believe, represents morbidity not confounded by financial and access to care-related

issues and therefore a more accurate measurement of the underlying burden of disease. We combined data from the Indian Rotavirus Strain Surveillance Network (IRSSN), the Million Death Study (MDS) [13] and statistics compiled by the World Health Organization (WHO) and UNICEF with data from five community-based cohorts to arrive at conservative estimates of the burden of rotavirus diarrhea across the disease spectrum and the economic costs related to the disease. The IRSSN is a geographically representative, hospital based diarrheal surveillance system that used standardized protocols for enrolment and diagnostic evaluation at eight sites across India during 2005–2009 [12]. This surveillance system sampled diarrheal hospitalization in the sentinel hospitals and provides the proportion of hospitalized diarrhea that was related to rotavirus.

The Million Death Study (MDS), being conducted between 1998 and 2014 by the Registrar General of India and collaborators to determine causes of death in India

Afatinib concentration derives its data from a nationally representative sample of 14 million people in 2.4 million households within the Sample Registration those System, a large, routine demographic survey performed by the Registrar General of India. All deaths in the surveyed families have a cause of death assigned according to the International Classification of Diseases Revision 10 and are characterized by age, gender and region [13]. Incidence of diarrhea, diarrheal outpatient visits and hospitalization was obtained from five community-based cohorts that were intensively followed up for enteric diseases till at least two years of age. Three of these cohorts were in Vellore while the fourth was located in an urban slum in Delhi. Four of these cohorts also involved rotavirus testing of diarrheal samples, while a fifth cohort (also based in Vellore) had fortnightly follow-up and healthcare access data but not rotavirus testing of diarrheal samples. The details of the five cohorts are presented in Table 1. The overall rates of gastroenteritis, outpatient visits and hospitalizations due to rotavirus in the first two years of life were obtained as a weighted average from the cohorts. The 95% confidence intervals (95% CI) were calculated using the Byar’s approximation of the exact interval for the Poisson distribution [17].

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The gene encoding FomA was cloned into an E coli vector-based sy

The gene encoding FomA was cloned into an E. coli vector-based system [37] for generation click here of vaccines against bacteria-induced gum inflammation ( Fig. 5) and production of antibodies against VSC emission ( Fig.

6). The E. coli vector-based system has been used in our laboratory to develop various non-invasive vaccines [37]. The E. coli vector (E. coli intact particle) has all E. coli components and exhibits an excellent and natural adjuvant effect that accelerates the evaluation of protein immunogenicity [38]. Most E. coli strains are harmless and are part of the normal flora in human. In addition, an UV-irradiated and non-pathogenic E. coli BL21(DE3) strain was used in this study to construct vaccines targeting FomA. The fact that F. nucleatum is not an indigenous

bacterium in murine oral cavities has hindered the development of animal models of abscesses and halitosis for evaluation of vaccines and drugs against oral infections. In humans, gum pockets appear in an empty space between the root of the tooth and the top edge of the gum. These pockets trap bacteria and are the perfect incubators for bacteria to grow biofilm and produce VSCs. An oral colonization model in which bacteria are administered directly into the mouse oral cavity using PBS selleckchem with carboxymethylcellulose [39] and [40] has been commonly used for studying oral infections. Undoubtedly, the model represents the natural route of oral infection. However, the ability to quantify the

bacterial colonization is limited due to the uneven distribution of infected sites. Furthermore, unlike humans, mice do not physically secrete abundant saliva [41]. Thus, it may be inappropriate to use this model for studying the in vivo effect of vaccine-induced secretory immunoglobulin A (S-IgA) on bacterial colonization. Alternatively, injection of F. nucleatum and P. gingivalis into gum tissues of ICR mice recapitulates a model of infection in a gum pocket [22], validating our use of this model for quantification of gum inflammation ( Fig. 4 and Fig. 5) in this study. It has been shown that prior exposure of mice to F. nucleatum modulates host response to not P. gingivalis [42]. All the T-cell clones derived from mice immunized with F. nucleatum followed by P. gingivalis were T-helper type 2 (Th2) subsets, while those from mice immunized with P. gingivalis alone belonged to T-helper type 1 (Th1) subsets based on the flow cytometric analysis and cytokine profiles [43]. Other studies have shown that exposure of mice to F. nucleatum prior to P. gingivalis interfered with the opsonophagocytosis function of sera against P. gingivalis [42]. However, our results demonstrated that mice immunized with E. coli BL21(DE3) FomA did not increase the severity of P. gingivalis-induced gum swelling ( Fig. 5A), suggesting that vaccination with F. nucleatum FomA may not alter the host susceptibility to other oral bacteria. After injection of F. nucleatum and P.

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Thus, changing our overall diet pattern might be most beneficial

Thus, changing our overall diet pattern might be most beneficial to those with the greatest psychosocial stress, who have the least healthful diet, and are least able to afford dietary supplements. This research was supported by the National Institutes of Health, RO1HL087103 [to CAS]. We would like to thank Vasiliki Michopoulos and Mark Wilson for sharing their cortisol data. “
“Stress is an important risk factor for many neuropsychiatric

disorders. However, most individuals check details who are exposed to a stressor do not go on to develop a clinical disorder. Mechanisms of resilience and vulnerability to the harmful consequences of chronic stress have received increasing attention and are thought to involve a complex interaction between multiple genetic, environmental, and psychosocial factors (Feder et al., 2009, McEwen, 2012 and Zhu et al., 2014). In vulnerable individuals, these factors converge to trigger pathophysiological processes that may

lead to psychiatric symptoms. Increasingly, neuroimaging studies indicate that changes in functional connectivity across neuroanatomically distributed brain networks are an important element of that pathophysiology. Abnormal patterns of corticocortical connectivity are a common feature of depression, anxiety disorders, post-traumatic stress disorder, and other stress-related neuropsychiatric conditions (Anand et al., 2005, Etkin and Wager, 2007, Greicius et al., 2007, Selleckchem SCR7 Milad et al., 2007, Zhao et al., 2007, Liberzon and Sripada, 2008, Monk et al., 2008 and Broyd et al., 2009). Functional connectivity changes, in turn, have been linked to specific symptoms and to recovery during treatment (Etkin

et al., 2009, Fox et al., 2012, Liston et al., 2014 and Salomons et al., 2014) How chronic stress leads to pathological patterns of functional connectivity in vulnerable individuals is not fully understood. The underlying mechanisms are complex and multifactorial, involving dynamic changes in glutamatergic signaling and synaptic strength; direct effects on neurotrophins and cell adhesion molecules; and interactions Mephenoxalone with noradrenergic, dopaminergic, and serotonergic neuromodulators (Sandi, 2004, Duman and Monteggia, 2006, Arnsten, 2009 and Popoli et al., 2012). In clinical populations, in particular, it is likely that no single mechanism can account for stress-related changes in functional connectivity, which emerge from complex interactions with genetic and neurodevelopmental factors that influence risk and resilience (Duman et al., 1997, De Kloet et al., 2005a and Lupien et al., 2009). Here, we review recent advances in our understanding of just one of these mechanisms: how glucocorticoid stress hormones affect dendritic remodeling and postsynaptic dendritic spine plasticity in susceptible brain regions, including the hippocampus, prefrontal cortex, and amygdala (Leuner and Shors, 2013).

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DALYs were calculated for each country separately using a disease

DALYs were calculated for each country separately using a disease natural history model with a single input parameter (annual measles incidence, adjusted for under-estimation) and the “BCoDE toolkit” software application was used to compute estimated DALYs according to country-specific and year-specific population age-distributions (data retrieved this website from Eurostat) [31]. The measles disease model was created from the information collected through an extensive literature review and via consultation with measles experts, by linking the incidence of measles to all possible sequelae (health outcomes) through a disease progression model, or outcome tree.

Health outcomes were considered part of the outcome tree if there was evidence of a causal relationship between measles and

learn more the health outcome (Fig. 1). In the disease burden calculations, years of life lost (YLL) were estimated using the Standard Expected Years of Life Lost (SEYLL) based on the highest observed life expectancy, which is that of the Japanese population. The Japanase population has been commonly used as a standard population in DALYs calculations since it has the longest life expectancy, so that in principle every human being can be expected to live at least as long [32], [33], [34], [35] and [36]. Data on mortality were embedded into the model and were taken from both national Edoxaban sources and Eurostat [31]. Severity weights (i.e., disability weights) for non-fatal health outcomes were obtained from the Global Burden of Disease (GBD) study [2] and [5]. In conditions for which no weights existed, weights were adapted from existing GBD severity weights for similar conditions. Transition probabilities and mean duration of each health outcome were derived from the literature review. Time discounting and age-weighting were not applied in the base case analysis. The modeling approach applied assumed a steady-state and is therefore not suitable

for forecasting of burden. Information on gender was not provided, so cases were distributed evenly between males and females in each age group. Cases (<1%) for which information on age was missing were not included in the analysis. Our dataset consists of time-series cross-sectional data [28], and therefore appropriate methods are required given the non-independence of observations. We used log-linear mixed-effect regression modeling approach to investigate a linear relation between natural logarithm-transformed outcome and predictor variables. The outcome variable was burden (in DALYs per 100,000 persons, transformed using log(DALYs + 1)), and the primary predictor variable was vaccination coverage (coded as a percentage).

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9 In addition, variation at TMCO1 has been associated with intrao

9 In addition, variation at TMCO1 has been associated with intraocular pressure, 16 while 9p21 and SIX1/SIX6 are associated with cup-to-disc ratio 17 in normal individuals. We provide evidence for association at SIX1/SIX6, 9p21, and nominally at TMCO1 with incident OAG. Thus, loci associated with advanced glaucoma and relevant biometric traits are also associated with the initial onset of OAG (incidence). Those SNPs discovered in previous cohorts with typical (nonadvanced) OAG are not found to be associated with AUY-922 molecular weight OAG

incidence in our cohort, although power to detect weaker associations or those at rarer SNPs is limited. The association of sex with incident OAG in the cohort has been previously reported, 11 as has the higher-than-expected level of hypertension in the BMES cohort. 18 and 19 The current cohort was sufficiently ZD1839 powered to detect an odds ratio of ∼1.6. This is larger than those observed in the original discovery cohorts of cross-sectional (prevalent OAG) patient recruitment, although significant effects were still observed in this study, suggesting that the SNPs may be more important in predicting disease onset than progression, or that the true effect size is larger than previously

reported. However, larger prospective cohorts will be needed to properly assess the 8q22 and CAV1/CAV2 loci in particular. A nominal association was observed at TMCO1. This SNP has a lower allele frequency than others in the study (11% in controls) and the finding did not reach significance here in the context of multiple testing, owing to the lower power of this study (∼36%) to detect an effect at the minor allele frequency of 11%. We have previously reported an association of this locus with prevalent OAG in the BMES cohort with odds ratio (OR) = PAK6 1.57, P = .022. 7 The odds ratio for incident OAG reported in the current study was larger (OR = 1.74, P = .013) despite the smaller sample size. We thus conclude that TMCO1 is also confirmed to be associated

with incident OAG. The current study shows that OAG loci that are associated with OAG-relevant ocular parameters (cup-to-disc ratio and intraocular pressure) are specifically associated with OAG incidence independently of other known risk factors. This suggests that these loci are responsible at least in part for the initiation of OAG, consistent with their role in determination of these risk factor traits, which are themselves predictive for OAG development. We show also that the loci specifically associated with advanced glaucoma may also be important in initiation of OAG, and thus could be important in risk stratification among glaucoma suspect and early glaucoma patients.

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Interestingly, microinjection of anisomycin at the time of later

Interestingly, microinjection of anisomycin at the time of later IS did not reduce the immunizing effects of earlier ES, even though muscimol does so (see above). These data support the 5-FU cell line idea that the original experience of control induces plastic changes in mPFC neurons that then respond to even uncontrollable stressors and inhibit

the DRN. In further support, Christianson et al. (2014) found that ES, but not IS increases phosphorylated ERK in the PL, and that the immunizing effects of ES are prevented by PL microinjection of AP5 or the MEK inhibitor U0126. It might be noted that the role of the DMS in control-induced plasticity is still under investigation. The PL and the PL-DMS act/outcome system are engaged under numerous MI-773 order conditions, and instrumental learning occurs frequently during development. Clearly, these experiences do not produce immunization against the impact of severe stressors. Thus, it must be the engagement of this system during an aversive experience that is critical. It is often stated that “neurons that fire together wire together”. This all suggests a

scheme as depicted in Fig. 6. Imagine a set of neurons that are activated by intense stressors and PL neurons that are activated by control or contingency. Only when both occur is the plasticity/connection process initiated, so that later, stressors themselves will activate the PL and its projecting neurons. If this model is correct, then simply activating PL projection neurons during exposure to even IS, should lead to immunization. Thus, intra-PL picrotoxin or vehicle was administered during

ES, yoked IS or control treatment. IS in a different environment not occurred 7 days later. The critical finding (Amat et al., 2008) was that even IS blocked the later DRN activating and behavioral effects of subsequent IS if the PL was activated during the experience. Consistent with the model, intra-PL picrotoxin was without effect if it was given in the absence of a stressor. That is, PL activation plus uncontrollable stressor was immunizing, whereas neither were by themselves. The mPFC projects to many structures other than the DRN, and the glutamatergic pyramidal projections often synapse on GABAergic interneurons that inhibit the principal cells in the region. For example, pyramidal neurons from the infralimbic cortex (IL) region of the vmPFC project to an intercalated cell cluster (ITC) in the amygdala (Vertes, 2006). The ITC consists of GABAergic cells that inhibit output from the central nucleus (Berretta et al., 2005). Thus, stimulation of ITC cells inhibits conditioned fear responses. Although we have conducted far less work here, stressor control also appears to activate this mPFC-to-amygdala pathway.

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n BLP-SV vaccination required BLP interaction with TLR2 Indeed,

n. BLP-SV vaccination required BLP interaction with TLR2. Indeed, the data showed that SIgA responses measured in nasal (Fig. 3B) and vaginal lavages (Fig. 3C) were TLR2 dependent. Previously, it was shown that i.n. vaccination with BLP vaccines induced enhanced SIgA at mucosal tissue in BALB/c mice compared

to parenteral vaccination [15] and [35]. The potency to induce a mucosal SIgA response was independent of the mouse strain tested, as both C57BL6/J and BALB/c mice induced strong responses (Fig. 3). Similar to the local immune response induced by BLP adjuvanted vaccination, also systemically induced immune responses in BALB/c and C57BL6/J Target Selective Inhibitor Library cell line are comparable as shown by enhanced IFN-? producing cells and IAV-specific IgG titres [17] and [35]. Although the IL-5 cytokine is a differentiation marker for B-cells that produce IgA [36] we did not detect significant IL-5

cytokine secretion after i.n. BLP-SV vaccination (Fig. 2B). Since TLR2 signalling can also trigger IgA production by human B-cells directly [37], we suggest that the SIgA responses are at least partly enhanced due to the interaction of BLP with TLR2 on B cells (Fig. 3B and C). Previously, it has been shown that BLP adjuvanted vaccines induce protective immunity to subsequent infection [15] and [17]. Moreover, recent data showed that i.n. vaccination with a BLP adjuvanted influenza vaccine results in improved protection against both homologous and heterologous influenza challenge infections Selleckchem INCB018424 as compared to protection levels observed after conventional parenteral influenza vaccination [35]. These data underline that enhanced systemic and mucosal B-cell responses induced by i.n. vaccination with BLPs result in a strong protective and broad immune response. In conclusion, the interaction of BLPs with TLR2 in vivo is required for the enhanced activation of systemic and local IAV-specific adaptive immune responses as

observed after i.n. BLP-SV vaccination. Especially the ability to induce local IAV-specific immune responses, in particular elevated levels of IAV-specific IFN-? Resminostat producing T-cells and IgA antibody secreting B-cells, make BLPs an attractive immune stimulator to be used in nasal vaccination against influenza infection. Source of funding: This work was supported by grants from the European Union FP7 TOLERAGE: HEALTH-F4-2008-202156, TI Pharma ProjectD5-106, BSIK VIRGO Consortium grant no. 03012, and the Dutch Arthritis Association. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Conflict of interest: The authors declare no conflict of interest. “
“Clostridium perfringens is a Gram positive, anaerobe, spore forming bacterium that is classified into five toxinotypes based on production of the four typing toxins (α-, β-, ɛ-, and ι-toxins) [1]. Epsilon toxin (Etx), a β-pore-forming toxin, is produced by C.

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