Short-lived sensitization of cardiovascular outcomes of postpartum endotoxemia in preeclamptic rats: Role of medullary solitary tract neuroinflammation.

Preeclampsia (PE) is a pregnancy-related disorder with serious maternal complications. Considering the increased importance of postpartum infection in maternal morbidity and mortality, we investigated whether preeclamptic maternal programming alters cardiovascular consequences of endotoxemia in rats and the role of cardiac and brainstem neuroinflammation in this interaction. Preeclampsia was induced by oral administration of L-NAME (50 mg/kg/day) for 7 days starting from day 14 of conception. Changes in blood pressure, heart rate, and cardiac autonomic function caused by lipopolysaccharide (LPS, 5 mg/kg i.v.) were assessed in mothers at 3 weeks (weaning time) and 9 weeks postnatally. Compared with respective non-PE counterparts, LPS treatment of weaning PE mothers caused significantly greater (i) falls in blood pressure, (ii) rises in heart rate and left ventricular contractility (dP/dtmax), (iii) reductions in time and frequency domain indices of heart rate variability and shifts in cardiac sympathovagal balance (low-frequency/high-frequency ratio, LF/HF) towards parasympathetic dominance, and (iv) attenuation of reflex bradycardic responses measured by the vasoactive method. The intensified LPS effects in weaning PE rats subsided after 9 weeks of delivery. Immunohistochemical studies showed increased protein expression of nuclear factor kappa B (NF-κB) in brainstem neuronal pools of the nucleus of the solitary tract (NTS), but not rostral ventrolateral medulla (RVLM), in endotoxic PE weaning rats compared with non-PE rats. Cardiac NF-κB expression was increased by LPS but this was similarly noted in PE and non-PE rats. Together, preeclamptic maternal programming elicits short-term exacerbation of endotoxic cardiovascular and autonomic derangements due possibly to exaggerated NTS neuroinflammatory insult.

Beta-endorphin inhibits the inflammatory response of bovine endometrial cells through δ opioid receptor in vitro.

Postpartum uterine infections are common reproductive diseases in postpartum cows. Evidence has shown that plasma ß-endorphins increase during bovine uterine inflammation. However, the effect of ß-endorphins on the inflammatory response in bovine endometrium has not been clarified. The aim of this study was to investigate the effect of ß-endorphins on the inflammatory response of bovine endometrial epithelial and stromal cells, and to explore the possible mechanism. The cells were treated with E. coli lipopolysaccharide (LPS) to simulate inflammation, which was characterized by the significant activation of NF-κB signaling pathway and the increased gene expression of the downstream proinflammatory cytokines (approximately 1.2- to 15-fold increase, P < 0.05). By using Western blot and qPCR techniques, we found that ß-endorphins inhibited the key protein expression of NF-κB pathway, and the gene expressions of TNF, IL1B, IL6, CXCL8, nitric oxide synthase 2, and prostaglandin-endoperoxide synthase 2 (P < 0.05). The co-treatment of ß-endorphins and opioid antagonists showed that the anti-inflammatory effect of ß-endorphins could be blocked (P < 0.05) by non-selective opioid antagonist naloxone or δ opioid receptor antagonist ICI 154129, but not the µ opioid receptor antagonist CTAP (P > 0.05). In conclusion, ß-endorphins may inhibit the inflammatory response of bovine endometrial epithelial and stromal cells through δ opioid receptor.

Disseminated tuberculosis after pregnancy progressed to paradoxical response to the treatment: report of two cases.

BACKGROUND: Early postpartum women are more likely to develop tuberculosis than nonpregnant women mainly due to immune reconstitution after delivery. Paradoxical response (PR) during antituberculosis treatment also arises via recovery from immunosuppression. However, no study focused on PR during antituberculosis treatment in a postpartum patient has been reported. CASE PRESENTATION: We present two sequential cases (Patient 1: 26-year-old; Patient 2: 29-year-old) of postpartum tuberculosis with pulmonary and extrapulmonary lesions (Patient 1: peritonitis; Patient 2: psoas abscess secondary to spondylitis). Both cases progressed to PR (worsening of pre-existing lung infiltrations (Patients 1, 2) and new contralateral effusion (Patient 2)) in a relatively short time after initiation of treatment (Patient 1: 1 week; Patient 2: 3 weeks), suggesting that immune modulations during pregnancy and delivery may contribute to the pathogenesis of both disseminated tuberculosis and its PR. The pulmonary lesions and effusion of both cases gradually improved without change of chemotherapy regimen. CONCLUSION: Physicians should recognize PR in tuberculosis patients with postpartum and then evaluate treatment efficacy.

Long-term impact of puerperal metritis on the profiles of peripheral blood leukocytes in peripartum dairy cows.

To determine the effects of puerperal metritis on the immune response, changes in the differential peripheral blood leukocyte counts were analyzed during the peripartum period in cows with or without metritis. Multiparous Holstein cows were examined for uterine health disorders and classified into two groups: healthy (n = 11) or metritis (n = 5) cows. The lymphocyte and monocyte counts and the proportion of CD8(+) lymphocytes were higher in cows with metritis compared to healthy cows. Moreover, the effects of puerperal metritis on the lymphocyte counts and CD4(+)/CD8(+) ratio persisted weeks after the uterine inflammation had self-resolved. Taken together, the findings of the present study indicate the possible long-term alterations of systemic immune responses in cows with puerperal uterine inflammation.

Intrauterine group A streptococcal infections are exacerbated by prostaglandin E2.

Streptococcus pyogenes (Group A Streptococcus; GAS) is a major cause of severe postpartum sepsis, a re-emerging cause of maternal morbidity and mortality worldwide. Immunological alterations occur during pregnancy to promote maternofetal tolerance, which may increase the risk for puerperal infection. PGE2 is an immunomodulatory lipid that regulates maternofetal tolerance, parturition, and innate immunity. The extent to which PGE2 regulates host immune responses to GAS infections in the context of endometritis is unknown. To address this, both an in vivo mouse intrauterine (i.u.) GAS infection model and an in vitro human macrophage-GAS interaction model were used. In C57BL/6 mice, i.u. GAS inoculation resulted in local and systemic inflammatory responses and triggered extensive changes in the expression of eicosanoid pathway genes. The i.u. administration of PGE2 increased the mortality of infected mice, suppressed local IL-6 and IL-17A levels, enhanced neutrophilic inflammation, reduced uterine macrophage populations, and increased bacterial dissemination. A role for endogenous PGE2 in the modulation of antistreptococcal host defense was suggested, because mice lacking the genes encoding the microsomal PGE2 synthase-1 or the EP2 receptor were protected from death, as were mice treated with the EP4 receptor antagonist, GW627368X. PGE2 also regulated GAS-macrophage interactions. In GAS-infected human THP-1 (macrophage-like) cells, PGE2 inhibited the production of MCP-1 and TNF-α while augmenting IL-10 expression. PGE2 also impaired the phagocytic ability of human placental macrophages, THP-1 cells, and mouse peritoneal macrophages in vitro. Exploring the targeted disruption of PGE2 synthesis and signaling to optimize existing antimicrobial therapies against GAS may be warranted.

Leukotriene B4 enhances innate immune defense against the puerperal sepsis agent Streptococcus pyogenes.

Puerperal sepsis is a leading cause of maternal mortality worldwide. Streptococcus pyogenes [group A Streptococcus; (GAS)] is a major etiologic agent of severe postpartum sepsis, yet little is known regarding the pathogenesis of these infections. Tissue macrophages provide innate defense against GAS, and their actions are highly regulated. The intracellular second messenger cAMP can negatively regulate macrophage actions against GAS. Because leukotriene (LT) B(4) has been shown to suppress intracellular cAMP in macrophages, we hypothesized that it could enhance innate defenses against GAS. We assessed the capacity of LTB(4) to modulate antistreptococcal actions of human macrophages, including placental and decidual macrophages and used a novel intrauterine infection model of GAS in mice lacking the 5-lipoxygenase enzyme to determine the role of endogenous LTs in host defense against this pathogen. Animals lacking 5-lipoxygenase were significantly more vulnerable to intrauterine GAS infection than were wild-type mice and showed enhanced dissemination of bacteria out of the uterus and a more robust inflammatory response than did wild-type mice. In addition, LTB(4) reduced intracellular cAMP levels via the BLT1 receptor and was a potent stimulant of macrophage phagocytosis and NADPH oxidase-dependent intracellular killing of GAS. Importantly, interference was observed between the macrophage immunomodulatory actions of LTB(4) and the cAMP-inducing lipid PGE(2), suggesting that interplay between pro- and anti-inflammatory compounds may be important in vivo. This work underscores the potential for pharmacological targeting of lipid mediator signaling cascades in the treatment of invasive GAS infections.

Postpartum group a Streptococcus sepsis and maternal immunology.

Group A Streptococcus (GAS) is an historically important agent of puerperal infections and sepsis. The inception of hand-washing and improved hospital hygiene drastically reduced the incidence of puerperal sepsis, but recently the incidence and severity of postpartum GAS infections has been rising for uncertain reasons. Several epidemiological, host, and microbial factors contribute to the risk for GAS infection and mortality in postpartum women. These include the mode of delivery (vaginal versus cesarean section), the location where labor and delivery occurred, exposure to GAS carriers, the altered immune status associated with pregnancy, the genetic background of the host, the virulence of the infecting GAS strain, and highly specialized immune responses associated with female reproductive tract tissues and organs. This review will discuss the complicated factors that contribute to the increased susceptibility to GAS after delivery and potential reasons for the recent increase observed in morbidity and mortality.

Bacteriological and cytological findings during the late puerperal period after two different treatments of retained placenta followed by acute puerperal metritis.

The aim of the study was to compare the effect of two acute puerperal metritis (APM) treatment protocols on uterine condition during the late puerperal period (5th to 7th week). Late gestation healthy cows (n = 21) were divided randomly in three equal groups. Parturitions were induced. Treatments of APM were started on the third day postpartum (PP). Group A was treated with an oxytocin analogue carbetocin for three days and intrauterine administration of cephapirin between days 15 and 17. Group B was given intramuscular injection of ceftiofur for five days followed by two injections of prostaglandin F2alpha, at an interval of 12 h, on the eighth day PP. Group C served as the control group with no treatment. Body temperature was recorded daily for 14 days PP. Uterine biopsies for bacteriology, and uterobrush samples for cytology, were taken once a week from the 5th to 7th week postpartum. No differences were found in body temperature on day 14 PP, presence of bacteriological infections and disappearance of uterine inflammatory signs diagnosed by cytological examination between experimental groups.

Immune reconstitution syndrome and exacerbation of infections after pregnancy.

Pregnancy is a state of subtle immunosuppression characterized by physiologic suppression of proinflammatory host responses that are meant to promote embryonic implantation. Rapid reversal of these changes and a rebound of inflammatory responses during the postpartum period can result in quiescent or latent infection manifesting as symptomatic disease. Infections due to several microbial pathogens and noninfectious diseases with an autoimmune basis have been shown to worsen or begin during the postpartum period. Awareness that symptoms resulting from immune reconstitution can occur in any host with a rapidly changing immunologic repertoire, including women in the postpartum phase, is a critical first step in fully understanding this phenomenon. Future studies to discern the precise pathophysiologic basis of immune reconstitution, to identify pregnant women at risk, and to determine markers that may be diagnostically helpful have significant implications for optimizing treatment of these patients.

Secondary infection of Nippostrongylus brasiliensis in lactating rats is sensitive to dietary protein content.

Lactating mammals usually exhibit a breakdown of immunity to parasites, i.e. they have larger worm burdens than their non-lactating counterparts. Here, we tested the hypothesis that a secondary infection with Nippostrongylus brasiliensis in lactating rats is sensitive to dietary protein content. We also tested whether this infection affects host food intake. Rats either remained uninfected throughout the study or were given a single infection before mating (primary infection) and re-infected on day 2 of lactation (secondary infection) with 1600 infective larvae. Infected rats were fed foods during lactation formulated to supply 100 (low protein; LP), 200 (medium protein; MP) or 300 (high protein; HP) g crude protein per kg DM; non-infected rats were fed either the LP or HP food. Litter size was standardized to ten pups between parturition (day 0) and secondary infection (day 2). Ten days after secondary infection, MP and HP rats had excreted fewer nematode eggs, and had fewer adult nematodes in their small intestine and nematode eggs in their colon than the LP rats. Primary infection increased food intake in late pregnancy, and increased maternal body weight and litter size at parturition. Secondary infection did not affect mean food intake, maternal and litter weight, although food intake was reduced for 1 d following infection. These results support the view that a secondary infection with N. brasiliensis is sensitive to dietary protein content, and that the latter infection does not impair lactational performance. Future studies may focus on elucidating the nutritional sensitivity of immune responses underlying the reduced secondary N. brasiliensis infection.

Changes in peripheral leukocyte subsets in dairy cows with inflammatory diseases after calving.

To clarify the cellular immune system in dairy cows with inflammatory diseases after calving, the leukocyte subsets were examined in Holstein dairy cows. Twenty Holstein cows reared in one herd, were used in this study. Nine cows (Group 1) experienced onset of mastitis or puerperal fever within 2 weeks after calving, and the other eleven cows remained healthy (Group 2) after calving. The numbers of CD3(+), CD4(+) and CD8(+) cells tended to be lower in Group 1 than in Group 2 from the day of calving through week 1. These results suggested that the cows with inflammatory diseases might have experienced a decline in T cells by the day of calving, before the onset of disease.

Role of ovarian progesterone and potential role of prostaglandin F2alpha and prostaglandin E2 in modulating the uterine response to infectious bacteria in postpartum ewes.

In sheep and cattle, the postpartum uterus is resistant to bacterial challenge until after corpora lutea develop. A 2 x 2 factorial arrangement of treatments was used to determine whether prostaglandins may mediate the effects of progesterone in transforming the postpartum uterus from resistant to susceptible. On d 14 postpartum, ewes (n = 6/group) were ovariectomized or sham ovariectomized, and the vena cava was catheterized for daily collection of uteroovarian-enriched blood. From d 15 to 20, ewes received twice daily intramuscular injections of progesterone in sesame oil or plain sesame oil. On d 20, each uterus received 75 x 10(7) cfu of Arcanobacterium pyogenes and 35 x 10(7) cfu of Escherichia coli. Uteri were collected on d 25 and examined for signs of infection. For each blood sample, unstimulated and mitogen-stimulated lymphocyte proliferation was measured as [3H]thymidine incorporation, smears were prepared for differential white blood cell (WBC) counts, and progesterone, prostaglandin F2alpha, (PGF2alpha), and prostaglandin E2 (PGE2) were quantified. All 12 progesterone-treated, but only two of the 12 oil-treated, ewes developed uterine infections (P < 0.001). Progesterone treatment increased (P < 0.001; 3.1 vs 1.5 ng/mL) and ovariectomy decreased (P < 0.001; 3.7 vs 0.9 ng/mL) vena caval progesterone. Progesterone treatment reduced (P < 0.01) PGF2alpha, (303.9 vs 801.3 pg/mL), and PGF2alpha was greater (P < 0.05) before than after inoculation (626.4 vs 478.8 pg/mL). The PGE2 concentration was greater in progesterone-treated, ovary-intact ewes than in ewes in the other groups (ovariectomy x progesterone treatment; P < 0.01). Ovariectomy increased (P < 0.005; 4.4 vs 2.9 pmol) and progesterone treatment decreased (P < 0.05; 3.2 vs 4.1 pmol) concanavalin A-stimulated lymphocyte proliferation. Ovariectomy increased lipopolysaccharides-stimulated proliferation (P < 0.05; 2.4 vs 1.9 pmol). For neutrophils per 100 WBC, the ovariectomy x progesterone and progesterone x period interactions were significant (P < 0.01). The ovariectomy x progesterone interaction was significant (P < 0.01) for lymphocytes per 100 WBC. Ovariectomy decreased monocytes (P < 0.001; 10 vs 13) and increased eosinophils (P < 0.001; 10 vs 5) per 100 WBC. Progesterone makes the postpartum uterus in ewes susceptible to infection, but ovariectomy allows ewes to remain resistant; uterine prostaglandins may mediate this change. This model creates opportunities to determine the mechanisms responsible for the shift from resistance to susceptible.

Blood and intrauterine leukocyte profile and function in dairy cows that spontaneously recovered from postpartum endometritis.

The profile and function of blood and uterine leukocytes were evaluated in 14 dairy cows that spontaneously recovered from postpartum endometritis (mild, n=6 and heavy, n=8; general health not affected). From a minimum of 2 weeks before parturition until 6 weeks postpartum, blood samples were obtained twice weekly for leukocyte counts and leukogram determination and once weekly for flow cytometry assessment of polimorphonuclear neutrophils (PMN) phagocytic capacity and oxidative burst activity. Uterine fluid-stained smears, obtained twice weekly from parturition until fluid was present in the uterus, were used for determination of the percentage of PMN, of phagocytizing PMN (phago-PMN) and of the mean number of phagocyted bacteria per phagocytizing PMN (phagocytic index; PI). Uterine swabs were obtained twice weekly from parturition until 35 days postpartum for bacteriological examination. The time of endometritis diagnosis was similar in cows with mild or heavy endometritis but the latter cows had a significantly longer persistence of the infection and of the isolation of Gram-negative anaerobes from the uterus. However, the effect of group (mild versus heavy) was not significant for all the blood and uterine parameters analysed. The effect of sampling day (within group effect) was significant (p<0.01 to p<0.00001) for all parameters, except for the blood monocyte count and the blood PMN phagocytic capacity, in which only a tendency for significance was observed (p<0.1). The effect of the interaction group x sampling day was significant only for the blood monocyte count. The phago-PMN and the PI were significantly correlated (r=0.70, p<0.001). A significant correlation was also observed between the uterine fluid phago-PMN and the blood PMN oxidative burst activity (r=-0.41, p<0.05). At the spontaneous recovery, the blood PMN oxidative burst activity was significantly higher (p<0.05) and the percentage of intrauterine phago-PMN and the PI were significantly lower (p<0.001 and p<0.01, respectively) than at diagnosis of endometritis. These results suggest that a decrease in blood PMN oxidative burst activity until the first week postpartum could be associated with an increased susceptibility to early postpartum endometritis. The later increase in this parameter as well as the increase in the intrauterine fluid phago-PMN and PI, might favour the spontaneous resolution of endometritis.

Modulation of the uterine response to infectious bacteria in postpartum ewes.

PROBLEM: Exogenous progesterone and prostaglandin E2 (PGE2) can downregulate uterine immune functions and render the uterus susceptible to bacterial infection. METHOD OF STUDY: Ewes were sham-ovariectomized (SHAM) or ovariectomized (OVEX) 9 days after parturition (day 0), and their uteri were inoculated with Arcanobacterium pyogenes and Escherichia coli on day 15. Vena caval blood was collected on day 14 and days 16-19, and uteri were collected on day 20. Ewes began receiving either canola oil (OIL) or progesterone in oil (PROG) on day 10. Lymphocytes from each blood sample were assigned to a 2 x 2 factorial array of in vitro treatments; 10(-7) M PGE2 and 10(-7) M indomethacin (INDO) were main effects. [3H]Thymidine incorporation (expressed in picomoles) was used to quantify proliferation. RESULTS: Progesterone was greater (P = 0.001) in PROG than in OIL ewes (3.6 versus 0.7 ng/mL), and only PROG ewes developed infections. Lymphocyte proliferation was least (P = 0.02) in PROG-OVEX ewes (4.1 versus 5.4, 5.7, and 5.8 pmol for OIL-SHAM, PROG-SHAM, and OIL-OVEX, respectively). Concanavalin A (Con-A)-stimulated proliferation was less (P < 0.01) for PGE2- and PGE2 + INDO-treated lymphocytes (7.5 and 8.3 pmol, respectively) than for control or INDO-treated cells (12.9 and 14.7 pmol, respectively). CONCLUSIONS: Progesterone treatment of postpartum ewes suppressed uterine immunity. In vitro PGE, treatment suppressed lymphocyte proliferation, regardless of PROG, and highlights a progesterone-independent level of regulation of uterine immune function.

Continuation of postpartum antiretroviral therapy in a cohort of women infected with human immunodeficiency virus.

A common dilemma for HIV-positive pregnant women is the issue of continuation or cessation of antiretroviral therapy (ART) postpartum. Current guidelines for ART during pregnancy offer no specific recommendations for postpartum ART care. The objective of this study was to ascertain characteristics that would predict cessation or continuation of ART postpartum. In this study, prenatal and medical clinic records were reviewed retrospectively for a cohort of 29 HIV-infected pregnant women who were seen in the Temple University High Risk obstetrics practice from 1997 to 1998. All women took ART during pregnancy, except for one who received i.v. AZT and nevirapine during labor. HIV-specific medical care was provided concurrently during the time of the woman's obstetrics visit by a nurse practitioner and a clinical nurse specialist in consultation with the physician. Factors that were included for review included race, age, use of ART at the time of pregnancy diagnosis, type of ART during pregnancy, CD4 count, HIV-1 ribonucleic acid polymerase chain reaction (RNA PCR) levels, current substance use, disclosure of HIV status to current partner, years of HIV infection, prior HIV infected child, and whether this was a first pregnancy. The two groups of women were divided between those who discontinued ART postpartum and those who continued ART. The data were analyzed with the Kruskal-Wallis test for two groups, or calculations of risk ratios with Fisher's exact test. Study results indicated that 15 out of 29 women (51%) continued ART postpartum. The significant factors for continuation included Latina ethnicity (risk ratio = 0.24, confidence interval = 0.06-0.87), CD4 < 200 mm3 (p = .04), and a greater number of drugs in the antiretroviral regimen 3 versus 2 (p = .05). This study showed that postpartum continuation of ART was associated with identified Latina ethnicity, lower CD4 counts, and a greater number of drugs in the pregnancy regimen. Further study is recommended to understand the clinical impact of intermittent ART, the strategies for postpartum therapy adherence, and clinical follow-up.

Autovaccination of dairy cows to treat post partum metritis caused by Actinomyces pyogenes.

Autovaccines are therapeutic vaccines manufactured from a disease causing micro-organism for individual treatment of patients, animals, or sometimes herds to treat chronic or recurrent infections. Despite the common use of autovaccines in veterinary medicine, their mechanism of action, i.e. the immunologic effector mechanism activated after administration, has never been investigated. Here we present data concerning the use of autovaccines to treat metritis infection in a group of dairy cows. Following autovaccination we observed a significant decrease in CD4+ cells paralleled by an increase in T-cells expressing the gammadelta-T-cell receptor (gammadelta-TCR) in the peripheral blood of the treated animals. Lymphocyte proliferation assays showed an initial increase in antigen-specific responsiveness followed by a decrease in this responsiveness during autovaccination treatment. We therefore conclude that administration of an autovaccine leads to the activation of immunologic effector mechanisms which contribute to recovery of the diseased animals.

Invasive pulmonary aspergillosis in a puerperant with drug-induced agranulocytosis.

Invasive pulmonary aspergillosis (IPA) is an acute infection of Aspergillus species to the lungs. It generally occurs in immunocompromised hosts, especially with neutropenia. We report a 30-year-old puerperant, who developed IPA from agranulocytosis. She had been treated for threatened labor with ritodrine and cefepime, one of which induced agranulocytosis. After vaginal delivery of twins, pneumonia emerged in the right lower lobe. She was diagnosed to have IPA according to the halo sign on computed tomography (CT) and positive circulating antibody against Aspergillus, and was treated successfully with oral itraconazole followed by surgical resection. It is important to note that IPA might arise in otherwise immunocompetent hosts when neutropenia is long-standing.