The change of bone mineral density and bone metabolism after gastrectomy for gastric cancer: a meta-analysis.

Bone mineral density (BMD) is significantly decreased after gastrectomy in patients with gastric cancer. Calcium malabsorption, secondary hyperparathyroidism, and dominant bone resorption appear to contribute to bone loss in these patients. Patients should undergo early surveillance and nutritional or pharmacologic intensive interventions for bone health. PURPOSE: Survivorship care, including bone health, has become an important issue in gastric cancer. We performed a meta-analysis of the available observational studies to determine whether and how osteoporosis risk is increased after gastrectomy in patients with gastric cancer. METHODS: A total of 1204 patients (802 men) from 19 cohort studies were included. We evaluated the prevalence of osteoporosis in postgastrectomy patients, comparing the incidence according to the type of gastrectomy and sex. Additionally, we evaluated changes in bone mineral density (BMD) and bone metabolism-related markers pre- to postoperatively and between patients who underwent gastrectomy and matched controls. Proportion meta-analysis was performed and pooled odds ratios (ORs) were calculated. RESULTS: The pooled incidence estimate was 36% [95% confidence interval (CI), 32-40]. The incidence of osteoporosis was significantly higher in women than in men (OR = 1.90, p < 0.001) but was similar between partial and total gastrectomy groups (OR = 0.983, p = 0.939). BMD was significantly decreased, and calcium, phosphorous, and parathyroid hormone levels were significantly increased in patients after gastrectomy compared to those before gastrectomy. BMD and calcium and 25OH-vitamin D levels were significantly decreased, and parathyroid hormone and 1,25OH-vitamin D levels were significantly increased in the gastrectomy group compared to that in the control group. CONCLUSION: We found that BMD is significantly decreased after gastrectomy in patients with gastric cancer. Vitamin D deficiency and secondary hyperparathyroidism are suggested to be common mechanism underlying BMD impairment. After resection, patients should undergo long-term nutritional and bone health surveillance, in addition to their oncological follow-up.

A focused update on preventing ceramic fractures in hip arthroplasty: is the 'cup' half full?

Ceramic bearings have several desirable properties, such as resistance to wear, hardness, and biocompatibility, that favour it as an articulating surface in hip arthroplasty. However, ceramic fracture remains a concern. We have reviewed the contemporary literature, addressing the factors that can influence the incidence of ceramic bearing surface fracture. Cite this article: Bone Joint J 2019;101-B:897-901.

Placental deposition of C-reactive protein is a common feature of human pregnancy.

This study examined the occurrence of placental C-reactive protein (CRP) in normal pregnancy with term delivery, spontaneous preterm delivery (sPTD), preeclampsia, and miscarriage. CRP immunoreactivity was detected in the syncytiotrophoblast. The immunopositive rate was significantly higher in sPTD than preeclampsia. The CRP immunopositive rate was also higher in acute chorioamnionitis than those without and showed a good correlation with the maternal serum CRP concentration. CRP mRNA expression was not detected in human and mouse placentas or choriocarcinoma cells. CRP may play a role in the pathological and physiological states of pregnancy.

Chronic chorioamnionitis is the most common placental lesion in late preterm birth.

OBJECTIVES: The pathogenesis of late preterm birth remains elusive for the mechanisms of disease responsible. Placental examination can often provide important clues for the pathogenesis of pregnancy complications. This study was conducted to determine placental pathologic findings according to the gestational age and the clinical circumstances of preterm birth. STUDY DESIGN: Placental pathologic findings and obstetrical and neonatal outcomes were reviewed in a consecutive preterm birth cohort from a single tertiary center (N = 1206). Placentas of term births (N = 300) were used as normal controls. RESULTS: Acute chorioamnionitis (22.7% vs. 16.7%), maternal vascular underperfusion (6.4% vs. 0.5%), and chronic chorioamnionitis (20.8% vs. 10.5%) were significantly more frequent in preterm births than in term births (P < 0.05, for each). Among preterm births, chronic chorioamnionitis was the most common pathology of late preterm birth (gestational age <37 and ≥34 weeks), while acute chorioamnionitis was the most common lesion of extremely preterm birth (gestational age <28 weeks). While the frequency of acute chorioamnionitis decreased with advancing gestation, that of chronic chorioamnionitis increased (P < 0.001, for each). The upward trend of the frequency of chronic chorioamnionitis was related to advancing gestation in both spontaneous and indicated preterm births (P < 0.001, for each). CONCLUSIONS: Chronic chorioamnionitis is a common pathology of late preterm birth. It is suggested that chronic chorioamnionitis, a feature of maternal anti-fetal rejection, is an important etiology of preterm birth, especially of late preterm birth.

Incidence of second hip fracture and compliant use of bisphosphonate.

UNLABELLED: We determined the incidence of second hip fracture and evaluated whether compliant users of bisphosphonate had a lower incidence of second hip fracture after prior hip fracture. INTRODUCTION: Bisphosphonate has been used to prevent osteoporotic fracture and is recommended for the secondary prevention after hip fracture. However, little is known regarding secondary prevention after first hip fracture. Our purpose was to determine the incidence of second hip fracture and to evaluate whether compliant use of bisphosphonate can reduce the risk of second hip fracture. METHODS: Eight hundred twenty-six patients who sustained the first hip fracture from May 2003 to October 2011 were retrospectively evaluated. The incidence of second hip fracture was compared between compliant users of bisphosphonate and nonusers. RESULTS: Seventy-one (8.6 %) patients suffered a second hip fracture at mean 30.0 months (SD 24.6, range 1 to 90 months) after the initial hip fracture. The cumulative incidence of second hip fracture was 5.1 % (42/826) at 2 years and 8.6 % (71/826) at 8 years. The incidence of second hip fracture was 4.2 % (12/283) in compliant users and 10.9 % (59/543) in nonusers (p = 0.001). CONCLUSIONS: Compliant use of bisphosphonate is effective in the prevention of second hip fractures.

A gene-specific primer extension and liquid bead array system for killer-cell immunoglobulin-like receptor genotyping.

A simple and accurate method for killer-cell immunoglobulin-like receptor (KIR) genotyping is developed using KIR gene-specific primer extension (GSPE) followed by bead array hybridization (GSPE method). After amplification of exons 4, 5, and 9, KIR GSPE and bead array hybridization were performed to verify the presence or absence of 16 KIR subfamilies. GSPE method was validated with natural killer/KIR reference panel I consisting of 48 cell types provided by 13th International Histocompatibility Working Group (IHWG) and genomic DNA from 17 peripheral blood cells, 8 cell lines, and 8 buccal cells. The results of reference panel from GSPE method were 100% concordant with the IHWG reference typing information. All genomic DNAs except reference panel were typed for KIR genes with sequence-specific primer methods and showed 100% identical typing results using this novel system. In addition, GSPE method can obtain results in 8 h from DNA with 10 ng genomic DNA in a 96-well-based assay format.

The presence of funisitis is associated with a decreased risk for the development of neonatal respiratory distress syndrome.

OBJECTIVES: Fetal lung maturation and respiratory outcomes are influenced by the exposure to intrauterine inflammation. Funisitis is considered as the histologic hallmark of fetal inflammatory response. This study was performed to determine if there is a difference in the rate of neonatal respiratory distress syndrome (RDS) according to the presence or absence of funisitis in preterm gestations. STUDY DESIGN: The relationship between the presence of funisitis and the development of neonatal RDS was examined in 301 consecutive singleton preterm births (24-32 weeks' gestation). Cases without placental histological examination and those with major congenital anomalies were excluded. Funisitis was diagnosed in the presence of neutrophil infiltration into the umbilical vessel walls or Wharton's jelly on the placental histological examination. RESULTS: Funisitis was diagnosed in 25% and RDS was diagnosed in 46% of cases. The rate of RDS in babies with funisitis was lower than in those without funisitis (28.4% vs. 51.1%, p = 0.001). Logistic regression analysis demonstrated that the presence of funisitis was associated with a decreased risk for RDS after adjusting for confounding variables (Odds ratio = 0.44, 95% CI 0.22-0.90). The downward trend of the frequency of RDS was related to the presence of histologic chorioamnionitis and funisitis (p < 0.001). CONCLUSIONS: The presence of funisitis is associated with a decreased risk for the development of neonatal RDS in preterm gestations. Furthermore, this observation suggests that the fetal involvement of placental inflammation may be beneficial to the maturation of the fetal lung.

Histologic chorioamnionitis is more common after spontaneous labor than after induced labor at term.

OBJECTIVE: Inflammation of the chorioamniotic membranes (histologic chorioamnionitis) is a risk factor for adverse neonatal outcome. Labor has many common features with inflammatory processes; therefore, an important question is whether the frequency of histologic chorioamnionitis in spontaneous labor at term is higher than that of women in labor after induction. This study was conducted to address this question. STUDY DESIGN: The frequency of histologic chorioamnionitis was compared between patients who delivered after the spontaneous onset of labor versus those who delivered after induction of labor at term in singleton gestations (> or = 37 weeks). Patients in whom uterotonic agents were used during the latent phase of labor were excluded. RESULTS: (1) The overall frequency of histologic chorioamnionitis was 20.2% (107/531); (2) histologic chorioamnionitis was significantly more frequent in women who delivered after the spontaneous onset of labor than in those who underwent induction of labor (24.3% [81/333] versus 13.1% [26/198], p < 0.005). This difference remained significant after adjusting for parity, gestational age at delivery, total duration of labor, the interval from rupture of membranes to delivery and the mode of delivery. CONCLUSION: Histologic chorioamnionitis is more common in women who delivered after the spontaneous onset of labor than in those who underwent induction of labor at term.

The frequency and clinical significance of intra-uterine infection and inflammation in patients with placenta previa and preterm labor and intact membranes.

OBJECTIVE: Histologic placental and/or intra-amniotic inflammation is frequently documented during ascending intra-uterine infections in patients with preterm labor and intact membranes. Placenta previa can be a clinical situation that shows the successive schema of histologic placental and intra-amniotic inflammation during the process of ascending intra-uterine infections. However, a paucity of information exists about the frequency and clinical significance of intra-uterine infections and inflammation in patients with placenta previa and preterm labor and intact membranes. The purpose of this study was to examine this issue. STUDY DESIGN: Amniocentesis was performed on 42 patients with placenta previa and preterm labor and intact membranes (gestational age <37 weeks). Amniotic fluid (AF) was cultured for aerobic and anaerobic bacteria and genital mycoplasmas, and AF white blood cell (WBC) count and matrix metalloproteinase-8 (MMP-8) concentrations were determined. The diagnosis of intra-amniotic inflammation was made in patients with an elevated AF MMP-8 (> or =23 ng/ml). Non-parametric statistics were used for analysis. RESULTS: 1) Intra-amniotic inflammation was present in 16.7% (7/42), proven AF infection in 4.9% (2/41), and histologic chorioamnionitis in 19.0% (8/42) of patients with placenta previa and preterm labor; 2) Patients with intra-amniotic inflammation had significantly higher rates of a positive AF culture, histologic chorioamnionitis, funisitis, and a shorter interval-to-delivery than those without intra-amniotic inflammation (p<0.05 for each); 3) Among patients with histologic chorioamnionitis, inflammation of the choriodecidua, which was exposed to the cervical canal, existed in all cases (8/8), but inflammation of the chorionic plate existed in 63% of patients (5/8); 4) Patients with inflammation of the chorionic plate had significantly higher median AF MMP-8 concentrations and WBC counts, and higher rates of intra-amniotic inflammation than those in whom inflammation was restricted to choriodecidua (p<0.05 for each). CONCLUSIONS: Placental inflammation was present in 19.0% and intra-amniotic inflammation was present in 16.7% of patients with placenta previa and preterm labor and intact membranes. The intra-amniotic inflammatory response was stronger when inflammation was present in the chorionic plate and choriodecidua, than when it was restricted to the choriodecidua only, which was exposed to the cervical canal in placenta previa.

Distribution of CD14+ and CD68+ macrophages in the placental bed and basal plate of women with preeclampsia and preterm labor.

OBJECTIVE: Macrophages play a key role in implantation, placentation and parturition. Yet, whether or not the number of macrophages at the fetomaternal interface (basal plate of the placenta and placental bed) is altered in women with preeclampsia is the subject of controversy. The purpose of this study was to compare the immunoreactivity and distribution patterns of CD14 and CD68 positive macrophages in both the basal plate and placental bed from preeclamptic and non-preeclamptic pregnancies. METHODS: A cross-sectional study was conducted. Paraffin embedded sections of placental tissues and placental bed biopsies were obtained from patients with early onset preeclampsia (n=10) and from those with preterm labor/delivery (n=10) without preeclampsia matched for gestational age. Double immunohistochemistry using antibodies to CD14 and CD68 was performed, and the density of double or single positive cells in the basal plate and placental bed was evaluated. Non-parametric statistics were used for analysis. RESULTS: 1) A unique subset of CD14-/CD68+ cells was identified. The cells in question were present at a higher level in the decidua than in the myometrial segment of the placental bed (p<0.01); 2) The density and proportion of CD14+/CD68+ cells (double positive cells) were significantly higher in the myometrial segment than in the basal plate (p=0.0003); and 3) There were no significant differences in the density and patterns of immunopositive macrophages in the basal plate, the decidua, and the myometrium between women with preeclampsia and those with preterm labor/delivery (p>0.05). CONCLUSION: The macrophages at the fetomaternal interface can be dichotomized by CD14 and CD68 immunoreactivity. A gradient of CD14+/CD68+ macrophages was demonstrated between the superficial myometrium and the basal plate regardless of the etiology of preterm birth (preeclampsia or spontaneous preterm labor). The biological function of single positive (CD14-/CD68+) and double positive (CD14+/CD68+) macrophages at the fetomaternal interface remains to be established. The overall findings also suggest that the discrepancies in the literature are due to the varying markers used to detect macrophages and in the anatomical plane of the fetomaternal junction analyzed.

Multicentre, parallel group, randomised, single-blind study of the safety and efficacy of atosiban versus ritodrine in the treatment of acute preterm labour in Korean women.

OBJECTIVE: To compare the efficacy and safety of atosiban with those of ritodrine in preterm labour. DESIGN: Multicentre, single-blind, randomised, controlled trial. SETTING: Obstetric units in six referral centres in Korea. POPULATION: Women with singleton pregnancies with preterm labour, between 24 and 33 + 6 weeks of gestation. METHODS: One hundred and twenty-eight women were randomised to receive intravenous atosiban (n= 63) or ritodrine (n= 65) and were stratified by gestational age (<28 weeks and >or=28 weeks). Atosiban or ritodrine was administered for up to 48 hours. Progression of labour was assessed by the frequency of contractions and cervical dilatation and effacement. Alternative tocolysis could be given as rescue therapy. MAIN OUTCOME MEASURE: Efficacy was assessed as the proportion of women in each group who did not deliver and did not need alternative tocolytic therapy at 48 hours and 7 days after therapy initiation. Safety was assessed as the numbers of maternal adverse events and neonatal morbidity. RESULTS: Tocolytic efficacy after 7 days was significantly better in the atosiban group than in the ritodrine group (60.3 versus 34.9%), but not at 48 hours (68.3 versus 58.7%). Maternal adverse events related to therapy were reported less frequently in the atosiban group (7.9 vs 70.8%; P= 0.0001), resulting in fewer early drug terminations due to adverse events (0 versus 20.0%; P= 0.0001). This, however, was not accompanied by a concurrent improvement in perinatal outcomes. CONCLUSION: The efficacy and safety of atosiban in the treatment of preterm labour were superior to those of ritodrine.

The prevalence and clinical significance of amniotic fluid 'sludge' in patients with preterm labor and intact membranes.

OBJECTIVE: To determine the prevalence and clinical significance of amniotic fluid (AF) 'sludge' observed during transvaginal ultrasound examination of the cervix in patients with preterm labor and intact membranes, and in those with uncomplicated pregnancies. METHODS: This retrospective study included patients with preterm labor and intact membranes (n = 84) and those with uncomplicated term pregnancies (n = 298). The outcome variables included the occurrence of documented microbial invasion of the amniotic cavity (MIAC), histological chorioamnionitis, examination-to-delivery interval, admission to the neonatal intensive care unit (NICU), a composite neonatal morbidity, perinatal death, and delivery within 48 h, 7 days, and < 35 weeks and < 32 weeks. Statistical analysis included Chi-square test, stepwise logistic regression analysis and survival analysis. RESULTS: The prevalence of AF 'sludge' was 1% (3/298) in patients with uncomplicated term pregnancies and 22.6% (19/84) in those with preterm labor and intact membranes. Among patients with preterm labor and intact membranes: (1) cervical length < or = 15 mm was present in 58.3% (49/84) of the patients; (2) the prevalence of MIAC and histological chorioamnionitis was 12.1% (7/58) and 32.9% (25/76), respectively; (3) the rate of spontaneous preterm delivery within 48 h, 7 days, and < 32 weeks and < 35 weeks of gestation was 13.6% (8/59), 28.8% (17/59), 39.5% (17/43) and 50.8% (30/59), respectively; (4) patients with AF 'sludge' had a higher frequency of positive AF cultures [33.3% (6/18) vs. 2.5% (1/40), P = 0.003] and histological chorioamnionitis [77.8% (14/18) vs. 19% (11/58), P < 0.001] than those without AF 'sludge'; (5) a higher proportion of neonates born to patients with AF 'sludge' was admitted to the NICU [64.3% (9/14) vs. 12.9% (8/62), P < 0.01], had a composite neonatal morbidity [36.8% (7/19) vs. 13.8% (9/65), P = 0.04] and died in the perinatal period [36.8% (7/19) vs. 4.6% (3/65), P = 0.001] than those born to women without 'sludge'; (6) a higher proportion of patients with AF 'sludge' had spontaneous delivery within 48 h [42.9% (6/14) vs. 4.4% (2/45), P = 0.001], within 7 days [71.4% (10/14) vs. 15.6% (7/45), P < 0.001], < 32 weeks [75% (9/12) vs. 25.8% (8/31), P = 0.005] and < 35 weeks [92.9% (13/14) vs. 37.8% (17/45), P < 0.001] than those without AF 'sludge'; and (7) patients with AF 'sludge' had a shorter examination-to-delivery interval than those without AF 'sludge' [AF 'sludge' median, 1 (IQR, 1-5) days vs. no AF 'sludge' median, 33 (IQR, 18-58) days; P < 0.001]. CONCLUSION: The presence of AF 'sludge' in patients with preterm labor and intact membranes is a risk factor for MIAC, histological chorioamnionitis and impending preterm delivery.

Fetal cardiac dysfunction in preterm premature rupture of membranes.

BACKGROUND: Preterm premature rupture of membranes (PROM) is associated with one-third of preterm births. In about 50% of preterm PROM cases, the fetuses will elicit a fetal inflammatory response syndrome (FIRS). FIRS is associated with the impending onset of preterm labor, periventricular leukomalacia, neonatal sepsis, and long-term handicap, including the development of bronchopulmonary dysplasia and cerebral palsy. The fetal myocardium is a potential target organ of proinflammatory cytokines released during FIRS. The objective of this study was to determine whether preterm PROM is associated with functional changes in the fetal heart, as determined by fetal echocardiography. METHODS: A retrospective study was conducted to assess the diastolic function of fetuses with preterm PROM with documented microbial invasion of the amniotic cavity (n = 25), preterm PROM without microbial invasion of the amniotic cavity (n = 42), and fetuses from normal pregnancies (control group = 150). Pregnancies with multiple gestation, fetal distress, fetuses that were small for gestational age, and major congenital anomalies were excluded. Fetal echocardiography studies were performed with two-dimensional ultrasound, color Doppler imaging and pulsed Doppler ultrasound. Non-parametric statistics were used for comparisons. A p value of < 0.05 was considered significant. RESULTS: The prevalence of positive amniotic fluid cultures for micro-organisms in patients with preterm PROM was 35.8% (24/67). Ureaplasma urealyticum was the most frequent isolate, either alone (41.7%; 10/24) or with other micro-organisms (29.2%; 7/24). Fetuses with preterm PROM had a higher delta early diastolic filling/atrial contraction (E/A) peak velocity ratio, a higher delta E/A velocity-time integral (VTI) ratio, a lower delta A peak velocity, a lower delta A VTI, and a lower A VTI/total VTI ratio in the mitral valve compared to those with uncomplicated pregnancies. The delta E/A peak velocity ratio was significantly higher and the delta A VTI significantly lower in fetuses with preterm PROM and microbial invasion of the amniotic cavity than in those with preterm PROM without microbial invasion of the amniotic cavity. CONCLUSIONS: Preterm PROM is associated with changes in fetal cardiac function consistent with increased left ventricular compliance. These observations were also noted in fetuses with microbial invasion of the amniotic cavity. Our findings suggest that fetal cardiac function is altered in preterm PROM and, in particular, in cases with intra-amniotic infection.

Retinoic acid-mediated induction of neurons and glial cells from human umbilical cord-derived hematopoietic stem cells.

Recent studies reporting trans-differentiation of mononucleated cells derived from human umbilical cord blood into neuronal cells aroused interest among investigators for their clinical implication and significance in regenerative medicine. In the present study, purified populations of hematopoietic stem cells were isolated via magnetic bead sorting and fluorescence-activated cell sorter (FACS) using a specific CD133 antibody, a cell type-specific marker for hematopoietic stem cells, and grown in culture in the presence of retinoic acid (RA). CD133+ hematopoietic stem cells expressed neuronal and glial phenotypes after RA treatment. RT-PCR analysis indicated that the RA treated CD133+ cells expressed mRNA transcripts for ATP-binding cassettes transporter ABCG2 (a universal stem cell marker), nestin (a specific cell type marker for neural stem cells), Musashi1 (a specific marker for neural stem cells) and RA receptors (RAR) including RAR-alpha, RAR-beta, and retinoid X receptor (RXR)-gamma. RA-treated CD133+ cells expressed mRNA transcripts for neuron-specific markers neurofilament proteins (NF-L, -M, -H) and synaptophysin as determined by RT-PCR, structural proteins characteristic of neurons including tubulin beta III and neuron specific enolase (NSE) by Western blot, and neuron-specific markers NeuN and microtubule-associated protein-2 (MAP2) by immunocytochemistry. RA-treated CD133+ cells also expressed the astrocyte-specific marker glial fibrillary acidic protein (GFAP), as demonstrated by RT-PCR, Western blot, and immunocytochemistry. In addition, RA-treated CD133+ cells expressed cell type-specific markers for oligodendrocytes including myelin basic protein (MBP) as shown by RT-PCR, proteolipid protein (PLP) by Western blot analysis, and cyclic nucleotide phosphodiesterase (CNPase) by immunostaining. Upregulated expression of several basic helix-loop-helix (bHLH) transcription factors important for early neurogenesis, including Otx2, Pax6, Wnt1, Olig2, Hash1 and NeuroD1, was also demonstrated in CD133+ cells after RA treatment. These results indicate that human cord blood-derived CD133+ hematopoietic stem cells could trans-differentiate into neural cell types of neuron-like cells, astrocytes, and oligodendrocytes by RA treatment.

Maternal and fetal inflammatory responses in unexplained fetal death.

OBJECTIVE: The role of intra-amniotic infection in the etiology of fetal death has been proposed. This study was conducted to determine the prevalence of microbial invasion of the amniotic cavity (MIAC) and the frequency of maternal and/or fetal inflammation in patients presenting with a fetal death. METHODS: A prospective study was conducted in patients with a fetal death. Amniocenteses were performed for clinical indications (karyotype), as well as to assess the microbiological and cytological state of the amniotic cavity. Fluid was cultured for aerobic and anaerobic bacteria and genital mycoplasmas. An amniotic fluid white blood cell count and glucose determinations were also performed. Histological examination of the placenta was conducted to identify a maternal inflammatory response (acute chorioamnionitis) or a fetal inflammatory response (funisitis). RESULTS: This study included 44 patients with intrauterine fetal death. The median gestational age at diagnosis was 30.1 weeks (range 16.3-40.4 weeks). One patient had documented MIAC (1/44). Acute histological chorioamnionitis was found in 20.9% (9/43), but a fetal inflammatory response was observed in only 2.3% (1/43) of cases. One patient had a positive amniotic fluid culture for Streptococcus agalactiae (group B streptococcus). CONCLUSION: Histological chorioamnionitis was present in 20.9% of cases, but MIAC could be demonstrated with conventional microbiological techniques in only one case. A fetal inflammatory response was nine times less frequent than a maternal inflammatory response (maternal 20.9% vs. fetal 2.3%, p = 0.008) in cases of fetal death.

C-reactive protein in umbilical cord blood: a simple and widely available clinical method to assess the risk of amniotic fluid infection and funisitis.

OBJECTIVE: The purpose of this study was to determine whether concentrations of C-reactive protein (CRP) in umbilical cord plasma at birth were elevated in neonates with sepsis, an inflammatory lesion of the umbilical cord (funisitis) or who were born to mothers with microbial invasion of the amniotic cavity. METHODS: Umbilical cord plasma was collected at birth from 313 singleton preterm neonates (20-35 weeks of gestation). The results of amniotic fluid culture performed within 5 days of birth, the occurrence of congenital neonatal sepsis and the presence of funisitis were assessed. Amniocentesis was performed in 152 patients within 5 days of birth. Amniotic fluid was cultured for aerobic and anaerobic bacteria and for mycoplasmas. The CRP concentration was measured with a highly sensitive immunoassay. RESULTS: The median cord plasma CRP concentration was significantly higher in neonates with a positive amniotic fluid culture than in those with negative culture (median 245.9 (range 11.6-4885.5) ng/ml vs. median 44.3 (range 2.3-7401.8) ng/ml; p < 0.001), in those with congenital proven sepsis than in those without this complication (median 789.5 (range 20.4-2584.3) ng/ml vs. median 41.5 (range 1.3-7401.8) ng/ml; p < 0.005) and in neonates with funisitis than in those without funisitis (median 403.8 (range 4.9-10897.4) ng/ml vs. median 31.0 (range 1.3-7401.8) ng/ml; p < 0.001). The sensitivity of CRP in the identification of amniotic fluid infection, neonatal sepsis and funisitis was similar to that of interleukin-6 (> 17.5 pg/ml). However, the specificity of CRP in the identification of neonatal sepsis and funisitis was significantly higher than that of interleukin-6 (74% vs. 69%, p < 0.05; 83% vs. 76%, p < 0.01). CONCLUSION: Umbilical cord plasma CRP concentrations were elevated in patients with amniotic fluid infection, congenital neonatal sepsis and funisitis.

Antimicrobial peptides in amniotic fluid: defensins, calprotectin and bacterial/permeability-increasing protein in patients with microbial invasion of the amniotic cavity, intra-amniotic inflammation, preterm labor and premature rupture of membranes.

OBJECTIVE: Neutrophil defensins (HNP 1-3), bactericidal/permeability-increasing protein (BPI) and calprotectin (MRP8/14) are antimicrobial peptides stored in leukocytes that act as effector molecules of the innate immune response. The purpose of this study was to determine whether parturition, premature rupture of the membranes (PROM) and microbial invasion of the amniotic cavity (MIAC) are associated with changes in amniotic fluid concentrations of these antimicrobial peptides. STUDY DESIGN: Amniotic fluid was retrieved by amniocentesis from 333 patients in the following groups: group 1, mid-trimester with a subsequent normal pregnancy outcome (n = 84); group 2, preterm labor and intact membranes without MIAC who delivered at term (n = 36), or prematurely (n = 52) and preterm labor with MIAC (n = 26); group 3, preterm PROM with (n = 26) and without (n = 26) MIAC; and group 4, term with intact membranes in the absence of MIAC, in labor (n = 52) and not in labor (n = 31). The concentrations of HNP 1-3, BPI and calprotectin in amniotic fluid were determined by specific and sensitive immunoassays. Placentae of patients in both preterm labor with intact membranes and preterm PROM groups who delivered within 72 h of amniocentesis were examined. Non-parametric statistics, receiver-operating characteristic (ROC) curves and Cox regression models were used for analysis. A p value of < 0.05 was considered statistically significant. RESULTS: Intra-amniotic infection was associated with a significant increase in amniotic fluid concentrations of immunoreactive HNP 1-3, BPI and calprotectin in both women with preterm labor and intact membranes, and women with preterm PROM. Preterm PROM was associated with a significant increase in amniotic fluid concentrations of immunoreactive HNP 1-3, BPI and calprotectin. Preterm parturition was associated with a significant increase in amniotic fluid concentrations of immunoreactive HNP 1-3, BPI and calprotectin, while parturition at term was associated with a significant increase in amniotic fluid concentrations of immunoreactive HNP 1-3. Among patients with preterm labor and intact membranes, elevation of amniotic fluid HNP 1-3, BPI and calprotectin concentrations was associated with intra-amniotic inflammation, histological chorioamnionitis and a shorter interval to delivery. CONCLUSION: MIAC, preterm parturition and preterm PROM are associated with increased amniotic fluid concentrations of immunoreactive HNP 1-3, BPI and calprotectin. Moreover, elevated amniotic fluid concentrations of BPI, immunoreactive HNP 1-3 and calprotectin are associated with intra-amniotic inflammation, histological chorioamnionitis and shorter amniocentesis-to-delivery interval in patients presenting with preterm labor with intact membranes.

Differences in the fetal interleukin-6 response to microbial invasion of the amniotic cavity between term and preterm gestation.

BACKGROUND/OBJECTIVE: Fetal inflammatory response has been implicated as a mechanism of multi-system organ injury in preterm and term neonates. Microbial invasion of the amniotic cavity (MIAC) is frequently associated with a fetal inflammatory response. However, there are no studies comparing the fetal response to MIAC in term and preterm gestations. The purpose of this study was to compare the umbilical cord plasma interleukin-6 (IL-6) concentrations in term and preterm neonates in the presence or absence of MIAC. STUDY DESIGN: Umbilical cord blood was obtained at birth from 252 neonates whose mothers had an amniocentesis within 48 h of delivery (preterm delivery, n = 62; term delivery, n = 190). MIAC was defined as a positive amniotic fluid culture for bacteria or genital mycoplasmas. IL-6 was measured by a sensitive and specific immunoassay. RESULTS: The median IL-6 concentration in umbilical cord plasma was significantly higher in preterm neonates than in term neonates (median 13.4 pg/ml, range 0.1-676 pg/ml vs. median 3.2 pg/ml, range 0.1-408 pg/ml; p < 0.0001). In the context of MIAC, the median umbilical cord plasma IL-6 concentration was significantly higher in preterm than in term neonates (median 31.6 pg/ml, range 1.4-676 pg/ml vs. median 11.7 pg/ml, range 1.3-82 pg/ml, respectively; p < 0.05). Neonates born to mothers with a positive amniotic fluid culture had a significantly higher median IL-6 concentration than neonates born to mothers with a negative amniotic fluid culture (preterm: median 31.6, range 1.4-676 pg/ml vs. median 8.0, range 0.1-656 pg/ml; p < 0.05 and term: median 11.7, range 1.3-82 pg/ml vs. median 3.1, range 0.1-408 pg/ml; p < 0.01, respectively). CONCLUSIONS: The preterm fetus is capable of mounting a systemic cytokine response as measured by IL-6 in its peripheral blood. In the setting of MIAC, a fetal IL-6 response is higher in preterm than in term gestation.

Neonates born to pre-eclamptic mothers have a higher percentage of natural killer cells (CD3-/CD56+16+) in umbilical cord blood than those without pre-eclampsia.

OBJECTIVE: Maternal endothelial dysfunction and intravascular inflammation have been implicated in the mechanisms of disease responsible for the clinical syndrome of pre-eclampsia. Recently, the activation of the innate limb of the immune response (neutrophils and monocytes) in the fetal circulation has been reported in neonates born to mothers with pre-eclampsia. Natural killer (NK) cells are identified morphologically as a subpopulation of lymphocytes, but functionally as one component of the innate immune system. NK cells participate in the control of viral or bacterial infection, regulation of hematopoiesis, production of cytokines and cytotoxicity of neoplastic cells. Accumulating evidence suggests that the innate system is required for mounting an adequate adaptive response. NK cells, originally defined as effector cells of the innate immune system, may also play a role as regulatory cells for the adaptive immune system. This study was designed to determine the proportion of the NK cell subset of lymphocytes in umbilical cord blood of neonates born to mothers with and without pre-eclampsia. METHODS: A cross-sectional study including neonates of mothers with (n = 48) and those without pre-eclampsia (control group) (n = 72) was conducted. Pre-eclampsia was diagnosed in the presence of hypertension and proteinuria. The control group consisted of neonates (premature and term) with no evidence of acute inflammation within the extraplacental membranes (chorioamnionitis). Umbilical cord blood was collected at the time of delivery, and assayed using monoclonal antibodies for selective cluster differentiation (CD) antigens in order to determine the proportion of NK cells as a percentage of total lymphocytes. The immunophenotypic characteristic was determined using flow cytometry, and NK cells were identified by positivity of CD16 and CD56 without CD3 (CD3-/CD56+16+). Log transformation of the percentage of NK cells was performed. Parametric statistics were used for analysis. Multiple regression analysis was utilized to examine the contribution of potentially confounding factors on the proportion of NK cells. A p value of < 0.05 was considered statistically significant. RESULTS: Neonates born to mothers with pre-eclampsia had a significantly higher percentage of NK cells (CD3-/CD56+16+) than those in the control group (pre-eclampsia, mean +/- SD 17 +/- 9% vs. control, mean +/- SD 12 +/- 7.5%; p = 0.001). Multiple regression analysis suggested that umbilical cord blood pH of < 7.2, labor with vaginal delivery and maternal pre-eclampsia were associated with an increased percentage of NK cells in umbilical cord blood. CONCLUSIONS: Pre-eclampsia is associated with a higher NK cell (CD3-/CD56+16+) subset of lymphocytes in umbilical cord blood than in the control group. This difference cannot be explained by fetal acidosis or the presence of labor.