Low-grade endometrial stromal sarcoma combined with leiomyoma (stromomyoma): A bizarre tumor of the uterus in a premenopausal woman.

OBJECTIVE: Uterine sarcomas are very rare malignancies, and when a hysterectomy is performed for benign causes, a risk of about 1/500 is mentioned for possible uterine sarcomas. Endometrial stromal neoplasms are a rare subgroup of uterine sarcomas that account for less than 10% of all uterine sarcomas. Mixed endometrial stromal and smooth muscle tumors, also known as stromomyomas, are defined as having at least 30% each of endometrial stromal and smooth muscle components. As a result, stromomyoma is an extremely rare malignant mixed mesenchymal tumor of the uterus. Both clinically and histologically, the differential diagnosis is challenging. Stromomyoma should be kept in mind in the differential diagnosis of large uterine masses, even if these masses are seen in an asymptomatic woman of reproductive age. In this study, we aimed to present this bizarre tumor of the uterus detected in a premenopausal woman.

Maternal venous SHARP1 levels in preeclampsia.

AIM: Owing to its mysterious etiology, pathogenesis of preeclampsia (PE) remains controversial. Here we aimed to compare the levels of an angiogenesis marker, split and hairy related protein-1 (SHARP1), in PE vs. normal pregnancy. METHODS: Thirty-one patients with early-onset PE (EOPE), 26 patients with late-onset PE (LOPE), and 33 patients as a control group were recruited for this study in a tertiary referral center in Ankara, Turkey. Maternal venous SHARP1 levels and individual characteristics of the three groups were compared. RESULTS: Age and body mass indices were similar among the three groups. SHARP1 levels in patients with PE (27.7±13.2 ng/mL) were significantly lower than in the control group (34.7±17 ng/mL) (P=0.006). Additionally, SHARP1 levels were significantly different among patients in EOPE, LOPE, and control groups (P=0.022). Birth weights and Apgar scores in patients in EOPE group were significantly lower than the other two groups and showed a gradual increase from the EOPE group to the LOPE and the control group. Binary logistic regression method demonstrated that maternal venous SHARP1 level was a risk factor for PE. CONCLUSIONS: Maternal venous SHARP1 levels in PE are lower than a normal pregnancy. Its clinical applicability and role as a candidate for making sense of the distinctive pathogenesis of the EOPE and LOPE remain to be elucidated.

Obstetric Outcomes in Non-Gynecologic Cancer Patients in Remission.

OBJECTIVE: The aim of the present study was to evaluate the obstetric and perinatal outcomes in treated women who were diagnosed with non-gynecologic cancer and to compare these findings with pregnant women with no history of cancer. MATERIALS AND METHODS: This retrospective study was conducted on 21 pregnant women with non-gynecologic cancer who were in remission (study group) and 63 pregnant women with no history of cancer (control group). The women were admitted to the high-risk pregnancy clinic of Zekai Tahir Burak Women's Health Training and Research Hospital with a diagnosis of pregnancy and cancer between January 2010 and January 2015. Obstetric outcomes and demographic characteristics of the patients were recorded. Age, gravida, parity, abortus, body mass index (BMI), gestational week, smoking, mode of delivery, gestational weight, and perinatal outcomes were examined for each woman. RESULTS: The most common cancer types were thyroid (28.5%) and breast cancers (23.8%), which constituted just over half of the non-gynecologic cancer cases during pregnancy. The time elapsed after the diagnosis was 3.8±2.2 (1-9) years. No statistically significant differences were found between the two groups with regard to age, obstetric history, BMI, gestational week, smoking, and obstetric and perinatal outcomes (p>0.05). CONCLUSION: Negative perinatal outcomes in non-gynecologic cancer patients in remission were found to be within acceptable levels.

An Unusual Origin of Fetal Lymphangioma Filling Right Axilla.

Fetal lymphangioma is a hamartomatous congenital anomaly of the lymphatic system, which is embracing the fetal skin (sometimes mucous membranes) and the subcutaneous tissue. The general consensus is that it occurs as a result of failure in lymphatic drainage. A 36-year-old pregnant woman was referred to our perinatology clinic at 22 weeks' gestation, because of a fetal right-sided axillary mass revealed by ultrasonography. The mass measuring 5x7x7cm in three dimensions had a multilocular structure without colour Doppler flow and well-circumscribed borders. Amniocentesis revealed a normal constitutional karyotyping. Lymphangioma was considered as prediagnosis. A healthy female baby weighing 3470 grams was delivered at term. Neonatal examination and the postnatal MRI confirmed the diagnosis. The baby is still on follow-up with the medical treatment of Sirolimus an anti-proliferative drug, and the mass got smaller significantly in 8 months after delivery.

Decreased placental and maternal serum TRAIL-R2 levels are associated with placenta accreta.

OBJECTIVES: TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) is produced both by decidual and trophoblast cells during pregnancy and known to participate in apoptosis. In this study, we aimed to determine and to compare maternal serum and placental TRAIL-R2 levels in patients with placenta accreta, non-adherent placenta previa and in healthy pregnancies. We also aimed to analyze the association of placenta accreta with the occurrence of previous C-sections. STUDY DESIGN: A total of 82 pregnant women were enrolled in this case-control study (27 placenta accreta patients, 26 non-adherent placenta previa patients and 29 age-, and BMI-matched healthy, uncomplicated pregnant controls). TRAIL-R2 levels were studied in both maternal serum and placental tissue homogenates. Determining the best predictor(s) which discriminate placenta accreta was analyzed by multiple logistic regression analyses. Adjusted odds ratios and 95% confidence intervals were also calculated. RESULTS: Both placental and serum TRAIL-R2 levels were significantly lower in placenta accreta group (median 34.82 pg/mg and 19.85 pg/mL, respectively) when compared with both non-adherent placenta previa (median 39.24 pg/mg and 25.99 pg/mL, respectively) and the control groups (median 41.62 pg/mg and 25.87 pg/mL, respectively) (p < 0.05). Placental TRAIL-R2 levels and previous cesarean section were found to be significantly associated with placenta accreta (OR: 0.934 95% CI 0.883-0.987, p = 0.016 and OR:7.725 95% CI: 2.717-21.965, p < 0.001, respectively). Placental and serum TRAIL-R2 levels were positively correlated. CONCLUSION: Decreased levels of placental TRAIL-R2 and previous history of cesarean section were found to be significantly associated with placenta accreta, suggesting a possible role of apoptosis in abnormal trophoblast invasion.

Serum angiogenic profile in abnormal placentation.

OBJECTIVE: To evaluate the circulating soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) levels in women with abnormal placentation and to compare the data with the results of women with normal pregnancy. MATERIAL AND METHODS: Serum biomarkers of angiogenesis and maternal and perinatal characteristics of 68 pregnant women, all in the third trimester, who were diagnosed to have vaginal bleeding due to complete placenta previa with and without concomitant placenta accreta, increta and percreta as the study group and 30 pregnant women without any placentation abnormality who eventually delivered at ≥37 weeks of gestational age as the control group were evaluated. RESULTS: There was no statistical difference in the maternal serum values of sFlt1, PlGF, sFlt1/PlGF ratio and VEGF in groups with placental abnormality as compared to controls. Not even a single case of preeclampsia and intrauterine fetal growth restriction was encountered in the study group. CONCLUSION: We demonstrated that regardless of the localization and the degree of the myometrial invasion of the placenta in the uterus, the circulatory biomarkers of angiogenesis and vascularization were comparable.

Role of inflammation in intrahepatic cholestasis of pregnancy.

AIM: Intrahepatic cholestasis of pregnancy (ICP), the most common liver disease in pregnancy, is characterized by elevated serum total bile acid and/or transaminase concentration, and pruritus. Interleukin-6 (IL-6) is a key regulator of the immune response, hematopoiesis and inflammation. We examined both IL-6 and the frequently used inflammatory marker high-sensitivity C-reactive protein (hs-CRP) at baseline in the same study population as for the primary endpoint, in order to provide a new perspective on the pathogenesis of ICP. METHODS: In this controlled cross-sectional study 65 consecutive pregnant women with ICP (34 with mild and 31 with severe disease) and 40 healthy women with uncomplicated pregnancies (control group) were examined. IL-6 and hs-CRP were compared between the groups. RESULTS: While serum IL-6 was significantly higher in the mild ICP (P = 0.01) and severe ICP (P = 0.001) groups than in the control group, hs-CRP was similar between the groups. CONCLUSION: Interleukin-6 may have an essential role, apart from CRP, in the pathogenesis of ICP and, also, is a more sensitive marker of inflammation.

Increased levels of serum granzyme-B is associated with insulin resistance and increased cardiovascular risk in adolescent polycystic ovary syndrome patients.

OBJECTIVES: Our aim was to determine serum perforin and granzyme-B levels in adolescent PCOS patients, and to investigate whether they are associated with some of the insulin sensitivity, obesity and cardiovascular (CV) risk markers and metabolic syndrome. STUDY DESIGN: A case-control study was carried out including a total of 172 adolescents (83 PCOS patients and 89 age-matched healthy controls). Participants were recruited consecutively. Homeostasis model assessment (HOMA-IR), lipid parameters, and anthropometric measurements were determined. Serum perforin and granzyme B levels were measured by commercially available ELISA kits. HOMA-IR>3.16 was considered to indicate the presence of insulin resistance. Logistic regression analysis was applied for the predictive value of granzyme-B for increased CV risk in PCOS patients. RESULTS: As body mass index (BMI) of the PCOS patients was significantly higher than the controls (median 24.6kg/m(2) and 21.4kg/m(2), respectively, p<0.001) all parameters were evaluated after adjustment for BMI. Adolescents with PCOS had significantly higher levels of fasting glucose, insulin, HOMA-IR and granzyme-B when compared with controls. According to the results of logistic regression analysis, granzyme-B levels were found to be significantly associated with increased HOMA-IR (OR=6.120, 95% CI: 2.352-15.926, p<0.001) in adolescent PCOS patients. Additionally, elevated levels of serum granzyme-B were predictive for increased CV risk in PCOS patients (OR=0.237, 95% CI: 0.091-0.616, p=0.003). CONCLUSIONS: Increased levels of serum granzyme-B are independently associated with insulin resistance and also with increased CV risk in adolescent polycystic ovary syndrome patients.

Diagnostic value of CA 19-9 in pregnancies complicated by spinal neural tube defects: a preliminary study.

OBJECTIVES: Various physiological and pathological conditions can induce significant variations in plasma concentrations of tumor markers, such as CA 19-9, which is present in the serum and amniotic fluid of pregnant women. Herein, we aimed to determine the clinical importance of maternal serum CA 19-9 levels in the diagnosis of neural tube defects (NTDs). MATERIAL AND METHODS: A total of 100 women were included in this controlled cross-sectional study. Thirty-three patients whose pregnancies were complicated by isolated meningocele or meningomyelocele constituted the study group, whereas 33 normal, healthy pregnant women constituted the control group, and 34 age- and body mass index (BMI)-matched non-pregnant women were chosen for the validation group. RESULTS: The mean maternal serum CA 19-9 levels were 17.2 ± 17.0 IU/mL, 7.1 ± 5.9 IU/mL, and 4.7 ± 3.6 IU/mL in the study, control, and validation groups, respectively (p < 0.001). ROC analyses showed that elevated CA 19-9 values may predict NTDs (p < 0.001). The cut-off value for CA 19-9 was found to be 9.6 IU/mL at 70% (51%-84%, 95% CI) sensitivity and 84% (74%-92%, 95% CI) specificity. CONCLUSIONS: CA 19-9 may be a promising noninvasive marker for NTDs. Further studies are needed to reveal the clinical applicability and diagnostic potential of maternal serum CA 19-9 levels in the identification of NTDs.

Management of a multiple endocrine neoplasia type 1 during pregnancy: A case report and review of the literature.

Multiple Endocrine Neoplasia Type 1 (MEN1) or Wermer's syndrome is a rare hereditary endocrine syndrome with high penetrance caused by mutations in MEN1 tumor suppressor gene. MEN1 is characterized by hyperplasia or tumoral enlargement in a number of endocrine organs (parathyroid glands, pancreas, pituitary gland, adrenal gland) and it could be hormonally active or inactive. MEN1 is a significant cause of morbidity due to hormone secretion and mass effect. Since it is a rare condition, there are no guidelines with respect to the follow-up of pregnant women with MEN1. Herein, we aimed to present the diagnosis and gestational follow-up of a 29-year-old pregnant with MEN1 syndrome.

First trimester interleukin-6 levels help to predict adverse pregnancy outcomes in both thyroid autoantibody positive and negative patients.

AIM: The aim of the present study is to compare pregnancy outcomes among patients with and without thyroid antibodies and/or subclinical hypothyroidism and investigate whether there is an association between first trimester maternal plasma interleukin-6 (IL-6) levels and adverse pregnancy outcomes. METHODS: A case-control study was carried out including 83 pregnant women (40 thyroid antibody positive and 43 healthy controls). The predictive value of first trimester maternal plasma IL-6 levels on adverse pregnancy outcomes were investigated. The optimal cut-off points of IL-6 for determining maternal and fetal outcomes were evaluated by receiver operating characteristic analyses. RESULTS: Compared with the control, median IL-6 levels were significantly higher in thyroid antibody positive pregnancies (median 1.58 vs 1.63 pg/mL; P = 0.047). IL-6 levels were found to be significantly higher in women who had suffered a miscarriage (P = 0.002), preterm delivery (P < 0.001), intrauterine growth restriction (P = 0.047), preterm premature rupture of membranes (P = 0.043) and overall prenatal complications (P < 0.001). A statistically significant negative correlation between gestational week at birth and IL-6 levels was also determined among all participants involved in the study (r = -0.385, P < 0.001). CONCLUSION: IL-6 levels are significantly increased in thyroid antibody positive patients and predictive for future adverse outcomes, irrespective of thyroid autoimmunity. Increased first trimester IL-6 levels independently predict adverse pregnancy outcomes, regardless of subclinical hypothyroidism.

First trimester biochemical markers in twin pregnancies.

OBJECTIVE: Our aim was to investigate the first trimester serum markers and nuchal translucency (NT) measurements in twin pregnancies in our population. MATERIALS AND METHODS: We reviewed the results of all double tests that were performed in our hospital over a three-year period. Out of them, we selected all twins and compared them with a group of three times as many singleton controls. NT measurements and the first trimester serum markers from 49 twin pregnancies were compared to those of 147 pregnant women with normal singleton pregnancy RESULTS: There were no statistically significant differences in age, gestational age and maternal weight between the two groups (p > 0.05). We found similar NT measurements in the two groups. The median MoM of Pregnancy-Associated Plasma Protein A (PAPP-A) and fß-hCG levels in twins were statistically significantly higher than those in singleton pregnancies. Twelve percent of the twins (12.2%) were the result of assisted reproduction technologies. IVF versus naturally conceived pregnancies showed similar MoM of PAPP-A (2.2 vs. 1.2, respectively) and fß-hCG (Mann-Whitney U; p = 0.195 and p = 0.958). CONCLUSIONS: Our study revealed that median PAPP-A and fß-hCG levels for twins were less than twice those of singleton values.

Plasma Visfatin Levels in Adolescents with Polycystic Ovary Syndrome: A Prospective Case-Control Study.

STUDY OBJECTIVE: We evaluated the plasma visfatin levels in hirsute female adolescents with polycystic ovary syndrome. DESIGN, SETTING, AND PARTICIPANTS: This prospective case-control study included 87 female patients who were seen in our adolescence department. Demographic characteristics and hormonal and biochemical parameters were evaluated between patients with and without polycystic ovary syndrome. Next, we divided the patients with polycystic ovary syndrome into the following subgroups: overweight or obese (body mass index [BMI] ≥ 25 kg/m(2)) vs normal weight (BMI < 25 kg/m(2)) and hirsute vs nonhirsute. RESULTS: There were statistically significant differences in the BMI, serum androgen levels, homeostasis model assessment-insulin resistance (HOMA-IR) levels, and insulin levels between patients with and without polycystic ovary syndrome (P < .05). The mean visfatin levels showed no statistically significant difference between these 2 groups (P > .05). The serum visfatin levels were similar between the 2 subgroups classified by BMI (P > .05). However, there were statistically significant differences in the total and free testosterone levels, 17-hydroxylase progesterone level, HOMA-IR level, and visfatin level between the 2 subgroups classified by hirsutism (P < .05). The plasma visfatin level was higher in hirsute PCOS than in nonhirsute PCOS patients. CONCLUSION: Significantly higher visfatin levels were found in hirsute than in nonhirsute adolescents with PCOS. According to these results, plasma visfatin levels may be a useful marker in hirsute adolescents with PCOS.

Outcomes after cesarean myomectomy versus cesarean alone among pregnant women with uterine leiomyomas.

OBJECTIVE: To determine whether myomectomy during cesarean delivery is safe and feasible among pregnant women with leiomyomas. METHODS: In a retrospective study, data were reviewed from pregnant women with uterine leiomyomas who delivered by cesarean at a center in Turkey between May 1, 2007, and April 30, 2014. Women were divided into two groups: cesarean myomectomy (CM) or cesarean only (CO). Data were analyzed for characteristics of the uterine leiomyomas, hematologic changes occurring between the preoperative and postoperative periods, duration of the operation, and length of hospital stay. RESULTS: Overall, 76 women formed the CM group and 60 formed the CO group. The mean diameter of the leiomyomas did not differ between CM and CO groups (4.6±2.5cm vs 5.2±2.2cm; P=0.175). More patients in the CM group than in the CO group had subserous (24 [31.6%] vs 7 [11.7%]; P=0.006) and uterine corpus (57 [75.0%] vs 30 [50.0%]; P=0.003) leiomyomas. Fewer patients in the CM group had intramural (44 [57.9%] vs 49 [81.7%]; P=0.003) and fundal (15 [19.7%] vs 25 [41.7%]; P=0.005) leiomyomas. CONCLUSION: Surgeons were more likely to remove corporal and subserous leiomyomas than other types; size did not seem to affect decision making. CM can be a safe operation for some patients.

The unprecedented recurrent diploid/tetraploid mosaicism of trisomy-18 (mixoploidy; 4n+18/2n+18): clinical report.

We report on a 32-year-old woman who presented at gestational age of 14 weeks. During ultrasonographic examination, we discovered that her fetus had several important abnormalities, including a cystic hygroma, craniofacial defects (low-set ears, broad nose), heart defects (single atrium, single ventricle), agenesis of corpus callosum, limb defects (clenched hands, pes equinovarus). Chorionic villus sampling and karyotyping revealed diploid/tetraploid mosaicism with trisomy 18 (mixoploidy; 4n+18/2n+18). Her second pregnancy was terminated because of the same clinical manifestations 1 year prior. Her first pregnancy resulted in the birth of an entirely healthy boy. As far as know, no other similar case has been presented in the literature.

Diagnosis of pentalogy of cantrell in the first trimester using transvaginal sonography and color Doppler.

We report the prenatal diagnosis of Cantrell syndrome in the first trimester. During a routine transabdominal ultrasonographic examination, a midline supraumbilical abdominal wall defect including herniated liver and ectopia cordis with a large omphalocele containing the intestines and cystic hygroma was incidentally identified at the 12th week of gestation. A transvaginal sonography examination revealed a severe lumbosacral scoliosis in addition to the inability to visualize the abdominal aorta which was indicative of a severe intracardiac defect. The parents opted for pregnancy to be terminated. In this case report, we discuss the complementary role of transvaginal sonography and Doppler imaging in the diagnosis of Cantrell syndrome in early pregnancy.

Efficacy of a real time optoelectronic device (TruScreen™) in detecting cervical intraepithelial pathologies: a prospective observational study.

OBJECTIVE: To assess the effect of TruScreen™ (an objective optoelectronic cervical screening device) in improving the sensitivity of cervical screening programs either alone or in combination with Papanicolaou (PAP) smear or human papilloma virus (HPV) DNA screening. MATERIAL AND METHODS: Our study was performed in 285 patients with abnormal Pap test results. TruScreen™ and HPV screening methods were performed in all participants. Consistency and differences between the tests were compared with cervical biopsy results. RESULTS: TruScreen™ was found to be an approach method in the determination of cervical pathologies (ROC curve area underlined=0.606) and with an 89.5% negative predictive value. HPV screening remains a counterpart to TruScreen™ with a 0.620 area underlined in the ROC curve and an 83% negative predictive value. CONCLUSION: As determined in our study, TruScreen™ with a sensitivity of 86.1% can be used as a screening test with instant and not professional dependent results for cervical cancer screening. Avoiding from subjectivity in interpretation of Pap smears and requirement for pathologists, TruScreen™ can be a used for cervical cancer screening especially in countries with a low socio-economic status. The combination of TruScreen™ and HPV screening was not able to demonstrate a significant rise of effectiveness in screening.

Evaluation of the Diagnostic Accuracy of Serum D-Dimer Levels in Pregnant Women with Adnexal Torsion.

We aimed to evaluate the diagnostic accuracy of serum D-dimer levels in pregnant women with adnexal torsion (AT). The pregnant women with ovarian cysts who suffered from pelvic pain were divided into two groups; the first group consisted of the cases with surgically proven as AT (n = 17) and the second group consisted of the cases whose pain were resolved in the course of follow-up period without required surgery (n = 34). The clinical characteristics and serum D-dimer levels were compared between the groups. Patients with AT had a higher rate of elevated serum white blood cell (WBC) count (57% vs. 16%, p = 0.04) and serum D-dimer levels (77% vs. 21%, p < 0.01) on admission in the study group than in the control group. Elevated D-dimer and cyst diameter larger than 5 cm yielded highest sensitivity (82% for each); whereas the presence of nausea and vomiting and elevated CRP had the highest specificity (85% and 88%, respectively). This is the first study that evaluates the serum D-dimer levels in humans in the diagnosis of AT, and our findings supported the use of D-dimer for the early diagnosis of AT in pregnant women.

Role of a risk of malignancy index in clinical approaches to adnexal masses.

OBJECTIVE: The aim of this study was to evaluate predictive role of risk of malignancy index in discriminating between benign and malignant adnexal masses preoperatively. METHODS: This retrospective study was conducted with a total of 569 patients with adnexal masses/ovarian cysts managed surgically at our clinic between January 2006 and January 2012. Obtained data from patient files were age, gravidity, parity, menopause status, ultrasound findings and CA125 levels. For all patients ultrasound scans were performed. For the assessment of risk of malignancy index (RMI) Jacobs' model was used. Histopathologic results of all patients were recorded postoperatively. Malignancy status of the surgically removed adnexal mass was the gold standard. RESULTS: Of the total masses, 245 (43.1%) were malignant, 316 (55.5%) were benign and 8 (1.4%) were borderline. The mean age of benign cases was lower than malign cases (35.2±10.9 versus 50.8±13.4, p<0.001). Four hundred and five of them (71.2%) were in premenopausal period. Malignant tumors were more frequent in postmenopausal women (81% versus 29%, p<0.001). All ultrasound parameters of RMI were statistically significantly favorable for malignant masses. In our study ROC curve analysis for RMI provided maximum Youden index at level of 163.85. When we based on cutoff level for RMI as 163.85 sensitivity, specificity , PPV, NPV was calculated 74.7%, 96.2%, 94% and 82.6%, respectively. CONCLUSIONS: RMI was found to be a significant marker in preoperative evaluation and management of patients with an adnexal mass, and was useful for referring patients to tertiary care centers. Although utilization of RMI provides increased diagnostic accuracy in preoperative evaluation of patient with an adnexal mass, new diagnostic tools with higher sensitivity and specificity are needed to discriminate ovarian cancer from benign masses.

Inflammation and glycemic tolerance status in pregnancy: the role of maternal adiposity.

BACKGROUND/AIMS: Although the association between inflammation and insulin resistance is well known, the data related to the role of inflammation in gestational diabetes mellitus (GDM) are conflicting. The aim of this study was to investigate the association of several inflammatory mediators with the glycemic status in pregnancy. METHODS: Leukocyte count, ferritin, C-reactive protein (CRP), fibrinogen and interleukin-6 levels were measured in 70 patients with normal glucose tolerance, in 57 patients with impaired glucose tolerance and in 35 patients with GDM as determined based on 50-gram oral glucose tolerance test (OGTT) and 100-gram OGTT results. RESULTS: A significant difference among the groups was seen only with regard to CRP and fibrinogen levels; however, no significant differences were observed after adjustment for body mass index (BMI). CRP was found to be strongly associated with current BMI in all three groups. CONCLUSION: Maternal serum levels of inflammatory mediators are not related to GDM at the time of the glucose challenge test in the late second or early third trimester. The significant difference in the levels of CRP in different strata of glycemic tolerance was not observed after adjustment for BMI. Adiposity may have a central role in GDM, causing an inflammatory response.