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Background Studies have commonly assessed the endocrinolgical status of women once miscarriage is threatened or suspected; few studies have explored the antecedent hormonal environment or used a longitudinal strategy. Using refined statistical techniques, we sought to re-evaluate whether gestational hormone trajectories in early pregnancy can identify future miscarriage in asymptomatic pregnancies. Methods This prospective cohort study followed 105 women over-conception; 72 had normal term pregnancy outcomes while 33 experienced early pregnancy failure between 35 and 115 days of gestation. Participants attended a pre-conception and antenatal clinic at Newcastle University, United Kingdom (UK). Evaluation methods included ultrasound, clinical assessments of pregnancy progress and serial measurements of gestational hormones by radioimmunoassays. Linear mixed-effects regression analysis examined hormone relationships with pregnancy outcomes. Results Detailed longitudinal illustration of gestational hormones, antecedent to miscarriage indications, revealed early pathophysiological trends. In particular, oestradiol showed as marked a deviation from normal as progesterone before miscarriage was evident, reflecting a deficiency in the ovarian response to rising human chorionic gonadotrophin (hCG) levels. Regression analysis provided equations for gestational hormone slopes that significantly differentiated asymptomatic women with subsequent early pregnancy failure, compared to women with normal term pregnancies. Both progesterone and oestradiol displayed negative mean slopes in pregnancies destined for failure; in this group, both human placental lactogen (hPL) and hCG revealed mean positive trajectories that imitated normal pregnancies but at slower rates of increase. Conclusions Oestradiol, progesterone and hCG trajectories, from 50 days of gestation, have good potential for revealing pathophysiology and for identifying which asymptomatic pregnancies are destined for subsequent failure. In asymptomatic patients where there is concern about viability and ultrasound diagnosis is ambiguous, a combined hormonal profile could contribute to guiding patient care decisions.

Stereotyped subset #2 (IGHV3-21/IGLV3-21) is the largest subset in CLL (~3% of all patients). Membership in subset #2 is clinically relevant since these patients experience an aggressive disease irrespective of the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene. Low-throughput evidence suggests that stereotyped subset #169, a minor CLL subset (~0.2% of all CLL), resembles subset #2 at the immunogenetic level. More specifically: (i) the clonotypic heavy chain (HC) of subset #169 is encoded by the IGHV3-48 gene which is closely related to the IGHV3-21 gene; (ii) both subsets carry VH CDR3s comprising 9-amino acids (aa) with a conserved aspartic acid (D) at VH CDR3 position 3; (iii) both subsets bear light chains (LC) encoded by the IGLV3-21 gene with a restricted VL CDR3; and, (iv) both subsets have borderline SHM status. Here we comprehensively assessed the ontogenetic relationship between CLL subsets #2 and #169 by analyzing their immunogenetic signatures. Utilizing next-generation sequencing (NGS) we studied the HC and LC gene rearrangements of 6 subset #169 patients and 20 subset #2 cases. In brief, IGHV-IGHD-IGHJ and IGLV-IGLJ gene rearrangements were RT-PCR amplified using subgroup-specific leader primers as well as IGHJ and IGLC primers, respectively. Libraries were sequenced on the MiSeq Illumina instrument. IG sequence annotation was performed with IMGT/HighV-QUEST and metadata analysis conducted using an in-house, validated bioinformatics pipeline. Rearrangements with identical CDR3 aa sequences were herein defined as clonotypes, whereas clonotypes with different aa substitutions within the V-domain were defined as subclones. For the HC analysis of subset #169, we obtained 894,849 productive sequences (mean: 127,836, range: 87,509-208,019). On average, each analyzed sample carried 54 clonotypes (range: 44-68); the dominant clonotype had a mean frequency of 99.1% (range: 98.8-99.2%) and displayed considerable intraclonal heterogeneity with a mean of 2,641 subclones/sample (range: 1,566-6,533). For the LCs of subset #169, we obtained 2,096,728 productive sequences (mean: 299,533, range: 186,637-389,258). LCs carried a higher number of distinct clonotypes/sample compared to their partner HCs (mean: 148, range: 110-205); the dominant clonotype had a mean frequency of 98.1% (range: 97.2-98.6%). Intraclonal heterogeneity was also observed in the LCs, with a mean of 6,325 subclones/sample (range: 4,651-11,444), hence more pronounced than in their partner HCs. Viewing each of the cumulative VH and VL CDR3 sequence datasets as a single entity branching through diversification enabled the identification of common sequences. In particular, 2 VH clonotypes were present in 3/6 cases, while a single VL clonotype was present in all 6 cases, albeit at varying frequencies; interestingly, this VL CDR3 sequence was also detected in all subset #2 cases, underscoring the molecular similarities between the two subsets. Focusing on SHM, the following observations were made: (i) the frequent 3-nucleotide (AGT) deletion evidenced in the VH CDR2 of subset #2 (leading to the deletion of one of 5 consecutive serine residues) was also detected in all subset #169 cases at subclonal level (average: 6% per sample, range: 0.1-10.8%); of note, the 5-serine stretch is also present in the germline VH CDR2 of the IGHV3-48 gene; (ii) the R-to-G substitution at the VL-CL linker, a ubiquitous SHM in subset #2 and previously reported as critical for IG self-association leading to cell autonomous signaling in this subset, was present in all subset #169 samples as a clonal event with a mean frequency of 98.3%; and, finally, (iii) the S-to-G substitution at position 6 of the VL CDR3, present in all subset #2 cases (mean : 44.2% ,range: 6.3-87%), was also found in all #169 samples, representing a clonal event in 1 case (97.2% of all clonotypes) and a subclonal event in the remaining 5 cases (mean: 0.6%, range: 0.4-1.1%). In conclusion, the present high-throughput sequencing data cements the immunogenetic relatedness of CLL stereotyped subsets #2 and #169, further highlighting the role of antigen selection throughout their natural history. These findings also argue for a similar pathophysiology for these subsets that could also be reflected in a similar clonal behavior, with implications for risk stratification. Disclosures Sutton: Abbvie: Honoraria; Gilead: Honoraria; Janssen: Honoraria. Stamatopoulos:Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Chatzidimitriou:Janssen: Honoraria.

Objective To investigate prospectively the prevalence of congenital cytomegalovirus (CMV) infection and the pathologic features of the placenta in cases of fetal growth restriction (FGR). Study design Forty-eight pregnant women who were diagnosed with FGR during pregnancy were enrolled for 15 months. Maternal CMV serologic tests, pathologic examinations of the placenta, and newborn urinary CMV-DNA polymerase chain reaction tests were performed in all the cases. The clinical characteristics and laboratory findings of the pregnant women and their newborns were collected. Biomarkers for inflammation, angiogenesis, and placental hormones were measured in the maternal serum at FGR diagnosis or in the neonatal urine at birth. Results One of the 48 cases with FGR was a congenital CMV infection. CMV antigen was detected in the placenta of 7 cases with FGR. The change rate of the estimated fetal body weight was significantly lower in FGR cases with placental CMV detection. Placental villitis was observed more frequently in FGR cases with placental CMV detection. Human placental lactogen was significantly decreased in FGR cases with placental CMV detection. Increased C-reactive protein and serum amyloid A levels in the maternal serum were observed more frequently in FGR cases with placental CMV detection. Newborn urine β-2 microglobulin levels were significantly higher in FGR cases with placental CMV detection. Conclusions Serologic tests for maternal CMV, the change rate of the estimated fetal body weight, analysis of several biomarkers, and placental pathologic examinations might be helpful in comprehensively predicting the possibility of congenital CMV infection.

Atypical germ cells or so-called carcinoma-in-situ of the testis are often found in the tissue adjacent to germ cell tumours. The present study was performed to investigate if tumour associated antigens demonstrated immunohistochemically in the tumours could also be demonstrated in the carcinoma-in-situ. Using indirect immunoperoxidase technique 39 orchidectomy specimens were examined for the presence of a series of antigens: alpha-foetoprotein (AFP), alpha1-antitrypsin (A1AT), human chorionic gonadotrophin (hCG). specific pregnancy β-glycoprotein (SP1), human placental lactogen (hPL), carcino-embryonic antigen (CEA) and ferritin (FER). FER was demonstrated in the atypical cells in 24/29 cases of carcinoma-in-situ of the testis. HCG was demonstrated in intratubular syncytiotrophoblast-like cells in one case and in atypical germ cells in another specimen. No staining reaction was found for the other antigens investigated Normal germinal epithelium and germinal epithelium in non-malignant pathological changes of the testis were never stained. These findings which indicate that FER may be a possible marker of carcinoma-in-situ of the testis is of utmost interest, however investigation of a larger series is mandatory.

Background Carbapenemase-producing Enterobacteriaceae (CPE) are a global threat. Risk of transmission of CPE in households remains poorly understood Methods Population-based surveillance for CPE colonization/infection is conducted in Toronto/Peel Region, Canada. In households with ≥1 consenting household contact (HC), groin, rectal swabs and urine samples are submitted every 3 months for both IC and HC until the IC has three consecutive negative swab sets. Swabs/urines are incubated overnight in BHI, direct PCR for carbapenemase genes is performed; specimens positive for PCR are then cultured. Results Eighty-five households and 150 HC have been enrolled. Most common species/gene combinations in IC are: E. coli/NDM (33), E. coli/OXA48 (15), Klebsiella spp./NDM (11). HCs have a median of eight swabs (range 2–14). 12 (8%) HCs were colonized with CPE (median 1.5 pos samples, range 1–8). IC and HC had same gene in 11(92%) cases, and same species/gene in seven (58%) cases. NDM+OXA48 ICs were more likely to have CPE colonized HC, see table. CPE colonized HC were older, more likely to be the IC’s spouse (OR 32, 95% CI 4–260), and more likely to have travelled outside Canada (OR 9.7, 95% CI 1.2–78). Conclusion HC colonization with CPE is uncommon, but not rare, and may be associated with either household transmission, or co-exposure of HC and IC via travel. Spouses are most often colonized. Characteristic CPE Positive N = 12 CPE Negative N = 138 P-Value Gender (n, % male) 3 (25%) 53 (38%) 0.27 Median age (range) 70y(24-89) 42y (4-98) 0.005 Chronic illness 6 (50%) 35 (25%) 0.08 Relationship to IC Spouse 11(92%) 35 (25%) 3 months 7/11(64%) 32/61(52%) 0.72 >6 months 6/10(60%) 23/53(43%) 0.49 Disclosures S. Poutanen, MERCK: Scientific Advisor, Speaker honorarium; COPAN: Speaker(but not part of a bureau), Travel reimbursement; Accelerate Diagnostics: Investigator, Research support; Bio-Rad: Investigator, Research support; bioMérieux: Investigator, Research support.

Choriocarcinoma is a germ cell tumor belonging to the spectrum of gestational trophoblastic diseases, and occurs most commonly in the gonads. Primary hepatic choriocarcinoma is very rare, especially in females. A 59-year-old woman was referred to our clinic with a history of upper right quadrant pain lasting 1 month. Computed tomography and magnetic resonance imaging revealed a large hypervascular mass in the right liver, characteristic of angiosarcoma. The patient underwent right hemihepatectomy without unexpected events. Histopathology revealed the tumor as a choriocarcinoma, with numerous syncytiotrophoblasts. Immunohistochemistry was positive for β-human chorionic gonadotropin and CK-19, with a Ki-67 labeling index of 90%. The tumor showed focal positivity for CD31 and human placental lactogen. The patient started chemotherapy (vincristine and cyclophosphamide) on postoperative day 16. The patient’s clinical condition improved and she was discharged on postoperative day 17. Primary hepatic choriocarcinoma in female adults is a rare aggressive tumor, and further studies are needed to improve its diagnosis and treatment.

This chapter reviews the pathophysiology of insulin resistance during pregnancy including the role of the placenta and placentally derived hormones such as cortisol and human placental lactogen. The teleological foundation of insulin resistance in human pregnancy and the etiology of gestational diabetes are also discussed.

Background: Diabetes mellitus (DM) is a multifactorial disease orphan of a cure. Regenerative medicine has been proposed as novel strategy for DM therapy. Human fibroblast growth factor (FGF)-2b controls β-cell clusters via autocrine action, and human placental lactogen (hPL)-A increases functional β-cells. We hypothesized whether FGF-2b/hPL-A treatment induces β-cell differentiation from ductal/non-endocrine precursor(s) by modulating specific genes expression. Methods: Human pancreatic ductal-cells (PANC-1) and non-endocrine pancreatic cells were treated with FGF-2b plus hPL-A at 500 ng/mL. Cytofluorimetry and Immunofluorescence have been performed to detect expression of endocrine, ductal and acinar markers. Bromodeoxyuridine incorporation and annexin-V quantified cells proliferation and apoptosis. Insulin secretion was assessed by RIA kit, and electron microscopy analyzed islet-like clusters. Results: Increase in PANC-1 duct cells de-differentiation into islet-like aggregates was observed after FGF-2b/hPL-A treatment showing ultrastructure typical of islets-aggregates. These clusters, after stimulation with FGF-2b/hPL-A, had significant (p < 0.05) increase in insulin, C-peptide, pancreatic and duodenal homeobox 1 (PDX-1), Nkx2.2, Nkx6.1, somatostatin, glucagon, and glucose transporter 2 (Glut-2), compared with control cells. Markers of PANC-1 (Cytokeratin-19, MUC-1, CA19-9) were decreased (p < 0.05). These aggregates after treatment with FGF-2b/hPL-A significantly reduced levels of apoptosis. Conclusions: FGF-2b and hPL-A are promising candidates for regenerative therapy in DM by inducing de-differentiation of stem cells modulating pivotal endocrine genes.

RU486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)-17 alpha- (prop-1-ynyl)-oestra-4,9-dien-3-one] a potent progesterone antagonist, was shown to induce abortions in humans. Human chorionic gonadotrophin (HCG) and pregnancy-associated plasma protein-A (PAPP-A) decreased after RU486 administration, but it was not clear whether these effects were due to RU486 or secondary to trophoblast damage. To answer this question we tested the in-vitro effects of RU486 on short-term cultures of trophoblastic and decidual explants. It was observed that RU486 induced a significant inhibition of the trophoblastic production rate of beta HCG and PAPP-A but not human placental lactogen. This effect could be overcome by addition of progesterone (for PAPP-A and beta HCG) or cortisol (for beta HCG). Decidual prolactin (Prl) or PAPP-A secretions were also inhibited by RU486. Progesterone antagonized these effects, whereas cortisol was ineffective. These results suggest that PAPP-A is a progesterone-dependent protein and that the abortifacient effect of RU486 in humans could at least partially be due to an inhibition of the production of HCG and/or PAPP-A.

A woman's reproductive history may affect her risk for coronary heart disease. Parity has been associated with increased coronary disease risk in some studies, while other studies have shown that nulliparous women are at increased risk (1-3). Pregnancy fre­quency (including frequency of spontaneous abortion (4, 5)) and age at first pregnancy (6) have also been associated with increased coronary disease risk. Although reports of associations of coronary disease risk with parity, age at menarche, or incidence of miscar­riage are not all consistent (7, 8), the majority of cohort studies have shown an increased risk of coro­nary disease among women with high gravidity or parity (9). Long-term effects of pregnancy on coronary disease risk factors, such as lipoproteins (10, 11), are potential mechanisms for an association between par­ity and coronary artery disease risk. Marked increases in lipoprotein concentrations oc­cur during pregnancy (12) and have been correlated with pregnancy-related increases in insulin, 17-beta estradiol, progesterone, and human placental lactogen (13). Total and low density lipoprotein (LDL) choles­terol and triglyceride levels progressively increase during gestation (10, 14). Although triglycerides have been reported to decrease rapidly during the postpar­tum period, total and LDL cholesterol levels may require several months to return to baseline (10, 14). High density lipoprotein (HDL) cholesterol, which has been shown to be inversely associated with coronary disease risk among women (15, 16), peaks at mid- gestation and then falls to levels approximately 15 percent above baseline at term (12). Few data are available on the long-term effects of pregnancy on lipoproteins; however, there are reports of inverse associations between parity and postpartum HDL cho­lesterol levels (17-20). In order to examine further relations of parity with lipid risk factors, we assessed plasma lipids at baseline and at the year 1 and year 2 follow-up examinations among young adult women in an ongoing epidemiologic study.

Background: Error detection is a critical part of the self-monitoring functions that guide efficient, goal-directed behaviors. Error-monitoring deficits are well described in schizophrenia, but the extent to which error processing deficits and their associated functional neuroanatomy are evident in individuals at clinical high risk (CHR) for developing schizophrenia is not well characterized.

Trophoblastic tumor of the placental bed is a highly malignant form of trophoblastic disease that occurs extremely rarely: 0.4-2% of all the trophoblastic tumors. In the world literature, there are reports on about 200 cases of this disease. The tumor occurs at a repro- ductive age (median age 30 years), occasionally even long after pregnancy, which makes the problem of diagnosis and treatment of the pathology particularly pressing. In 30% of cases, there are metastases more frequently to the lung and vagina. The diagnostic features of a placental bed tumor include the low serum levels of chorionic gonadotropin β-subunits and the higher level of human placental lactogen. Due to low tumor susceptibility to chemotherapy, the patients should undergo surgical intervention as uterine extirpation at the first treatment stage, which is followed by chemotherapy.

The robust and tissue-specific activation of the human growth hormone (hGH) gene cluster in the pituitary and placenta constitutes an informative model for analysis of gene regulation. The five-gene hGH cluster is regulated by two partially overlapping sets of DNase I hypersensitive sites (HSs) that constitute the pituitary (HSI, II, III and V) and placental (HSIII, IV, and V) locus control regions (LCRs). The single placenta-specific LCR component, HSIV, is located at -30 kb to the cluster. Here we generate a series of hGH/BAC transgenes specifically modified to identify structural features of the hGH locus required for its appropriate placental expression. We find that placental specificity is dependent on the overall multigene configuration of the cluster whereas the distance between the cluster and its LCR impacts the level of placental expression. We further observe that a major function of the placental hGH LCR is to insulate the transgene locus from site-of-integration effects. This insulation activity is linked to placenta-specific occupancy of the chromatin architectural protein, CTCF, at HSIV. These data reveal a remarkable combination of structural configurations and regulatory determinants that must work in concert to insure robust and tightly controlled expression from a complex multigene locus.

Objective This study aimed to identify a set of predominantly placental (PP) mRNAs, which are associated with later-developing twin-to-twin transfusion syndrome (TTTS). Method First, out of 50 PP mRNAs we previously reported, we select target mRNAs that are ordinarily detectable in maternal plasma. Plasma concentrations of these PP mRNAs were measured in monochorionic diamniotic twin (MCDA-T) pregnancies complicated by TTTS later (n = 11) and in uncomplicated MCDA-T pregnancies (n = 17). Finally, the diagnostic values of the PP mRNAs in plasma were evaluated. Results From 50 PP mRNAs, nine [human placental lactogen (hPL); pregnancy-specific glycoproteins 2 (PSG2); human pregnancy-specific glycoproteins 3 (PSG3); syncytin; syncytin 2; retinoic acid-induced 14; A disintegrin and metalloproteinase domain-containing protein 12 (ADAM12); chorionic glycoprotein hormones, alpha polypeptide; and chorionic glycoprotein hormones, and beta polypeptide] were selected as target mRNAs. Changes in six PP mRNAs [increased hPL, PSG2, and PSG3 and decreased syncytin, syncytin2, and ADAM12] in maternal plasma were detected in MCDA-T pregnant women who subsequently developed TTTS. Finally, mRNA signatures gave elevated AUCs (hPL/PSG2: 0.8717; hPL/PSG3: 0.8449; hPL/ADAM12: 0.8396) compared with single hPL mRNA. Conclusion Quantitative aberration of plural cell-free PP mRNAs in maternal plasma precedes the appearance of clinically apparent TTTS. This suggests that pathophysiological changes in the placenta are associated with morbid conditions of TTTS. © 2013 John Wiley & Sons, Ltd.

Objective Rapid eye movement sleep behavior disorder (RBD) affects 33-46% of patients with Parkinson’s Disease (PD) and may be a risk factor for neuropsychological impairment. However, the cognitive profile in PD patients with RBD has yet to be fully determined. This study examined differences in neuropsychological performance among non-demented PD patients with (PD/RBD+) and without RBD (PD/RBD-), and healthy controls (HC). Methods One hundred seventy-five participants, including 45 PD/RBD+ patients, 78 PD/RBD- patients, and 52 HC, completed the RBD sleep questionnaire and underwent a comprehensive neuropsychological battery assessing attention/working memory, language, visuospatial function, verbal and visual learning and memory, and executive function. Results The PD/RBD+ group demonstrated significantly poorer global neuropsychological performance compared to both the PD/RBD- and HC groups (p’s < .003; η_p^2 = .16). MANOVA demonstrated significant group differences on all individual cognitive domains (p’s < .001), except visuospatial function (p = .10). Both PD/RBD+ and PD/RBD- patients had significantly lower scores compared to the HCs in the domains of attention/working memory, language, learning, and memory. Additionally, the PD/RBD+ group had significantly lower executive functioning scores compared to the HCs, and poorer learning performance compared to the PD/RBD- group. Conclusions Compared to PD patients without RBD, PD/RBD+ patients have greater levels of cognitive impairment specific to the acquisition of new information. Moreover, PD/RBD+ patients have greater executive dysfunction compared to HCs, underscoring the importance of RBD assessment for improved detection and treatment of neuropsychological impairment (e.g., targeted cognitive interventions). Longitudinal investigations are needed to determine the enduring effects of RBD in PD.

Purpose Our study examined the influence of hormonal contraceptives (HC) on pre-injury (baseline) ImPACT performance in female collegiate athletes. Methods Participants in our cross-sectional study consisted of 304 NCAA Division I female athletes who self-reported taking (HC+ [n=154]) or not taking (HC- [n=154]) HC. HC+ participants were matched to HC- participants for height, weight, sport, and position. HC+ participants had an average age of 19.0±1.33 years, height of 170.5–8.70 cm, and mass of 64.2–10.58 kg. HC- participants had an average age of 19.0±1.24 years, height of 170.3–9.19 cm, and mass of 64.2–9.75 kg. Participants completed ImPACT as part of their preseason baseline assessment. Only participants with valid ImPACT assessments were included in our analyses. Chi-squared (χ2) tests were performed to compare groups in terms of medical history variables. Independent t-tests were used to compare groups in terms of demographic variables, self-reported hours of sleep, and ImPACT (Verbal and Visual Memory, Visual Motor Speed [VMS], Reaction Time [RT], and Total Symptom Severity [TSS]) outcome scores. Analyses were performed with α=0.05. Results No differences were observed between groups for demographic variables, hours of sleep, or medical history variables (p Conclusion Our results suggest HCs may influence ImPACT performance in female collegiate athletes. Clinicians must consider the role of HCs when interpreting ImPACT outcome scores.

Objective To investigate the expression level of Bruton's tyrosine kinase (Btk) on CD19+B lymphocytes in peripheral blood (PB) of autoimmune hemolytic anemia (AIHA)/Evans patients. Methods The expression of Btk and Phosphorylated Btk(p-Btk) on CD5+CD19+B and CD5-CD19+B lymphocytes were detected using flow cytometry in AIHA/ Evans patients with different disease states, healthy controls (HC) and chronic lymphocytic leukemia (CLL) patients and analyzed its correlation with clinical parameters. Results 36 AIHA/ES patients (16 hemolytic, 20 remission), 11 CLL patients and 15 healthy controls (HC) were enrolled in this study. The expression of Btk and p-Btk on CD5+B lymphocytes in AIHA/Evans patients were higher than those in HCs and CLL patients, the latter two groups had no significant difference, and were positively correlated with the quantity of IgE. The ratio of p-Btk to Btk on CD5+B lymphocytes of hemolytic group and remission group was obviously higher than that on CD5-B lymphocytes [(74.62±6.42)%, (29.63±10.19)%, P=0.001], [(77.95±9.57)%, (26.29±6.86)%, P=0.006]. The ratio of p-BTK to BTK on CD5+B lymphocytes [(54.89±9.56)%] and CD5-B lymphocytes [(30.86±12.47)%, P=0.109)] showed no significant difference in HCs. There was no significant difference of Btk on CD5+B and CD5- B lymphocytes in AIHA/Evans patients, but the expression of p-Btk on CD5+B lymphocytes significantly higher than that on CD5-B lymphocytes in AIHA/Evans patients. Conclusion The expression levels of p-BTK in different B cell subsets of AIHA/Evans patients were significantly different, the expression levels of p-BTK in CD5+B cells were obviously higher than that in CD5-B cells, and higher than that in CD5+ B cells in CLL patients, and positively correlated with the number of serum IgE. Key words: anemia hemolytic autoimmune; Bruton's tyrosine kinase, Phosphorylated Bruton's tyrosine kinase; B cell subsets Disclosures No relevant conflicts of interest to declare.

Introduction ATP-sensitive potassium channels (K ATP channels) have been identified in a variety of tissues. Nevertheless, the presence and role of such metabolism-sensitive K + channels still remain to be unraveled in the reproductive system. Methods The study evaluates the presence of K ATP channel subunits in human term placental explants by immunohistochemistry, proximity ligation assay, Western blot and RT-PCR techniques. The potential involvement of K ATP channels in human placental lactogen (hPL) and human chorionic gonadotrophin (hCG) release has been assessed radioimmunologically from human term placental explants incubated in the presence of different K ATP channel modulators. Results Immunolocalization of the K ATP channel subunits documented both the Kir6.2 and SUR2 subunits in the syncytiotrophoblast of human term placenta. Their colocalization was demonstrated by proximity ligation assay and their presence was further confirmed by immunoblotting and RT-PCR. Kir6.1 subunit was immunolocalized in blood vessels media. SUR1 was not expressed at the mRNA level. Incubation of human term placental explants in the presence of increasing concentrations of modulators of K ATP channels such as glibenclamide, tolbutamide, pinacidil or diazoxide did not affect the measured hCG and hPL secretory rates. Discussion Our study reports, for the first time, the presence of the K ATP channel subunits Kir6.2 and SUR2 in the human term syncytiotrophoblast. However, under the present experimental conditions, the activation or inhibition of these putative K ATP channels by different pharmacological agents did not affect the hPL and hCG secretory rate of human term placental explants. Conclusion The present findings suggest that the human term syncytiotrophoblast might be endowed with K ATP channels. Further studies should clarify their implication in the syncytiotrophoblast ionic homeostasis and hormone regulation.

Starvation ketosis outside pregnancy is rare and infrequently causes a severe acidosis. Placental production of hormones, including glucagon and human placental lactogen, leads to the insulin resistance that is seen in pregnancy, which in turn increases susceptibility to ketosis particularly in the third trimester. Starvation ketoacidosis in pregnancy has been reported and is usually precipitated by a period of severe vomiting. Ketoacidosis is likely to have important implications for fetal survival as ketoacidosis in women with type 1 diabetes mellitus is associated with intrauterine death. This article features four cases of women with vomiting in the third trimester of pregnancy associated with a severe metabolic acidosis. The mechanism underlying ketogenesis, the evidence for accelerated ketogenesis in pregnancy and other similar published cases are reviewed. A proposed strategy for management of these women is presented.

Poor prognosis of ovarian cancer, the deadliest of the gynecologic malignancies, reflects major limitations associated with detection and diagnosis. Current methods lack high sensitivity to detect small tumors and high specificity to distinguish malignant from benign tissue, both impeding diagnosis of early and metastatic cancer stages and leading to costly and invasive surgeries. Tissue microarray analysis revealed that >98% of ovarian cancers express the prolactin receptor (PRLR), forming the basis of a new molecular imaging strategy. We fused human placental lactogen (hPL), a specific and tight binding PRLR ligand, to magnetic resonance imaging (gadolinium) and near-infrared fluorescence imaging agents. Both in tissue culture and in mouse models, these imaging bioconjugates underwent selective internalization into ovarian cancer cells via PRLR-mediated endocytosis. Compared with current clinical MRI techniques, this targeted approach yielded both enhanced signal-to-noise ratio from accumulation of signal via selective internalization and improved specificity conferred by PRLR upregulation in malignant ovarian cancer. These features endow PRLR-targeted imaging with the potential to transform ovarian cancer detection. Cancer Res; 77(7); 1684–96. ©2017 AACR.