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PubMed2006

Association of factor V gene polymorphisms (Leiden; Cambridge; Hong Kong and HR2 haplotype) with recurrent idiopathic pregnancy loss in Tunisia. A case-control study.

Inherited thrombophilia has been shown to be linked with fetal loss. We performed a case-control study on the association between thrombosis-related polymorphisms in the factor V (FV) gene (Leiden, Cambridge, Hong Kong; HR2 haplotype) and idiopathic recurrent pregnancy loss (RPL) in Tunisian women. A total of 348 women with RPL, and 203 control women were studied, corresponding to 1,250 pregnancy losses and 1,200 successful pregnancies. FV Leiden was seen in 19.4% of patients (4.3% in the homozygous state) and in 5.5% of controls. The prevalence of the FV HR2 haplotype was similar in patients and controls, but with 7 homozygous patients for 1 control. FV Cambridge and Hong Kong were absent from both patients and controls. The study of all pregnancy losses evidenced that the frequency of the factor V Leiden polymorphism was zero in women who had mis-carried before 7 weeks of gestation, and then sharply increased to a plateau. After categorization of pregnancy losses (before 8 weeks of gestation; weeks 8 and 9; weeks 10 to 12; from the 13th week of gestation onwards), heterozygous and homozygous factor V Leiden polymorphisms, and homozygous FV HR2 haplotype, were associated with significant and independent risks of pregnancy loss during weeks 8 and 9, which increased during weeks 10 to 12, then culminated after week 12. In Tunisian women with idiopathic RPL, factor V Leiden polymorphism and homozygous FV HR2 haplotype are not a risk factor for very early pregnancy loss, before 8 weeks of gestation, but are thereafter associated with significant clinical risks, which gradually increase from the 8th week onwards.

Abortion, Habitual↗
PubMed2006

[Expressions of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 mRNA in endometriosis].

OBJECTIVE: To investigate mRNA expression of matrix metalloproteinase (MMP-9) and tissue inhibitor of metalloproteinase (TIMP-1) in ectopic endometriosis tissue and uterine endometrium from women with and without endometriosis. METHODS: Thirty-eight women with endometriosis (Revised American Fertility Society classification, RAFSI-IV) were selected as study group. Thirty-eight specimens of ovarian endometrioma (ovarian chocolate cysts, OCC), 16 red peritoneal endometriotic lesions (RPL), and 35 matched eutopic endometrium (Eu) were collected from them simultaneously at the time of surgery. Twenty specimens of endometrium from reproductive women undergoing laparoscopic surgery without endometriosis were obtained as control group. The mRNA expressions of MMP-9 and TIMP-1 were detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Expression of TIMP-1 mRNA was detected in all samples. The level from endometriosis patients and control group was similar (2.31 +/- 1.21, 2.40 +/- 0.89). However, ectopic endometrium expressed significantly fewer TIMP-1 mRNA (OCC 1.67 +/- 0.79, RPL 1.45 +/- 0.68) compared with eutopic endometrium from both endometriosis and endometriosis-free patients (P < 0.05). The positive expression rate of MMP-9 mRNA was not distinctively different among all samples. The density of MMP-9 mRNA expression in endometrium (0.49 +/- 0.28) from endometriosis patients was similar to that in ectopic endometriosis (OCC 0.46 +/- 0.22, RPL 0.33 +/- 0.12), but was significantly higher compared with endometrium (0.29 +/- 0.12) without endometriosis (P < 0.05). CONCLUSIONS: An increase of MMP-9 mRNA expression of eutopic endometrium with endometriosis might enhance the endometrial implantation ability, thus facilitate the ectopic implantation of endometrium. Ectopic lesions express significantly less TIMP-1 mRNA, indicating they have increased invasive ability, which might facilitate the development of endometriosis.

Actins↗
PubMed1990

Nimesulide, indomethacin, BW 755 C, phenidon, mepacrin and nedocromil inhibit the activation of human and rat leucocytes.

This study confirms the strong inhibition of therapeutic concentrations of the antiinflammatory agent nimesulide (NI) on the chemiluminescence (CL) of human leucocytes (HL) after stimulation with opsonized zymosan (C3Z), and extends the findings to peritoneal (RPL) and bronchoalveolar leucocytes (RBAL) collected from actively immunized rats 24 h after i.v. injection of Sephadex. Additionally we demonstrate that NI is a strong inhibitor of proteinase release (PR) from HL. The reference drugs tested for comparison were indomethacin (I), BW 755 C (BW), phenidon (PH), mepacrin (M) and nedrocromil (NE). The rank order of potency for suppression of PR and CL was nearly independent of the cell type and stimulus: PH greater than or equal to BW greater than M greater than NI = 4-OH-NI much greater than I greater than NE. NI was the superior inhibitor of HL activation compared with I as measured either by PR or CL (factor 7), and also of CL of RPL and RBAL (factor 2-3). NI inhibited the PR from HL and CL of RPL or RBAL almost equipotently (IC30: 10-20 micrograms/ml), whereas PH, BW, M and I were 6-10 times more effective as CL inhibitors compared with their PR inhibition. In contrast NE showed a preferential inhibition of PR. This unique inhibition profile on leucocyte activation in vitro may be related to the differences of NI and I which are also existing in their antiinflammatory activities in vivo.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMedDate not supplied

Status of endogenous avian RNA tumor virus in Marek's disease lymphoblastoid cell lines and susceptibility of those lines to exogenous RNA tumor viruses.

Three lymphoblastoid cell lines from Marek's disease (MD) tumors, two MD virus (MDV) producer lines (MSB-1 and HPRS-1), and a nonproducer line (RPL-1) were studied for the expression of avian leukosis sarcoma (ALS) viruses. The MSB-1 line was free of all known endogenous expressions, including replicating virus (RAV-O), group-specific (gs) antigens, and chick helper factor (chf). The RPL-1 and HPRS-1 were positive for gs antigens and chf. The RPL-1 and MSB-1 lines showed no evidence of an exogenous DNA provirus by nucleic acid hybridization (HPRS-1 line was not tested for that DNA). All three lymphoblastoid cell lines were susceptible to exogenous infection with both sarcoma and leukosis viruses of subgroup A but varied in susceptibility to subgroups B and C. All were resistant to subgroups D and E.

Animals↗
PubMed1987

The thyroid and hypoxic moderation of systemic hypertension in the spontaneously hypertensive rat.

Surgically thyroidectomized (TX), sham-operated euthyroid (EU), or thyroidectomized with dietary hormone replacement (RPL), 8-week-old male spontaneously hypertensive rats were subjected to 4 weeks of either of two altitude treatments: normoxia (N; lab altitude = 1520 m) or hypobaric hypoxia (H; simulated altitude = 3658 m). Systolic blood pressure (SBP) was attenuated in all hypoxic and in TX-N rats (p less than 0.05). Thyroidectomy reduced oxygen consumption, rectal temperature, and hormonal indices of thyroid function, as well as attenuating hypoxia-induced polycythemia and right ventricular hypertrophy. Thyroidectomy decreased the sensitivity of aortic rings to KCl and isoproterenol with no differences between EU-N and EU-H or between TX-N and TX-H apparent. Vessel responsiveness in RPL-H was consistent with the hypothyroid status indicated by hormonal measurement, while RPL-N vessel responsiveness was characteristic of euthyroid vessels. Since EU-H rats were euthyroid, with similar vascular responses to EU-N, hypoxia-induced attenuation of SBP does not require hypothyroid-like vascular alterations. Thus, hypoxia and thyroidectomy appear to mitigate systemic hypertension by different mechanisms.

Altitude↗
PubMedDate not supplied

Low-dose aspirin and prednisone treatment of pregnancy loss caused by lupus anticoagulants.

The objective of this study was to ascertain the complications and the efficacy of low-dose aspirin (LDA) and prednisone therapy in women with pregnancy loss and "lupus anticoagulants" (LAC). During the period 1985 to 1993, 255 patients with two or more pregnancy losses (RPL) were tested for LAC with an activated partial thromboplastin time (aPTT) and a tissue thromboplastin inhibition index (TTI, normal value < 1.3). The diagnosis of LAC was established if two TTI values were > or = 1.3 or if a prolonged aPTT was measured in the patient's plasma that did not correct to normal by 1:1 mixing with normal plasma. We excluded patients with RPL who had only anticardiolipin antibodies. We treated 28 pregnancies in 21 women with LDA/prednisone for RPL associated with LAC. Therapy with LDA/prednisone was initiated as soon as a viable pregnancy was diagnosed. Therapy was continued until delivery in all but one case. Prednisone dose was minimized by measuring TTI and aPTT every 2 weeks and adjusting the dosage to maintain a TTI < or = 1.2 and to correct the aPTT to less than 36 seconds. Among the 28 pregnancies there were four (14%) first-trimester spontaneous abortions and four (14%) second-trimester fetal deaths. Of 20 surviving neonates (72%), seven were delivered after 37 weeks and 13 before 37 weeks (mean 35.9 +/- 2.3 weeks, range 31.5 to 40.4 weeks). Pre-term premature rupture of membranes occurred in three pregnancies, hypertensive disorders in six, and four small-for-gestational-age neonates were delivered (two stillborn). Mean birth weight of 20 surviving neonates was 2736 +/- 763 gm (range 900 to 3920 gm). Mean daily prednisone dose in 20 live births was 24.1 +/- 8.5 (SD) mg (range 11.3 to 49.3 mg/day) with mean duration of LDA/prednisone therapy of 185 +/- 40 days (range 97 to 223 days). Maximum prednisone dose was 60 mg/day (mean 36.8 +/- 12.7 mg/day). Only one serious maternal complication of LDA/prednisone therapy was observed. One neonate had talipes equinovarus that resolved without surgical therapy. LDA/prednisone therapy seemed effective and reasonably well tolerated in this population. These findings should be confirmed in a prospective, controlled investigation if such a trial can be organized and performed.

Abortion, Habitual↗
PubMed1995

Rat GP-3 is a pancreatic lipase with kinetic properties that differ from colipase-dependent pancreatic lipase.

The pancreas contains three homologous proteins, colipase-dependent pancreatic lipase (PL) and two recently described pancreatic lipase-related proteins, PLRP1 and PLRP2. Rat (r) PLRP2 was first identified as a zymogen granule membrane protein, GP-3. Subsequently, we showed that rPLRP2 could cleave fatty acids from triglycerides, but the kinetic properties of rPLRP2 have not been further investigated. To further characterize rPLRP2, we expressed the recombinant enzyme in a baculovirus system, purified the secreted protein, and measured its kinetic properties. rPLRP2 had a broad pH optimum and the curve was similar to that of rPL. At pH 7.5, rPLRP2 cleaved short, medium, and long chain triglycerides by a kinetic mechanism that did not include interfacial activation. The activity against these substrates was not affected by bile salts. In particular, rPLRP2 did not show the bile salt inhibition typical of PL. Although colipase increased rPLRP2 activity in the presence of bile salts, the increase was only 2- to 5-fold compared to the absolute requirement for colipase that rPL had under these conditions. Finally, rPLRP2 could hydrolyze phospholipids, a substrate poorly hydrolyzed by PL. Our characterization of rPLRP2 demonstrates clear differences among the kinetic properties of rPLRP2 and rPL, rPLRP2, and PLRP2 homologues isolated from guinea pig and coypu pancreas. These findings have important implications for the physiological function of rPLRP2.

Amino Acid Sequence↗
PubMed1996

What is the appropriate follow-up after treatment?

Close follow-up after surgery for low volume nonseminomatous testicular cancer is important for early detection of recurrence. However, follow-up involves expense and adds to the burden of treatment. To minimize follow-up, we examined medical literature reports of results in early stage testicular cancer. Additionally, we analyzed our own data for the specific patterns of failure in stages I and II after retroperitoneal lymphadenectomy (RPL) and stage I on surveillance. We conclude that the most rigorous protocols should be reserved for stage I on surveillance and stage II on observation after RPL. Less frequent follow-up is needed for the other treatment options. For all patients, follow-up must be most intense early on, because of the high relapse rate in the first 1 to 2 years. Because there was no correlation noted between the site and timing of relapse in any group, physical examination and marker determination must be performed at every visit. In addition, where the retroperitoneum has been sterilized by RPL, chest x-ray must be performed, but computed tomography (CT) of the abdomen and pelvis is generally unnecessary. For stage I on surveillance, abdominopelvic CT is needed but the value of chest x-ray is questionable.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

A review of the genetics of recurrent pregnancy loss.

The field of recurrent pregnancy loss (RPL) has seen a blossoming of investigations in the etiology and treatment of this condition over the last few years. Despite all of this activity, there remains much controversy in all aspects of the field. This ranges from discrepancies in the definition of recurrent pregnancy loss to elements in the work-up and the very existence of certain conditions for which aggressive therapeutic modalities are proposed. We will discuss the genetic component of RPL which is one of the few etiologies for RPL which has achieved near universal acceptance.

Abortion, Spontaneous↗
PubMed2026

miRNA-mediated control of TLR-NLR interplay in the uterus: A hidden corner of recurrent pregnancy loss.

Toll-like receptors (TLRs) and NOD-like receptors (NLRs) are crucial pattern recognition receptors that initiate inflammatory responses and immunological activation upon detecting pathogen- or damage-associated molecular patterns (PAMPs/DAMPS) in the female reproductive tract, thereby maintaining homeostasis and supporting pregnancy success. Their signaling pathways play a significant role in reproductive disorders by mediating the immune response to various pathogenic stimuli. Recurrent pregnancy loss (RPL), defined as the natural ending of two or more pregnancies before 24 weeks of gestation, approximately half of these patients remain idiopathic without precise prognostic, diagnostic, and therapeutic plans. Emerging data point that microRNAs are essential for immunological control in the female reproductive tract. MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression by binding to mRNA and preventing translation into protein. miRNAs play a role in many biological processes, including the development and differentiation of trophoblasts, the activation and implantation of embryos, immune tolerance, and the receptivity of the endometrium during implantation. Given their capacity to regulate up to 30&#x202f;% of the human genome, miRNAs offer a promising avenue for understanding the immunopathogenesis of pregnancy complications. Recent research has detected differential expression of specific miRNAs in reproductive system pathologies. This review focuses on microRNAs and their association with idiopathic recurrent miscarriage, a condition characterized by considerable heterogeneity. Future studies identifying the precise mechanisms linking miRNA-mediated immune dysregulation in RPL immunopathogenesis could open the way for novel personalized therapeutic and diagnostic strategies.

Female↗
PubMed1997

Prolactin-mediated inhibition of 20alpha-hydroxysteroid dehydrogenase gene expression and the tyrosine kinase system.

The rat luteal 20alpha-hydroxysteroid dehydrogenase plays a key role at catabolizing progesterone and at decreasing the level of this steroid secreted by the ovaries. Throughout pregnancy and before parturition neither the mRNA nor the protein for this enzyme could be detected. In this investigation we set to examine whether PRL and PRL-like hormone from placental origin silence the expression of this gene and whether PRL action involves tyrosine kinase activity and/or de novo protein synthesis. The results revealed that PRL and PRL-like hormone from rat placental origin (rPL-1 and rPL-2), but not rat growth hormone, caused a rapid and profound inhibition of 20alpha-HSD mRNA expression in highly luteinized granulosa cells. Immunoprecipition and western blot analysis indicate that PRL-R associates with JAK2 and Stat5, and this association is increased within 30 seconds with PRL treatment. Although both JAK2 and Stat5 were phosphorylated on tyrosine upon PRL treatment, the PRL mediated inhibition of 20alpha-HSD was not reversed by either tyrosine kinase inhibitors, AG18 and genistein, but was largely reversed by the protein synthesis inhibitor cycloheximide. In summary, results of this investigation indicate that although PRL can activate the JAK2/Stat5 system in the corpus luteum, the down regulation of 20alpha-HSD mRNA by PRL does not appear to involve tyrosine kinase activity but depends on de novo synthesis of protein(s).

20-Hydroxysteroid Dehydrogenases↗
PubMed2006

[Relapsing reversible posterior leukoencephalopathy after chemotherapy with cisplatin and 5-fluorouracil].

We report a 37-year-old patient with gastric cancer who suffered two distinct episodes of generalized tonic-clonic seizures during ongoing chemotherapy with cisplatin and 5-fluorouracil. Cranial MRI revealed reversible posterior leukoencephalopathy (RPL) that remitted completely without any specific therapy after discontinuation of the chemotherapeutic drugs. Interestingly, RPL occurred repeatedly in our patient following the single chemotherapy cycles, which has not been described so far. This syndrome is clinically relevant for differential diagnosis of bilateral ischemia of the posterior cerebral arteries. An overview of the literature and necessary diagnostic procedures is given.

Adult↗
PubMed2002

Phage-displayed random peptide libraries in mice: toxicity after serial panning.

PURPOSE: In vivo screening of phage-displayed random peptide libraries (RPLs) has been used to identify peptide ligands to targets found on endothelial cells of blood vessels supplying specific tissues such as brain, kidney, and tumor tissue. Peptides that bind specifically to blood vessels supplying tumor tissue have been conjugated to cytotoxic agents and used to successfully eradicate tumors in a mouse model. With the ultimate goal of developing similar methods for treating human cancer, we describe an in vivo RPL screening process that, unlike previous in vivo experiments, does not harm the animal being screened. METHODS: RPLs were administered to FVB, BalbC, and tumor-bearing MRL/MpJ-fas(LPR) mice in a variety of dosing formats. Tumor nodules were excised 10 min following infusion and phage were amplified from the specimens. Phage were reinjected into the same animal within 48 h. This process was repeated twice for a total of three in vivo screens of mouse tumor tissue within the same animal. Mice were observed for systemic side effects, histopathologic damage, and presence of phage in organs. Peptide sequences were determined from several third-pan phage clones. RESULTS: Overall there was minimal toxicity from administration of single or repeat doses of RPLs. Amino acid consensus sequences were identified and some of the sequences were similar to those of peptide ligands that bind matrix metalloproteinases. CONCLUSIONS: Serial administration of an RPL is well tolerated and serial panning in individual mice leading to consensus sequence motifs is possible. Based on these preclinical data the Food and Drug Administration has approved the implementation of human clinical trials with this technique.

Amino Acid Sequence↗
PubMed2004

A study of pregnancy loss in 352 women with recurrent miscarriages.

AIM: The aim of the study was to investigate the type of pregnancy loss (PL) in women with recurrent miscarriages. MATERIALS AND METHODS: The study population included 411 women with a history of recurrent pregnancy loss (RPL) attending the Recurrent Miscarriage Clinic of the 2nd Department of Obstetrics and Gynecology, University of Athens (tertiary referral center). Subjects were divided in groups according to their underlying pathology and in some of them appropriate treatment was applied. RESULTS: The study of the 323 pregnancies achieved after referral, revealed that the PL after ultrasonographic detection of fetal heart (FH) is overall increased, is more common in women with anatomical uterine anomalies and unexplained RPL, and treatment reduces its rate in women with anatomical uterine anomalies and an inadequate luteal phase. The PL before the detection of FH is reduced after treatment in women with thrombotic tendency and an inadequate luteal phase.

Abortion, Habitual↗
PubMed1986

A preliminary classification of the healing potential of medicinal plants, based on a rational analysis of an ethnopharmacological field survey among Bedouins in the Negev desert, Israel.

In the course of an ethnopharmacological survey carried out among the Bedouins of the Negev desert, it was noticed that in addition to the use of modern medical services, medicinal plants were also being employed. We deemed it worthwhile, therefore, to investigate the current status of herbal medicine among the Negev Bedouins and to evaluate the relative efficiency of the plants used. To evaluate plant effectiveness by enquiries among patients once treated was found to be difficult and impractical. Hence, each interviewed informant was first requested to volunteer information on the plants and their uses. Next, to avoid the risk of memory failure, a list of 50 commonly used species was read out and the informant was asked to provide information on any that were familiar to him as medicinal herbs. Of 81 plant species mentioned by our 27 informants, 41 were named or recognized by more than 3. These species were arranged in accordance with the percentage of informants suggesting the same medicinal use for a given species as compared with the total number of informants reporting any sort of use for that plant. The obtained ratio was defined as the fidelity level (FL). The rank-order priority (ROP) of the plants was derived from these FL values. The relative popularity level (RPL) of the plants encountered was determined and plants were accordingly designated as "popular" or "unpopular". FL values were further adjusted, according to RPL value. We found that the bark of Phagnalon rupestre is widely used to induce deliberate burns for the healing of various ailments (ROP = 100), while infusion of the shoots of Teucrium polium, or of Artemisia herba-alba is employed to a lesser degree (ROP = 66 and 56, respectively) to relieve stomach disorders. Because the latter two species show fairly high ROP and are seen to be directly curative, they merit further investigation. Additional findings and implications of our ethnopharmacological survey are duly discussed.

Humans↗
PubMed2004

ATP-binding cassette protein E is involved in gene transcription and translation in Caenorhabditis elegans.

ATP-binding cassette protein E (ABCE) gene has been annotated as an RNase L inhibitor in eukaryotes. All eukaryotic species show the ubiquitous presence and high degree of conservation of ABCEs, however, RNase L is present only in mammals. This indicates that ABCEs may function not only as RNase L inhibitors, but also may have other functions that have yet to be determined. As an initial investigation into the novel functions of ABCE, we characterized the gene (Y39E4B.1) in Caenorhabditis elegans by a combination of data mining and functional assays. ABCE promoters drove GFP expressions in hypoderm, pharynx, vulvae, head, and tail neurons at all developmental stages. Three genes, rpl-4, nhr-91, and C07B5.3, were previously found to interact with ABCE. Our expression data showed overlapping expression patterns of ABCE and rpl-4 and nhr-91, but not C07B5.3. RNAi against ABCE resulted in embryonic lethality and slow growth. These data suggest that ABCE protein might be involved in the control of translation and transcription, work as shuttle protein between cytoplasm and nucleus, and possibly as a nucleocytoplasmic transporter. In addition, RNAi data suggest that ABCE and NHR-91 may function in vulvae development and molting pathways in C. elegans. Furthermore, our data suggest that ABCE, along with its interacting components, functions in a well-conserved pathway.

ATP-Binding Cassette Transporters↗
PubMed2004

Analysis of the human and ape foot during bipedal standing with implications for the evolution of the foot.

The ratio of the power arm (the distance from the heel to the talocrural joint) to the load arm (that from the talocrural joint to the distal head of the metatarsals), or RPL, differs markedly between the human and ape foot. The arches are relatively higher in the human foot in comparison with those in apes. This study evaluates the effect of these two differences on biomechanical effectiveness during bipedal standing, estimating the forces acting across the talocrural and tarsometatarsal joints, and attempts to identify which type of foot is optimal for bipedal standing. A simple model of the foot musculoskeletal system was built to represent the geometric and force relationships in the foot during bipedal standing, and measurements for a variety of human and ape feet applied. The results show that: (1) an RPL of around 40% (as is the case in the human foot) minimizes required muscle force at the talocrural joint; (2) the presence of an high arch in the human foot reduces forces in the plantar musculature and aponeurosis; and (3) the human foot has a lower total of force in joints and muscles than do the ape feet. These results indicate that the proportions of the human foot, and the height of the medial arch are indeed better optimized for bipedal standing than those of apes, further suggesting that their current state is to some extent the product of positive selection for enhanced bipedal standing during the evolution of the foot.

Animals↗