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Despite evidence that microRNAs (miRNAs) are essential in modulating tumorigenesis, a major challenge in cancer treatment is to achieve tumor-specific selectivity and efficient yet safe delivery of miRNAs in vivo. In this study, we have developed a light-inducible silver nanoparticle nucleic acid delivery system that demonstrates precise spatiotemporal control, high cellular uptake, low cytotoxicity, escape from endosomes and release of functional miRNA into the cytosol. Using this approach, we delivered exogenous miR-148b to induce apoptosis in Ras-expressing keratinocytes and murine squamous cell carcinoma cells while avoiding cytotoxicity in untransformed keratinocytes. When administered to transgenic mice with HRas G12V -driven skin tumors, a single dose of silver nanoparticle conjugates followed by 415 nm LED irradiation at the tumor site caused a rapid and sustained reduction in tumor volume by 92.8%, recruited T cells to the tumor site, and acted as a potent immunomodulator by polarizing the cytokine balance toward Th1 both locally and systemically. In summary, our results demonstrate that spatiotemporal controlled miR-148b mimic delivery can promote tumor regression efficiently and safely., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

This study explores the use of differential heating of magnetic nanoparticles with different sizes and compositions (MFe 2 O 4 (M = Fe, Co)) for heteroplexed temporal controlled release of conjugated fluorophores from the surface of nanoparticles. By exploiting these differences, we were able to control the amount of hysteretic heating occurring with the distinct sets of magnetic nanoparticles using the same applied alternating magnetic field radio frequency (AMF-RF). Using thermally labile retro-Diels-Alder linkers conjugated to the surface of nanoparticles, the fluorescent payload from the different nanoparticles disengaged when sufficient energy was locally generated during hysteretic heating. 1H, 13C NMR, ESI-MS, and SIMS characterized the thermally responsive fluorescent cycloadducts used in this study; the Diels Alder cycloadducts were modeled using density functional theory (DFT) computations. The localized point heating of the different nanoparticle compositions drove the retro-Diels-Alder reaction at different times resulting in higher release rates of fluorophores from the CoFe 2 O 4 compared to the Fe 3 O 4 nanoparticles., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Differentiation of progenitors in a controlled environment improves the repair of critical-sized calvarial bone defects; however, integrating micro RNA (miRNA) therapy with 3D printed scaffolds still remains a challenge for craniofacial reconstruction. In this study, we aimed to engineer three-dimensional (3D) printed hybrid scaffolds as a new ex situ miR-148b expressing delivery system for osteogenic induction of rat bone marrow stem cells (rBMSCs) in vitro, and also in vivo in critical-sized rat calvarial defects. miR-148b-transfected rBMSCs underwent early differentiation in collagen-infilled 3D printed hybrid scaffolds, expressing significant levels of osteogenic markers compared to non-transfected rBMSCs, as confirmed by gene expression and immunohistochemical staining. Furthermore, after eight weeks of implantation, micro-computed tomography, histology and immunohistochemical staining results indicated that scaffolds loaded with miR-148b-transfected rBMSCs improved bone regeneration considerably compared to the scaffolds loaded with non-transfected rBMSCs and facilitated near-complete repair of critical-sized calvarial defects. In conclusion, our results demonstrate that collagen-infilled 3D printed scaffolds serve as an effective system for miRNA transfected progenitor cells, which has a promising potential for stimulating osteogenesis and calvarial bone repair., (Copyright © 2019 Elsevier B.V. All rights reserved.)

It is becoming more apparent in tissue engineering applications that fine temporal control of multiple therapeutics is desirable to modulate progenitor cell fate and function. Herein, the independent temporal control of the co-delivery of miR-148b and miR-21 mimic plasmonic nanoparticle conjugates to induce osteogenic differentiation of human adipose stem cells (hASCs), in a de novo fashion, is described. By applying a thermally labile retro-Diels-Alder caging and linkage chemistry, these miRNAs can be triggered to de-cage serially with discrete control of activation times. The method relies on illumination of the nanoparticles at their resonant wavelengths to generate sufficient local heating and trigger the untethering of the Diels-Alder cycloadduct. Characterization of the photothermal release using fluorophore-tagged miRNA mimics in vitro is carried out with fluorescence measurements, second harmonic generation, and confocal imaging. Osteogenesis of hASCs from the sequential co-delivery of miR-21 and miR-148b mimics is assessed using xylenol orange and alizarin red staining of deposited minerals, and quantitative polymerase chain reaction for gene expression of osteogenic markers. The results demonstrate that sequential miRNA mimic activation results in upregulation of osteogenic markers and mineralization relative to miR-148b alone, and co-activation of miR-148b and miR-21 at the same time., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: The objective of this study is to estimate optimal cut-off values for mean fetal lung volume (FLV) and pulmonary artery resistance index (PA-RI) as non-invasive measures to predict neonatal respiratory distress syndrome (RDS) in preterm fetuses., Methods: A prospective study conducted at Ain Shams University Maternity Hospital, Egypt from May 2015 to July 2017: 80 eligible women diagnosed with preterm labor were recruited at 32-36 weeks' gestation. Before delivery, three-dimensional ultrasound was used to estimate FLV using virtual organ computer-aided analysis (VOCAL), while PA-RI was measured by Doppler ultrasonography., Results: A total of 80 women were examined. Thirty-seven (46%) of the newborns developed neonatal RDS. FLV was significantly lower in neonates who developed RDS (p = .04), whereas PARI was significantly higher in those who did not (p = .02). Cut-off values of FLV ≤27.2 cm 3 and PARI ≥0.77 predicted the subsequent development of RDS. Combining both cut-offs generated a more sensitive and specific methodical approach for the prediction of RDS (sensitivity 100%, specificity 88.5%)., Conclusion: Measurement of FLV or PA-RI can predict RDS in preterm fetuses. Combined use of both measures bolstered their predictive significance.

The present study explores alternate pericyclic chemistries for tethering amine-terminal biomolecules onto silver nanoparticles. Employing the versatile tool of the retro-Diels-Alder (rDA) reaction, three thermally-labile cycloadducts are constructed that cleave at variable temperature ranges. While the reaction between furan and maleimide has widely been reported, the current study also evaluates the reverse reaction kinetics between thiophene-maleimide, and pyrrole-maleimide cycloadducts. Density Functional Theorem (DFT) calculations used to model and plan the experiments, predict energy barriers for the thiophene-maleimide reverse reaction to be greatest, and the pyrrole-maleimide barriers the lowest. Based on the computational analyses, it is projected that the cycloreversion rate would occur slowest with the thiophene, followed by furan, and finally pyrrole would yield the promptest release. These thermally-responsive linkers, characterized by Electrospray Ionization Mass Spectrometry, 1 H and 13 C NMR, are thiol-linked to silver nanoparticles and conjugate single stranded siRNA mimics with 5' fluorescein tag. Second harmonic generation spectroscopy (SHG) and fluorescence spectroscopy are used to measure release and rate of release. The SHG decay constants and fluorescence release profiles obtained for the three rDA reactions confirm the trends obtained from the DFT computations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Photothermal release of oligonucleotides from the surface of plasmonic nanoparticles represents a promising platform for spatiotemporal controlled drug delivery. Here we demonstrate the use of novel gold-silver-gold core-shell-shell (CSS) nanoparticles to study the photothermal cleaving and release of micro-RNA (miRNA) mimics or small interfering RNA (siRNA) under nearinfrared (NIR) irradiation. The furan-maleimide-based Diels-Alder adduct cleaves thermally above 60 °C and is used to bind siRNA to the colloidal nanoparticle surface in water. We investigate the photothermal cleaving kinetics of siRNA under different NIR laser powers using surface-sensitive time-dependent second-harmonic generation (SHG) spectroscopy. The photothermal release of siRNA from the surface of CSS nanoparticles is significantly higher than that from the surface of gold nanoparticles (GNPs) under similar experimental conditions. These results demonstrate that plasmonic CSS nanoparticles with photothermal cleaving linkers have important potential applications for nanoparticle-based NIR-mediated drug-delivery systems., Competing Interests: Notes The authors declare no competing financial interest.

Background/objective: This study aimed to evaluate accuracy of five-dimensional long bones (5D LB) compared to two-dimensional ultrasound (2DUS) biometry to predict fetal weight among normal term women., Methods: Fifty six normal term women were recruited at Ain Shams Maternity Hospital, Egypt from 14 May to 30 November 2015. Fetal weight was estimated by Hadlock's IV formula using 2DUS and 5D LB. Estimated fetal weights (EFW) by 2DUS and 5D LB were compared with actual birth weights (ABW)., Results: Mean femur length (FL) was 7.07 ± 0.73 cm and 6.74 ± 0.67 cm by 2DUS and 5D LB (p = .02). EFW was 3309.86 ± 463.06 g by 2DUS and 3205.46 ± 447.85 g by 5D LB (p = .25). No statistical difference was observed between ABW and EFW by 2DUS (p = .7) or 5D LB (p = .45). Positive correlation was found between EFW by 2DUS, 5D LB, and ABW (r = 0.67 and 0.7; p < .001). There was strong agreement between FL measured by 2DUS and 5D LB (ICC = 0.78), and perfect agreement between EFW by 2DUS and EFW by 5D LB (ICC = 0.918). 2DUS and 5D LB showed mean absolute percentage error for EFW of 10 ± 7% and 8 ± 7% compared to ABW (p = .15)., Conclusions: 2DUS and 5D LB had same accuracy for fetal weight estimation at normal term pregnancy.

Background: In spite of the progress made in neoadjuvant therapy for operable non small-cell lung cancer (NSCLC), many issues remain unsolved, especially in locally advanced stage IIIA., Methods: Retrospective data of 163 patients diagnosed with stage IIIA NSCLC after surgery was analyzed. The patients were divided into two groups: a preoperative chemotherapy group including 59 patients who received platinum-etoposide doublet treatment before surgery, and an upfront surgery group including 104 patients for whom surgical resection was the first treatment step. Adjuvant chemotherapy or/and radiotherapy was administered to 139 patients (85.3%), while 24 patients (14.7%) were followed-up only., Results: The rate of N2 disease was significantly higher in the upfront surgery group ( P  < 0.001). The one-year relapse rate was 49.5% in the preoperative chemotherapy group compared to 65.4% in the upfront surgery group. There was a significant difference in relapse rate in relation to adjuvant chemotheraphy treatment ( P  = 0.007). The probability of relapse was equal whether radiotherapy was applied or not ( P  = 0.142). There was no statistically significant difference in two-year mortality ( P  = 0.577). The median survival duration after two years of follow-up was 19.6 months in the preoperative chemotherapy group versus 18.8 months in the upfront surgery group ( P  = 0.608 > 0.05)., Conclusion: There was significant difference in preoperative chemotherapy group regarding relapse rate and treatment outcomes related to the lymph node status comparing to the upfront surgery group. Neoadjuvant/adjuvant chemo-therapy is a part of treatment for patients with stage IIIA NSCLC, but further investigation is required to determine optimal treatment., (© 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

The photocleaving dynamics of colloidal microRNA-functionalized nanoparticles are studied using time-dependent second harmonic generation (SHG) measurements. Model drug-delivery systems composed of oligonucleotides attached to either silver nanoparticles or polystyrene nanoparticles using a nitrobenzyl photocleavable linker are prepared and characterized. The photoactivated controlled release is observed to be most efficient on resonance at 365 nm irradiation, with pseudo-first-order rate constants that are linearly proportional to irradiation powers. Additionally, silver nanoparticles show a 6-fold plasmon enhancement in photocleaving efficiency over corresponding polystyrene nanoparticle rates, while our previous measurements on gold nanoparticles show a 2-fold plasmon enhancement compared to polystyrene nanoparticles. Characterizations including extinction spectroscopy, electrophoretic mobility, and fluorimetry measurements confirm the analysis from the SHG results. The real-time SHG measurements are shown to be a highly sensitive method for investigating plasmon-enhanced photocleaving dynamics in model drug delivery systems.

Objective: This study aimed to investigate the effect of endometrial injury using Pipelle catheter in the follicular phase (cycle day 5, 6, or 7) of the stimulation cycle on pregnancy rates in patients undergoing intrauterine insemination., Methods: This prospective randomized controlled study was carried out in the Assisted Reproductive Technology Unit of Ain Shams University Maternity Hospital, Cairo, Egypt, from July 1, 2013 to August 31, 2015. Three hundred sixty women, 20 to 35 years of age, with patent fallopian tubes, mild male factor infertility, or unexplained infertility were recruited. Participants were allocated randomly into 2 groups: experimental arm and control arm. Women in the experimental arm underwent endometrial biopsy using a Pipelle catheter on day 5, 6, or 7 of the stimulation cycle combined with intrauterine insemination. Women in the control group underwent intrauterine insemination with no endometrial biopsy done. The primary outcomes were the clinical and chemical pregnancy rates., Results: Data of 344 participants were statistically analyzed. The chemical pregnancy rate was 23.66% in the experimental arm and 10.85% in the control arm (P = .002). The clinical pregnancy rate was 18.93% in the experimental arm and 7.42% in the control arm (P = .003)., Conclusion: Endometrial injury using a Pipelle catheter in the stimulation cycle may improve pregnancy rates in women undergoing intrauterine insemination., (© The Author(s) 2016.)

Objective: To study the efficacy of 100 μg intravenous shot of carbetocin compared to 20 IU oxytocin intravenous infusion to prevent placental retention in second trimester medical termination of pregnancy., Methods: A double-blinded randomized controlled trial was conducted at Ain Shams University Maternity Hospital from 1 April 2013 to 30 November 2013. A total of 132 women between 14 and 24 weeks gestation indicated for termination were randomized to receive either 20 IU oxytocin infusion (n = 66) or 100 μg carbetocin shot (n = 66) after fetal expulsion. Patients were observed for time elapsed between fetal and placental expulsion, presence of placental retention and blood loss., Results: Third stage was 33.4 ± 20.4 min in oxytocin group & 23.1 ± 16.8 min in carbetocin group (p = 0.002). Eight patients (12.1%) in oxytocin group had complete placental retention versus two patients (3.0%) in carbetocin group (p = 0.05). Eight patients (13.8%) received oxytocin had remnants of placenta compared to four patients (6.2%) received carbetocin (p = 0.04). Sixteen patients (24.2%) received oxytocin and six patients (9%) received carbetocin needed surgical curettage (p = 0.04). Third stage blood loss was 87.2 ± 33.7 ml in carbetocin and 206.9 ± 35.2 ml in oxytocin groups (p = 0.001)., Conclusion: Carbetocin is superior to oxytocin infusion for management of placental delivery in second trimester abortion.

The aim is to compare hysteroscopy, two-dimensional transvaginal ultrasound (2D TVUS), and three-dimensional (3D) Virtual Organ Computer-aided AnaLysis™ (VOCAL) to detect endometrial polyps (EPs) in premenopausal women with abnormal uterine bleeding (AUB). This prospective study was done at Ain Shams Maternity Hospital, Egypt, from March 5, 2015, to December 30, 2015, enrolling 118 premenopausal women with AUB. 2D TVUS, 3D VOCAL, and hysteroscopy were done. 109 patients reached final analysis. 36 women (33%) were diagnosed with EP by 2D TVUS. 50 (45.9%) had EP by hysteroscopy. Endometrial thickness was 10.1 mm by 2D TVUS and endometrial volume was 4.92 mL by VOCAL in women with EP by hysteroscopy compared to 9.9 mm and 3.50 mL in women with no EP, respectively ( P = 0.223; P = 0.06). 2D TVUS has sensitivity, specificity, and positive and negative predictive values of 54%, 84.7%, 75%, and 68.5%, respectively. Endometrial thickness of >7.5 mm has sensitivity, specificity, positive and negative predictive values, and overall accuracy of 82%, 37.3%, 52.6%, 71%, and 57.8%, respectively. Endometrial volume of >1.2 mL has sensitivity, specificity, positive and negative predictive values, and overall accuracy of 90%, 42.4%, 57%, 83.3%, and 64.2%, respectively. 3D VOCAL may be used as a noninvasive method for the diagnosis of EP in premenopausal women with AUB., Competing Interests: All authors declare no competing interests.

Objective: The aim of this study was to estimate the accuracy of prenatal assessment of interventricular septum (IVS) thickness, right myocardial wall thickness (RMWT), and left myocardial wall thickness (LMWT) by two-dimensional (2D) ultrasound for the prediction of perinatal mortality and postnatal diagnosis of hypertrophic cardiomyopathy (HCM) among diabetic pregnant women., Subjects and Methods: A total of 120 diabetic pregnant women at 35 weeks or more were enrolled in this study from January 1, 2012, to June 30, 2014, at Ain Shams Maternity Hospital, Cairo, Egypt. The 2D ultrasound was done once for all the participants at the time of recruitment; IVS thickness, RMWT, and LMWT were measured. The glycosylated hemoglobin (HbA1c) levels of the participants were recorded. Neonatal assessment including postnatal echocardiography was done after 48 hours. Postnatal results were compared with the prenatal predictive results., Results: Higher thickness values for IVS, RMW, and LMW were obtained in the uncontrolled diabetic cases (HbA1c > 6.5%) than in the controlled diabetic cases (HbA1c < 6.5%; P < 0.01). Of the included 120 neonates, 10 (8.3%) were stillborn, 99 (82.5%) had a five-minute Apgar score ≥7, and 4 (3.3%) had a five-minute Apgar score ≤3. The four neonates with severe neonatal distress died after admission to neonatal intensive care unit within one week after delivery. Out of 110 live-born neonates, 4 (3.6%) neonates had a low ejection fraction (EF) (<50%) due to HCM; of them 2 (1.8%) died within one week after delivery, while 2 (1.8%) survived. Another two (1.8%) neonates died from severe respiratory distress syndrome. A cutoff value of ≥4.5 mm for prenatal IVS thickness was predictive of neonatal distress due to HCM with a sensitivity of 82%, specificity of 68%, and diagnostic accuracy of 72%. A cutoff value of <1.18 for the ratio of IVS thickness to LMWT had a sensitivity of 82%, specificity of 72%, and diagnostic accuracy of 74% for the prediction of neonatal distress due to HCM. In this study, 8 of the 10 fetuses with intrauterine demise and the 2 neonates who died within one week after delivery due to heart failure had a prenatal IVS thickness of ≥4.5 mm, while 7 of the 10 fetuses with intrauterine demise and the 2 neonates who died postnatal from heart failure had a prenatal IVS thickness to LMWT ratio of ≤1.18., Conclusion: A prenatal IVS thickness of ≥4.5 mm or an IVS/LMWT ratio of ≤1.18 seems to be predictive of HCM and is associated with almost twofold higher risk of intrauterine fetal death and almost threefold higher risk of possibly relevant perinatal mortality.

Photoactivated drug delivery systems using gold nanoparticles provide the promise of spatiotemporal control of delivery that is crucial for applications ranging from regenerative medicine to cancer therapy. In this study, we use second harmonic generation (SHG) spectroscopy to monitor the light-activated controlled release of oligonucleotides from the surface of colloidal gold nanoparticles. MicroRNA is functionalized to spherical gold nanoparticles using a nitrobenzyl linker that undergoes photocleaving upon ultraviolet irradiation. The SHG signal generated from the colloidal nanoparticle sample is shown to be a sensitive probe for monitoring the photocleaving dynamics in real time. The photocleaving irradiation wavelength is scanned to show maximum efficiency on resonance at 365 nm, and the kinetics are investigated at varying irradiation powers to demonstrate that the nitrobenzyl photocleaving is a one-photon process. Additional characterization methods including electrophoretic mobility measurements, extinction spectroscopy, and fluorimetry are used to verify the SHG results, leading to a better understanding of the photocleaving dynamics for this model oligonucleotide therapeutic delivery system.

Objective: To develop reference cutoff values for mean fetal lung volume (FLV) and pulmonary artery resistance index (PA-RI) for prediction of neonatal respiratory distress syndrome (RDS) in low-risk term pregnancies., Methods: As part of a cross-sectional study, women aged 20-35 years were enrolled and admitted to a tertiary hospital in Cairo, Egypt, for elective repeat cesarean at 37-40 weeks of pregnancy between January 1, 2012, and July 31, 2013. FLV was calculated by virtual organ computer-aided analysis, and PA-RI was measured by Doppler ultrasonography before delivery., Results: A total of 80 women were enrolled. Neonatal RDS developed in 11 (13.8%) of the 80 newborns. Compared with neonates with RDS, healthy neonates had significantly higher FLVs (P<0.001) and lower PA-RIs (P<0.001). Neonatal RDS is less likely with FLV of at least 32 cm(3) or PA-RI less than or equal to 0.74. Combining these two measures improved the accuracy of prediction., Conclusion: The use of either FLV or PA-RI predicted neonatal RDS. The predictive value increased when these two measures were combined., (Copyright © 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

The role of Bcl-2 in initiation and progression of endometrial carcinoma is still with inconsistent results. The aim of this study is to determine the role of Bcl-2 in endometrial tumorigenesis. It is a retrospective cross sectional study. We used 100 endometrial paraffin embedded specimens for Bcl-2 oncoprotein immunohistochemical staining; 20 samples of normal endometrium, 40 specimens of endometrial hyperplasia (simple, complex and atypical) and 40 specimens of endometrioid adenocarcinoma. The results were statistically analyzed. There was a significant increase in Bcl-2 staining from normal through complex and atypical hyperplasia into well differentiated adenocarcinoma ( P =0.002, P =0.0008 and P =0.0001, respectively). There was a significant difference between the staining of different types of endometrial hyperplasia; as it up streamed from the simple through the complex up to the atypical types ( P <0.05). Bcl-2 staining showed no significant correlation with the moderately, poorly differentiated and the different stages of adenocarcinoma ( P =0.6, P =0.29 and P =0.1 respectively). These results might indicate a substantial role for Bcl-2 as one of the initiating drives for endometrial tumorigenesis, but not in further tumor progression.

Objective: Placenta accreta is a general term describes abnormal adherent placenta to the uterine wall. When the chorionic villi invade the myometrium, the term placenta increta is appropriate. Nowadays, it is one of the increasing causes of materno-fetal morbidities and mortality. The aim of this research was to evaluate density of decidual natural killer cells (dNK, CD56+(bright)) in decidua basalis in patients with placenta accreta., Study Design: We recruited 76 patients from Ain Shams Maternity Hospital between June 2012 to August 2013, they were divided into study subgroup (A) which included 10 patients who underwent cesarean hysterectomy due to unseparated placenta accreta, study subgroup (B) included 16 patients with separated placenta accreta, a comparison group included 25 patients with placenta previa and a control group included 25 patients with normally situated placenta. All patients underwent elective cesarean delivery. Decidual biopsies were taken during the operation. An immunohistochemical staining for (dNK, CD56+(bright)) and a semi quantitative scoring were done. One-way ANOVA and Fisher Exact tests were used for statistical correlation., Results: The mean dNK cells scores were (0.4±0.5, 1.9±1, 3.3±0.5 and 3.5±0.5) for study subgroups (A), (B) comparison and control groups respectively) with a highly significant statistical difference (P<0.001). There was a significant statistical difference between study subgroups (A) and (B) P=0.002 .There was an insignificant statistical correlation between dNK scores and number of previous uterine scars (P=0.46)., Conclusion: These findings suggest that low dNK score was associated with cases of morbidly adherent placenta accreta., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate endometrial and ovarian effects, and bleeding patterns, among users of Depo-Provera(®), Norplant(®), and Implanon(®)., Study Design: One-hundred and fifty women, who had been using one of these long-acting progestin-only contraceptives (LAPCs) for at least the previous six months, with fifty in each of the groups, were assessed., Results: All results are mentioned in the following sequence: (1) Depo-Provera(®), (2) Norplant(®), and (3) Implanon(®). Normal bleeding was reported by 0%, 52%, and 8%; amenorrhoea or infrequent bleeding by 68%, 24%, and 72%; and abnormal bleeding by 32%, 24%, and 20%, respectively (p < 0.001). Histological evaluation revealed an atrophic endometrium in 84%, 32%, and 28%, respectively (p < 0.0001); a progestin effect in 16%, 28%, and 62%, respectively (p < 0.0001), and a proliferative pattern in 0%, 40%, and 10%, respectively (p < 0.0001). Endometrial thickness was 3 ± 0.41 mm, 3.62 ± 0.65 mm, and 5.2 ± 0.84 mm, respectively (p < 0.0001). Follicular growth in the ovaries was observed at ultrasound in 12%, 40%, and 72%, respectively (p < 0.001)., Conclusion: Bleeding patterns, endometrial thickness, ovarian activity, and endometrial histology among Egyptian users of LAPCs differed significantly depending on the nature of the contraceptive.

Nonviral vectors present considerable advantages over viral counterparts in gene transfer. However, the poor expression efficiency of the transfected genes poses a challenge for their use in gene therapy, primarily due to the inability of these vectors to overcome various barriers, including the biological barriers. Here, we report that ZNF511-PRAP1 may be involved in the recognition and inactivation of transfected plasmids. ZNF511-PRAP1 is induced by transfection of plasmid DNA and suppresses the transcription of transfected plasmids. It binds directly to the p21 promoter in transfected plasmids but not the endogenous counterpart. Similarly, ZNF511-PRAP1 suppresses the expression of the green fluorescent protein reporter gene on transiently transfected plasmids but not an integrated red fluorescence reporter gene with the same cytomegalovirus (CMV) promoter. Therefore, ZNF511-PRAP1 is able to differentiate between exogenous/nonintegrated and endogenous/integrated DNA. The suppression by ZNF511-PRAP1 is independent of DNA methylation and can be abolished by trichostatin A (TSA) treatment and knockdown of HDAC2 and/or ZNF511-PRAP1. Furthermore, ZNF511-PRAP1 interacts directly with HDAC2. Our results revealed that transfected plasmids are recognized by ZNF511-PRAP1 and suppressed by a repressor complex comprising ZNF511-PRAP1 and HDAC2 and suggest that ZNF511-PRAP1 could play a role as a potential molecular barrier in nonviral transgene expression.

Palladin is a scaffold protein involved in the formation of actin-associated protein complexes. Gene expression array analysis on the poorly metastatic HCT116 colon cancer cell line and a metastatic derivative cell line (E1) with EMT (epithelial-mesenchymal transition) features showed a down-regulation of palladin gene expression in the latter. Knockdown of palladin expression in the HCT116 cells suppressed junctional localization of E-cadherin, reduced intercellular adhesion and collective cell migration, showing that palladin plays an important role in maintaining the integrity of adherens junctions. The acquisition of the EMT features by the E1 cell line was dependent on the Erk pathway. Inhibition of this pathway by U0126 treatment in E1 cells resulted in the re-expression of palladin, relocalization of E-cadherin to the adherens junctions and a reversal of EMT features. The re-establishment of intercellular adhesion was dependent on palladin expression. The down-regulation of palladin was also observed in poorly-differentiated tumor tubules and dissociated tumor cells that have undergone de-differentiation in human primary colon tumors. Our data show that palladin is an integral component of adherens junctions and plays a role in the localization of E-cadherin to the junctions. The loss of palladin may be an integral part of EMT, an early step in the metastatic spread of colon carcinoma.

Objective: To find the pattern of idiopathic thrombocytopenic purpura (ITP) (acute/chronic) and to describe presenting features and clinical characteristics of the disease in children below 14 years of age in a newly developed Arabian society., Methods: This retrospective, descriptive study was carried out at the Pediatric Department of the Hamad General Hospital, Hamad Medical Corporation, Qatar. A total of 50 children below 14 years of age who were diagnosed with ITP during the period 2000-2005 were included., Results: Among the studied children (50), 62% were diagnosed with acute ITP and 38% with chronic ITP. Acute ITP was more prevalent in boys (64.5%) when compared with girls (35.5%), whereas for chronic ITP, nearly an equal distribution was found in boys (57.9%) and girls (42.1%). Preceding viral infection was common in both acute (71%) and chronic (63.2%) ITP cases; 68% of the children with ITP showed a platelet count below 20x10(9)/L at the time of presentation. Most of the studied children were treated with intravenous immunoglobulin (74%)., Conclusions: The study revealed a high incidence of ITP among children in Qatar. The study findings are in line with other international reports.

Successful tumor development and progression involves the complex interplay of both pro- and anti-oncogenic signaling pathways. Genetic components balancing these opposing activities are likely to require tight regulation, because even subtle alterations in their expression may disrupt this balance with major consequences for various cancer-associated phenotypes. Here, we describe a cassette of cancer-specific genes exhibiting precise transcriptional control in solid tumors. Mining a database of tumor gene expression profiles from six different tissues, we identified 48 genes exhibiting highly restricted levels of gene expression variation in tumors (n = 270) compared to nonmalignant tissues (n = 71). Comprising genes linked to multiple cancer-related pathways, the restricted expression of this "Poised Gene Cassette" (PGC) was robustly validated across 11 independent cohorts of approximately 1,300 samples from multiple cancer types. In three separate experimental models, subtle alterations in PGC expression were consistently associated with significant differences in metastatic and invasive potential. We functionally confirmed this association in siRNA knockdown experiments of five PGC genes (p53CSV, MAP3K11, MTCH2, CPSF6, and SKIP), which either directly enhanced the invasive capacities or inhibited the proliferation of AGS cancer cells. In primary tumors, similar subtle alterations in PGC expression were also repeatedly associated with clinical outcome in multiple cohorts. Taken collectively, these findings support the existence of a common set of precisely controlled genes in solid tumors. Since inducing small activity changes in these genes may prove sufficient to potently influence various tumor phenotypes such as metastasis, targeting such precisely regulated genes may represent a promising avenue for novel anti-cancer therapies., Competing Interests: The authors have declared that no competing interests exist.

There is a paucity of information on the molecular basis of beta-thalassemia (thal) in Qatar, a country in the southern part of the Arabian Gulf. To decipher the molecular spectrum of beta- thalassemic alleles present in Qatar, we studied 31 clinically recognized patients, including three with sickle cell disease and beta-thal, and an additional six cases referred for unexplained microcytic anemia. We found 12 different beta-thalassemic alleles and two yet to be defined alleles, mutations likely occurring elsewhere than in the beta-globin gene per se. This is quite striking, given the small size of the study population, and highlights not only the ethnic diversity, but also the necessity of further investigating the thalassemic spectrum.

The CCAAT/enhancer binding protein alpha (C/EBPalpha) is vital for establishing normal hepatic energy homeostasis and moderating hepatocellular growth. CEBPA loss-of-function mutations identified in acute myeloid leukemia patients support a tumor suppressor role for C/EBPalpha. Recent work showed reductions of C/EBPalpha levels in human hepatocellular carcinoma with the reductions correlating to tumor size and progression. We investigated the potential of reactivating c/ebpalpha expression during hepatic carcinogenesis to prevent tumor cell growth. We have developed a c/ebpalpha knock-in mouse in which a single-copy c/ebpalpha is regulated by one allele of the alpha-fetoprotein (AFP) gene promoter. The knock-in mice are physically indistinguishable from wild-type (WT) controls. However, knock-in animals were found to deposit fetal hepatic glycogen earlier than WT animals. Quantitative real-time PCR confirmed early c/ebpalpha expression and early glycogen synthase gene activation in knock-in fetuses. We then used diethylnitrosamine to induce hepatocellular carcinoma in our animals. Diethylnitrosamine produced half the number of hepatocellular nodules in knock-in mice as in WT mice. Immunohistochemistry showed reduced C/EBPalpha content in WT nodules whereas knock-in nodules stained strongly for C/EBPalpha. The p21 protein was examined because it mediates a C/EBPalpha growth arrest pathway. Nuclear p21 was absent in WT nodules whereas cytoplasmic p21 was abundant; knock-in nodules were positive for nuclear p21. Interestingly, only C/EBPalpha-positive nodules were positive for nuclear p21, suggesting that C/EBPalpha may be required to direct p21 to the cell nucleus to inhibit growth. Our data establish that controlled C/EBPalpha production can inhibit liver tumor growth in vivo.

Can the paravertebral plexus of veins adjacent to the spinal nerve root within the narrow confines of the lateral neural canal be a collateral generator of radicular pain when no other evidence of spinal pathology is evident? A patient with complaints of intractable lumbar radiculopathy and an otherwise unremarkable clinical neuromusculoskeletal examination, as well as normal imaging and electrodiagnostic studies, is reviewed with special reference to symptomatic and paravertebral venous responses to both a Valsalva maneuver and dipyridamole infusion as imaged by magnetic venous angiography.

Cytokines have been reported to be potential biological markers of, disease status in cancer patients. Tumor necrosis factor-alpha (TNF-alpha) is a key cytokine released from monocytes and macrophages. TNF-alpha is involved in essential biological functions such as immunoregulation, modulation of cell growth and differentiation. In this work, the role of TNF-alpha release in ovarian cancer patients was investigated. Fifty-five patients with ovarian cancer and 20 controls of matched age and parity were included in this study. TNF-alpha concentrations were measured in sera and cytosolic fractions of both groups. The results demonstrated a significant increase in TNF-alpha concentrations among patients compared to the control subjects (P < 0.001). Furthermore, a non-significant increase (P = 0.05, was observed between the different types (serous, Mucinous, and endometrioid) of epithelial ovarian cancers. Also TNF-alpha concentrations did not correlate with the disease stage. Moreover, immunohistochemical analysis of tissue specimens stained for TNF-alpha was positive in malignant lesions and negative for the normal ovarian tissue. These findings confirmed the TNF-alpha kinetics obtained by ELISA assays. Interestingly, TNF-alpha levels were also elevated in culture supernatants of PBMC stimulated by cytosolic fractions from malignant ovarian tissues. Blastogenic assays using cytosolic fractions from malignant ovarian specimens to stimulate healthy donor peripheral blood mononuclear cells (PBMC) showed a marked decrease in 3H-thymidine uptake compared to the cells stimulated by normal cytosols. To establish a cause-effect relationship between TNF-alpha release and inhibition of cell proliferation, the experiments showed that 3H-thymidine uptake by PBMC was markedly inhibited by recombinant human TNF-alpha (rh TNF-alpha) and that inhibition was significantly reversed when TNF-alpha monoclonal antibody was added to the cells. The data presented in this work indicate that TNF-alpha may play an important role in the biology of ovarian cancer and hence, tumor pathogenesis.

Paraspinal muscle metastasis as initially suggested by an electromyographic pattern of isolated posterior primary ramus denervation and subsequently confirmed by magnetic resonance imaging has been reported. However, despite widespread systemic tumor dissemination, metastases to other skeletal muscle occurs infrequently. Uniquely, the paraspinal muscles are drained by the paravertebral plexus of veins. Valveless and at very low pressures, they communicate directly by collaterals with the portal system. Valsalva maneuvers with sudden increases of pressure within the intra-abdominal and intrathoracic cavities can force venous blood from the systemic circulation into the paravertebral plexus of veins. These same venous surges potentially carry tumor emboli to the vertebrae and/or from the vertebral medulla to the adjacent paravertebral muscle by the venous communicators. The inherent increased vascularity of metastatic tumor relative to the surrounding paraspinal muscle as demonstrated by magnetic venous angiography for the first time now permits earlier confirmation and biopsy of the electromyographic-suspected metastatic lesion. In this reported instance of a magnetic resonance imaging-recognized primary lung metastasis confirmed by magnetic resonance venography, there is the future promise of identifying earlier and smaller lesions by this technique.

The interdisciplinary approach to the management of MS patients includes the services of both physical and occupational therapy. These professions complement one another in their concerted effort to mobilize the patient, thereby minimizing the symptoms of progressive weakness, fatigue, and spasticity. The ambulant patient is far less likely to develop complications of inactivity such as contractures, decubitus ulcers, venous thrombosis, or osteoporosis (with its associated fatigue fractures), as well as bowel or bladder complications.

This current review is intended to provide a brief overview of the major design and psychometric issues inherent in the development of psychological instruments to assess human sexual functioning. Particular emphasis has been placed on those issues which derive from the implementation of psychological tests as outcomes measures in clinical trials. Cardinal psychometric parameters are identified and reviewed, as are supplementary measurement criteria. Five specific psychological instruments are recommended and discussed, and each instrument's design characteristics, psychometric evaluation, and program of validation is briefly reviewed and evaluated.

Objective: Analysis, results, and implications of a supply and demand workforce model for physical medicine and rehabilitation. Explicit issues addressed include: (1) the supply implications of maintaining current (1994-1995) output of physiatrists from residency programs; (2) the implications of continued growth in managed care on the demand for the services of physiatrists; (3) likely future supply and demand conditions; and (4) strategies to adapt to future conditions., Design: A workforce model of the supply and demand for physiatrists was developed. Parameters of the model are estimated using econometric models and by applying the judgments of a consensus panel. The model evaluated several different scenarios regarding managed care growth, competition from other providers and other factors., Results: Based on the analysis, physiatrists will continue to be in excess demand through the year 2000. More aggressive growth in managed care can affect this result., Conclusions: Based on an overall assessment of supply and demand conditions, and under the assumption that the supply of new entrants each year remains in the range of 1994-1995 levels, demand for physiatrists will continue to exceed supply, on average, through the year 2000. Excess supply has, and will, emerge in selected geographic areas. If the profession is successful in informing the market regarding the advantages of physiatry, the profession can continue to grow without experiencing excess supply, in the aggregate, for the foreseeable future.

The prognosis in ovarian cancer patients remains poor, and there is a need to identify patients who are less likely to respond to treatment. In a prospective study of patients with ovarian carcinoma treated by a standard protocol, variables such as age, tumor type, International Federation of Gynecology and Obstetrics stage, histologic grade, results from flow cytometry, receptors for estrogen (ER) and progesterone (PR), and serum CA 125 were correlated to relapse and survival. Univariate analysis revealed that stage, histologic grade, DNA ploidy, ER, PR, and CA 125 were of significant association to survival, but only stage, DNA ploidy, PR, and CA 125 were found to be of significant value to relapse. Multivariate analysis identified DNA ploidy as an independent prognostic variable for both relapse and survival.

Anorexia nervosa (AN) is a chronic eating disorder characterized by self-imposed semi-starvation that affects 1% of adolescent females. AN predisposes to osteoporosis through hypothalamic dysfunction, which may lead to elevated cortisol as well as diminished estrogen and progesterone. The osteoporosis associated with AN affects both trabecular and cortical bone and increases the risk of osseous fracture. Fractures in this population may go unrecognized, because planar X-rays may be nondiagnostic for 6 weeks or more. Four women with AN ranging in ages from 22 to 34 with skeletal pain and nondiagnostic roentgenographs are described. Stress fractures in these patients were subsequently identified by bone scan. Although moderate exercise in patients with AN-associated osteoporosis may be beneficial, strenuous exercise can be detrimental, with its potential risk of stress fractures and exacerbation of the underlying neurohormonal abnormalities. This risk for fracture may persist well after improvement in the patient's AN.

Although the mechanical and positional stresses of pregnancy are the primary inciting factors contributing to lumbosacral pain accompanying gestation, in approximately 1:10,000 cases a herniated disk (HNP) can be identified as the proximal cause of pain. Six patients are described, all of whom without antecedent history of pain presented with acute, disabling, gestational lumbosacral, and sciatic radiculopathy. Their ages ranged from 29 to 36, their parity from 0 to 1, and their gestational age at onset of symptoms from 6 weeks to 32 weeks. Each by magnetic resonance imaging (MRI) was identified as having an HNP, 2 at the L4-5 level and 4 at the L5-S1 level. During pregnancy, an MRI evaluation permits a detailed spinal examination without the ionizing effects of x-ray and its acknowledged biological risk to the developing fetus. This potential for an immediate and accurate diagnosis has significant implications for the management and subsequent planning of delivery.

Lumbosacral pain is a significant complaint in approximately one-half of all pregnancies. In 15%, the pain can be disabling. Although the mechanical and positional stresses of pregnancy have been cited as the primary source of this discomfort, in approximately 1:10,000 cases a herniated lumbar disc (HNP) can be identified as the proximal cause of pain. A 35-yr-old G4AB3PO patient presenting at 10 wk of pregnancy with severe incapacitating lumbar radiculopathy is described. Magnetic resonance imaging, selected by the patient as a diagnostic option, demonstrated a clinically suspected large midline HNP at the L5-S1 level. In the past, visualizing the presence of a HNP during pregnancy by either computerized axial tomography scan or myelography has exposed the fetus to ionizing radiation. However, magnetic resonance imaging now permits a more detailed evaluation without similar x-ray exposure. To date, no recognized biologic effect of MRI on the developing fetus has been reported. Although the long-term effects of an magnetic resonance imaging on the developing fetus have not been conclusively evaluated, its potential for accurate diagnosis and subsequent patient management, as well as planning the delivery, appears to outweigh any recognized hazard to the developing fetus.