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The availability of robust protocols to differentiate induced pluripotent stem cells (iPSCs) into many human cell lineages has transformed research into the origins of human disease. The efficacy of differentiating iPSCs into specific cellular models is influenced by many factors including both intrinsic and extrinsic features. Among the most challenging models is the generation of human bronchial epithelium at air-liquid interface (HBE-ALI), which is the gold standard for many studies of respiratory diseases including cystic fibrosis. Here, we perform open chromatin mapping by ATAC-seq and transcriptomics by RNA-seq in parallel, to define the functional genomics of key stages of the iPSC to HBE-ALI differentiation. Within open chromatin peaks, the overrepresented motifs include the architectural protein CTCF at all stages, while motifs for the FOXA pioneer and GATA factor families are seen more often at early stages, and those regulating key airway epithelial functions, such as EHF, are limited to later stages. The RNA-seq data illustrate dynamic pathways during the iPSC to HBE-ALI differentiation, and also the marked functional divergence of different iPSC lines at the ALI stages of differentiation. Moreover, a comparison of iPSC-derived and lung donor-derived HBE-ALI cultures reveals substantial differences between these models., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objectives/hypothesis: Patients with olfactory dysfunction benefit from repeated exposure to odors, so-called olfactory training (OT). This does not mean occasional smelling but the structured sniffing of a defined set of odors, twice daily, for a period of 4 months or longer. In this prospective study, we investigated whether the effect of OT might increase through the use of more odors and extension of the training period., Study Design and Methods: This study shows OT results when performed with four or 12 odors for 36 weeks in patients with postinfectious olfactory dysfunction. A total of 85 subjects participated (mean age 45.6 ± 10.5 years, range 24-68 years). Three groups were formed: 1) In the modified olfactory training (MOT) group, patients used three sets of four different odors sequentially. 2) Participants in the classical odor training (COT) group used four odors. 3) Participants in the control group did not perform OT. All groups were matched for age and sex distribution of participants., Results: Both participants in the COT and MOT groups reached better scores than controls in terms of odor discrimination and odor identification. Continuing OT with four different odors after the 12th and 24th weeks produced better results in terms of odor discrimination and odor identification scores as compared to using the same four odors throughout the entire study., Conclusion: This study confirmed the effectiveness of OT. Increasing the duration of OT and changing the odors enhances the success rate of this therapy., Level of Evidence: 2b. Laryngoscope, 125:1763-1766, 2015., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: The aims of this study were to evaluate atrial electromechanical delay, inflammation, and oxidative stress parameters, along with to investigate clinical and laboratory characteristics affecting atrial electromechanical delay in patients with chronic obstructive pulmonary disease (COPD)., Methods: Forty-three patients with COPD (60.5 ± 9.9 years) and 50 healthy controls (59.6 ± 7.1 years) were included in the study. Atrial electromechanical delay intervals were measured from lateral mitral annulus corrected PA (cPA lateral) and lateral tricuspid annulus (cPA tricuspid) using tissue Doppler imaging (TDI), and corrected for heart rate. Left and right ventricles functions were examined using conventional and TDI. Plasma levels of high-sensitive C-reactive protein (hsCRP) and oxidative stress parameters were also measured. Factors associated with atrial electromechanical delay were evaluated by stepwise multiple regression analysis., Results: Corrected PA lateral and cPA tricuspid were significantly higher in patients with COPD (69.8 ± 10.4 vs. 62.2 ± 8.9 msec, P < 0.001 and 45.4 ± 10.2 vs. 33.5 ± 5.1 msec, P < 0.001, respectively). Plasma levels of hsCRP and malondialdehyde, an indicator of oxidative stress, were increased in patient's group (15.7 ± 31.7 vs. 4.8 ± 4.7 mg/L, P = 0.01 and 17.1 ± 10.3 vs. 11.6 ± 7.9 nmol/L, P = 0.005, respectively). cPA lateral is independently related to lateral Em /Am ratio (β = -0.29, P = 0.004) and forced expiratory volume in 1st second/forced vital capacity (FEV1 /FVC) ratio (β = -0.24, P = 0.02). cPA tricuspid is independently related to only FEV1 /FVC ratio (β = -0.51, P < 0.001)., Conclusions: This study shows that atrial electromechanical delay intervals are prolonged in patients with COPD. Prolongation of atrial electromechanical delay measured from lateral tricuspid annulus was independently related with FEV1 /FVC ratio in these patients., (© 2013, Wiley Periodicals, Inc.)

Aim: Hyperthyroidism is a well-known cause of atrial fibrillation (AF) which is associated with increased morbidity and mortality. Atrial electromechanical delay (EMD) is a significant predictor of AF. The aim of this study was to assess the atrial EMD and diastolic functions in subclinical and overt hyperthyroidism by using tissue Doppler imaging (TDI)., Methods and Results: The study population consisted of 3 groups: group I (30 healthy subjects), group II (38 patients with subclinical hyperthyroidism), and group III (25 patients with overt hyperthyroidism). Atrial electromechanical coupling was measured with TDI. Standard echocardiographic measurements and parameters of diastolic function were obtained by conventional echocardiography and TDI. Intra- and inter-atrial EMD were significantly prolonged in subclinical and overt hyperthyroidism compared with control group (P = 0.03 and P < 0.001 for intra-atrial EMD; P < 0.001 for inter-atrial EMD). In groups II and III, mitral A velocity (P = 0.005 and P = 0.001) and mitral E-wave deceleration time (P < 0.001 and P = 0.02) were significantly increased, and mitral E/A ratio (P = 0.005 and P = 0.001) was significantly decreased compared with the control group. The lateral mitral Em /Am ratio in group II and group III was significantly lower than controls (P = 0.001). Mitral Em /Am ratio (β = -0.32, P = 0.002) and thyroid stimulating hormone (TSH) level (β = -0.27, P = 0.009) were negatively and independently correlated with inter-atrial EMD., Conclusion: This study showed that intra- and inter-atrial electromechanical intervals were prolonged and diastolic function was impaired in both overt and subclinical hyperthyroidism. TSH level and mitral Em /Am ratio were found as independent predictors of atrial EMD., (© 2013, Wiley Periodicals, Inc.)

Background: Women with postmenopausal bleeding should be evaluated efficiently to exclude endometrial carcinoma., Aims: To estimate the risk of endometrial cancer using individual case characteristics among women with postmenopausal bleeding in whom the endometrial thickness is >4 mm., Methods: Women with postmenopausal bleeding underwent clinical evaluation followed by transvaginal ultrasonography and endometrial biopsy. Clinical evaluation included age, body mass index, duration of menopause, number of bleeding episodes and amount of bleeding., Results: This study included 142 women, and endometrial carcinoma was found in 18 (12.7%). Older age, higher body mass index, longer duration of menopause, longer lasting bleeding episodes, higher amount of bleeding and recurrent bleeding episodes were the clinical characteristics associated with endometrial cancer. However, multivariate analysis revealed >55 years of age during postmenopausal bleeding, history of recurrent bleeding episodes and bleeding exceeding 5 pads per day in each episode as significant parameters, which predicted the presence of endometrial cancer among women with postmenopausal bleeding., Conclusions: Prompt evaluation is required in women with postmenopausal bleeding to exclude endometrial cancer. Transvaginal ultrasonography is a reasonable first-line approach, and invasive sampling is required when ultrasonographic endometrial thickness is above 4 mm. However, about 90% of women with postmenopausal bleeding will finally be found to have a nonmalignant condition. Therefore, women who are at increased cancer risk should further be distinguished. This may be achieved using individual patient characteristics that result in a more accurate evaluation strategy with lower rates of unnecessary invasive procedures., (© 2013 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Objective: The pathophysiology of the most common joint disease, osteoarthritis (OA), remains poorly understood. Since synovial fluid (SF) bathes joint cartilage and synovium, we reasoned that a comparative analysis of its protein constituents in health and OA could identify pathways involved in joint damage. We undertook this study to perform a proteomic analysis of knee SF from OA patients and control subjects and to compare the results to microarray expression data from cartilage and synovium., Methods: Age-matched knee SF samples from 10 control subjects, 10 patients with early-stage OA, and 10 patients with late-stage OA were compared using 2-dimensional difference-in-gel electrophoresis and mass spectrometry (MS). MS with a multiplexed peptide selected reaction monitoring assay was used to confirm differential expression of a subset of proteins in an independent OA patient cohort. Proteomic results were analyzed by Ingenuity Pathways Analysis and compared to published synovial tissue and cartilage messenger RNA profiles., Results: Sixty-six proteins were differentially present in healthy and OA SF. Three major pathways were identified among these proteins: the acute-phase response signaling pathway, the complement pathway, and the coagulation pathway. Differential expression of 5 proteins was confirmed by selected reaction monitoring assay. A focused analysis of transcripts corresponding to the differentially present proteins indicated that both synovial and cartilage tissues may contribute to the OA SF proteome., Conclusion: Proteins involved in the acute-phase response signaling pathway, the complement pathway, and the coagulation pathway are differentially regulated in SF from OA patients, suggesting that they contribute to joint damage. Validation of these pathways and their utility as biomarkers or therapeutic targets in OA is warranted., (Copyright © 2013 by the American College of Rheumatology.)

Precision attachments have been used for many years to retain removable partial dentures (RPDs). Common reasons for a failed attachment-retained RPD are fracture of the framework, fracture of the roots or teeth, and irretrievable decrease of retention. When an RPD framework major connector has been fractured, it should be remade. This article describes a technique to remake a fractured mandibular RPD using cast round profile attachment analogs without the need for replacement of the fixed partial denture., (© 2012 by the American College of Prosthodontists.)

Ascending aortic aneurysms are commonly associated with bicuspid aortic valves in adults but are rarely seen in childhood. We now report the management of an ascending aortic aneurysm in a 12-year-old male with an associated bicuspid aortic valve and a coarctation., (© 2011 Wiley Periodicals, Inc.)

Scimitar syndrome, or pulmonary venolobar syndrome, is a rare congenital anomaly, in which all the right pulmonary veins drain into the inferior vena cava. In this study, we review the diagnostic features, clinical management, and surgical strategy in the Scimitar syndrome and discuss the significance of new generation diagnostic imaging methods for this rare anomaly. , (© 2011 Wiley Periodicals, Inc.)

Objective: This study was designed to investigate the validity of brain natriuretic peptide (BNP) levels for the estimation of the shunt size in young adults with atrial septal defect (ASD), and to determine the relationship between BNP levels and echocardiographic parameters of right heart chambers., Methods: Fifty-six patients with ASD (mean age 22.9 ± 2.0 years) were studied. The control group consisted of 31 age-gender matched healthy volunteers (mean age 22.7 ± 1.9 years). Coventional echocardiography, tissue Doppler imaging (TDI) and plasma BNP level measurement was performed in all participants. The ratio of pulmonary to systemic blood flow (Qp/Qs) was measured noninvasively using transthoracic echocardiography., Results: Plasma BNP levels were significantly higher in ASD patients than in controls (42.9 ± 29.4 vs. 8.3 ± 2.6 pg/mL, P < 0.05). Pulmonary artery pressure (PAP) (P = 0.0001), right atrium (RA) volume (P = 0.0001), and right ventricular end-diastolic volume (RVEDV) (P = 0.0001) values were higher in ASD patients. There was a powerful correlation between plasma BNP levels and Qp/Qs ratio (r = 0.71, P < 0.0001). The plasma BNP levels significantly correlated with PAP (r = 0.61, P < 0.0001), RA volume (r = 0.54, P < 0.0001), RVEDV (r = 0.55, P < 0.0001), and right ventricular myocardial performance index (r = 0.50, P < 0.0001)., Conclusion: This study shows that there is a significant correlation between right heart echocardiographic parameters and concentrations of BNP in the plasma of young adults with ASD. BNP levels may provide a supplemental data to predict of shunt size in these patients., (© 2011, Wiley Periodicals, Inc.)

Objectives/background: The aim of this study is to investigate the predictive value of intraoperative parathormone measurement addressing successful surgical resection in patients with secondary hyperparathyroidism., Methods: The study included 42 consecutive patients operated on between May 2006 and July 2008. Patients were grouped according to successful surgery (Group 1, n = 36) and persistent postoperative hyperparathyroidism (Group 2, n = 6). Serum phosphorus (P), total calcium (tCa), ionized calcium (iCa), intact parathormone (iPTH), and alkaline phosphatase (ALP) were drawn preoperatively and intraoperatively upon 15 minutes after completion of resection (iPTH(15)). The rate of decrease of pith detected by iPTH(15) compared to preoperative values was calculated (iPTH(%))., Results: Preoperative P, tCa, iCa, iPTH, and ALP were comparable. Subtotal parathyroidectomy (sPx) (n = 27) and total parathyroidectomy with autotransplantation (tPx) (n = 15) were performed. Mean iPTH(15) value, iPTH(%) rates were 145.9 +/- 12.3 pg/mL, % 91.6 +/- 0.7, and 522.5 +/- 85.4 pg/mL, % 75.1 +/- 2.0 (P = ,001) in Groups 1 and 2, respectively. Mean serum tCa and iCa at POD#1 in Group 1 were 7.6 +/- 0.1 mg/dL, 0.910 +/- 0.4 mmol/L, and Group 2 were 8.3 +/- 0.3 mg/dL, 1.050 +/- 0.4 mmol/L (P < .05), respectively. ALP levels were similar., Conclusion: iPTH(15) value and iPTH(%) rate accurately predicts the completeness of resection in secondary hyperparathyroidism. The rate of decrease in serum iPTH detected intraoperatively compared to preoperative baseline levels exceeding 90% in sPx, 95% in tPx, accurately predicts the success of surgery. Postoperative normocalcemia without calcium replacement would raise a suspicion about completeness of surgical resection.

Advance directives are not a part of the healthcare service in Turkey. This may be related with the fact that paternalism is common among the healthcare professionals in the country, and patients are not yet integrated in the decision-making process adequately. However, starting from the enactment of the Regulation of Patient Rights in 1998, this situation started to change. While the paternalist tradition still appears to be strong in Turkey, the Ministry of Health has been taking concrete measures in the recent years to ensure that patient rights are implemented in healthcare practice. Therefore, Turkey now seems to be in a transitional period where a move towards a more patient-autonomy centred approach is being supported by the regulatory authorities, as well as the academic circles and the public at large. In the light of this background, this paper aims to examine the potential benefits of advance directives, particularly with regard to their possible effect in the clinical decision-making process of Turkey's context. It will be argued that advance directives, if correctly understood and implemented in the right settings, may be beneficial, particularly for improving communication between patients and healthcare professionals and for implementing of the right to refuse treatment.

Background: The vaginal route is more effective than the other drug delivery routes for some specific indications., Aim: To compare the efficacy of a vaginal progesterone preparation with that of oral dydrogesterone., Methods: A total of 69 women with irregular dysfunctional uterine bleeding were randomly assigned into one of two groups: oral dydrogesterone group (n = 35) and vaginal progesterone group (n = 34). At the end of a three-month treatment period, the women were re-evaluated. The endometrial histology findings and menstrual cycle characteristics were used as primary outcome measures. Pearson chi-square and Fisher's exact test were used for data analysis., Results: Findings from 54 eligible women were evaluated. There was no statistically significant difference in both menstrual recordings and endometrial histology results between the groups., Conclusions: Vaginal micronised progesterone could be an alternative to oral preparations in the treatment of dysfunctional uterine bleeding. This needs to be further evaluated in adequately controlled randomised trials against other effective treatments.

Objective: The aim of this study was to evaluate atrial conduction abnormalities obtained by Doppler tissue imaging (DTI) and electrocardiogram analysis in ankylosing spondylitis (AS) patients., Methods: A total of 40 patients with AS (22 males /18 females, 37.82 +/- 10.22 years), and 42 controls (22 males/20 females, 35.74 +/- 9.98 years) were included. Systolic and diastolic left ventricular (LV) functions were measured by using conventional echocardiography and DTI. Interatrial and intraatrial electromechanical coupling (PA) intervals were measured with DTI. P-wave dispersion (PD) was calculated from the 12-lead electrocardiogram., Results: Atrial electromechanical coupling at the left lateral mitral annulus (PA lateral) was significantly delayed in AS patients (61.65 +/- 7.81 vs 53.69 +/- 6.75 ms, P < 0.0001). Interatrial (PA lateral - PA tricuspid), intraatrial electromechanical coupling intervals (PA septum - PA tricuspid), maximum P-wave (Pmax) duration, and PD were significantly longer in AS patients (23.50 +/- 7.08 vs 14.76 +/- 5.69 ms, P < 0.0001; 5.08 +/- 5.24 vs 2.12 +/- 2.09 ms, P = 0.001; 103.85 +/- 6.10 vs 97.52 +/- 6.79 ms, P < 0.0001; and 48.65 +/- 6.17 vs 40.98 +/- 5.37 ms, P < 0.0001, respectively). Reflecting LV diastolic function mitral A-wave and E/A, mitral E-wave deceleration time (DT), Am and Em/Am were significantly different between the groups (P < 0.05). We found a significant correlation between interatrial electromechanical coupling interval with PD (r = 0.536, P < 0.01). Interatrial electromechanical coupling interval was positively correlated with DT (r = 0.422, P < 0.01) and inversely correlated with E/A (r =-0.263, P < 0.05) and Em/Am (r =-0.263, P < 0.05)., Conclusion: This study shows that atrial electromechanical coupling intervals and PD are delayed, and LV diastolic functions are impaired in AS patients.

Anomalies of pulmonary veins are uncommon and vary widely in their anatomic spectrum and clinical presentation. A 20-year-old woman with complaints of effort-induced dyspnea and easy fatigability was diagnosed with a third left pulmonary vein with abnormal return and arteriovenous fistula accompanied by a secundum atrial septal defect (ASD). Complete surgical repair was performed by ASD closure with a pericardial patch and triple ligation of the left vertical vein and associated third pulmonary vein. The patient was discharged on the seventh postoperative day in good health. Her last control examination was performed in the second postoperative year, revealing normal echocardiographic findings with an excellent clinical course.

Background: Beta-thalassemia major (beta-TM) is a congenital hemolytic disorder characterized by impaired left ventricular and endothelial function. However, elastic properties of the aorta have not been sufficiently investigated in patients with beta-TM. We investigated whether beta-TM is related to impaired ascending aortic elastic properties., Methods: We studied 36 patients with beta-TM (age: 15.8 +/- 2.6 years) and 30 age- and sex-matched control subjects by echocardiography. Aortic elastic indexes, aortic strain (%), distensibility (cm(2) dyn(-1) 10(-3)), and stiffness index were calculated from the echocardiographically derived thoracic aortic diameters (mm/m(2)), and the measurement of pulse pressure obtained by cuff sphygmomanometry., Results: Patients versus control subjects had increased aortic diameters (P < 0.001), lower mean aortic strain (9 +/- 3.6 vs. 14.9 +/- 3.2, P < 0.001) and distensibility (0.6 +/- 0.36 vs. 0.8 +/- 0.2, P < 0.012), and higher mean stiffness index (5.3 +/- 2.4 vs. 2.8 +/- 0.6, P < 0.001). Aortic elastic indexes were significantly associated with ferritin level, while stiffness index was significantly related to platelet count., Conclusion: Elastic properties of ascending aorta are impaired in patients with beta-TM. Impaired functions of aorta may lead to deterioration of left ventricular function.

Objective: The aim of the study is to compare the efficiency of three different materials (Silicone, Gore-Tex, and irradiated cartilage) used in medialization laryngoplasty. Local tissue reaction to implants in laryngeal skeleton has been examined for this purpose., Study Design and Methods: In this prospective study, New Zealand rabbits were used. Different materials have been implanted in the paraglottic space of both sides of the larynx to enable a better comparison of the different materials used. Limited medialization was applied. Special care has been taken not to narrow the airway and cause breathing problems. The reaction of the tissue in this region against the materials used has been studied. Each material was implanted 14 times in total. The rabbits were killed 6 months after the implementation to study their larynx. For each material, the fibrous capsule formation, histiocyte infiltration, foreign body giant cell infiltration, eosinophil infiltration, neutrophil infiltration, and lymphoplasmacytic infiltration levels were investigated histologically., Results: Best fibrous capsule formation has been observed around silicone. Allergic reactions and inflammatory responses were minimal for this material. Fibrous capsule formation was more limited with Gore-Tex. Some degree of chronic inflammatory response (in few cases) has been observed against this material. Severe allergic response was observed against irradiated cartilage, and the implant material was resorbed completely in most cases., Conclusion: According to histopathologic results of this study (tissue compatibility of three materials), silicone is the most suited material among the study materials for medialization. Gore-Tex can also be used for this purpose. Irradiated cartilage, on the other hand, appears not to be a suitable material for medialization laryngoplasty.

Background: The management of the apical multiple muscular ventricular septal defects (VSDs) remains still controversial. There are various surgical techniques and approaches for closure of "Swiss-cheese" VSDs. In this study, we report the outcome of multiple muscular VSDs repair, using the septal obliteration technique., Methods: We used the septal obliteration technique in five "Swiss-cheese" ventricular septal defects cases through right atriotomy. Four of the cases had isolated multiple VSDs. One case also had an aortic arch interruption type A, which was repaired prior to cardiopulmonary bypass. Their ages varied between 43 days and 6 years., Results: We did not experience any mortality or serious morbidity. Tracheostomy was required in one patient. There was no important residual shunt in postoperative period, except a minimal shunt in one case., Conclusion: The closure technique of "Swiss-cheese" trabecular multiple VSDs using a large single patch was not troubling. Transatrial approach prevented postoperative problems of ventricular incision. Using a large needle with a large pledgett is the key, which provides deep tissue penetration to avoid residual shunt.

Background: It has been hypothesised that oral oestrogen replacement therapy may increase levels of C-reactive protein (CRP), a marker of inflammation associated with increased risk of future cardiovascular events. However, it is possible that intranasal oestrogen replacement therapy have different effects on serum CRP levels., Aim: To investigate the effect of postmenopausal intranasal oestrogen replacement therapy on serum levels of CRP. A prospective comparative study was carried out., Methods: Twenty-nine healthy hysterectomised, postmenopausal women received 300 micro g/day of intranasal 17beta-oestradiol (E2). The serum levels of CRP after 3 and 6 months after starting treatment were compared with baseline values., Results: There were no significant changes in the values of CRP after 3 and 6 months of treatment (P = 0.305, P = 0.149, respectively)., Conclusions: The data from the present study suggest that intranasal administration of E2 does not affect CRP levels, possibly by avoiding a hepatic first-pass effect. The possible cardiovascular protective role of intranasal oestrogen might be related to its effect of not increasing CRP levels.

The purpose of the present study was to evaluate the effects on lipid metabolism of a new low-dose monophasic combination oral contraceptive with 100 microg levonorgestrel and 20 microg ethinylestradiol. Sixty healthy women aged 18-45 years were administered the medication during three cycles. The study participants were screened for lipid changes. The differences in cholesterol and triglyceride levels were not statistically significant, but high-density lipoprotein levels were significantly lower and low-density lipoprotein levels were significantly higher than the baseline. Women at risk of cardiovascular disease should be carefully monitored even when using low-dose preparations.

Objective: To study the value of creatine kinase in ectopic pregnancy with reference to tubal histopathology., Design: Prospective controlled study., Setting: Academic tertiary-care institution., Population: Thirty-two women with ectopic pregnancy and 20 controls with intrauterine pregnancies., Methods: Creatine kinase and beta-hCG levels were measured on admission. Ectopic pregnancies were removed at surgery and examined histologically., Main Outcome Measures: Tubal localisation and integrity of ectopic pregnancies as judged at surgery and later histologically, and placental growth patterns in unruptured ectopic pregnancies classified as intraluminal, extraluminal or mixed as determined histologically., Results: Creatine kinase levels were higher in isthmic than ampullary ectopic pregnancies (P = 0.011), and higher in ruptured than in unruptured cases (P = 0.003) and normal pregnancies (P < 0.0001). A creatine kinase value >120iu/L was 65% sensitive and 87% specific in discriminating ruptured from unruptured ectopic pregnancies. Creatine kinase levels were above this cutoff in two of five unruptured ampullary ectopic pregnancies with invasive trophoblastic growth, yet in none of nine cases with intraluminally confined placentation (P = 0.04). Creatine kinase was positively correlated with gestational age in ruptured (P = 0.007), but not in unruptured ectopic pregnancies or normal pregnancies., Conclusions: Serum creatine kinase may help in discriminating ruptured from unruptured ectopic pregnancies, while it is not useful for the primary diagnosis of ectopic pregnancy. An increase in creatine kinase levels accompanying muscular damage in ectopic pregnancy probably antedates tubal rupture, and may be related to trophoblastic growth patterns.