Peter Takacs

Comparison of long-term immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine in healthy women aged 18-45 years: End-of-study analysis of a Phase III randomized trial

The observer-blind, randomized, age-stratified, head-to-head study (NCT00423046) comparing immunogenicity and safety of HPV-16/18 and HPV-6/11/16/18 vaccines in healthy women aged 18-45 y was completed. Five y after vaccination, in subjects from the Month 60 according-to-protocol cohort (seronegative and DNA negative for HPV type analyzed at baseline), serum neutralizing antibody (nAb) responses induced by HPV-16/18 vaccine remained 7.8-fold (18-26-y stratum), 5.6-fold (27-35-y stratum) and 2.3-fold (36-45-y stratum) higher than those induced by HPV-6/11/16/18 vaccine for HPV-16. For HPV-18, the fold differences were 12.1, 13.0 and 7.8, respectively. At Month 60, all (100%) subjects in HPV-16/18 vaccine group and the majority (95.7%-97.5%) in HPV-6/11/16/18 vaccine group were seropositive for HPV-16. For HPV-18, the majority (98.1%-100%) of subjects in HPV-16/18 vaccine group were seropositive; however, seropositivity rates in HPV-6/11/16/18 vaccine group decreased considerably (61.1%-76.9%) across the 3 age strata. In the total vaccinated cohort (received ≥ 1 dose regardless of baseline HPV serostatus and DNA status), geometric mean titers for anti-HPV-16 and anti-HPV-18 nAb were higher in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. Based on the 5-y data, piece-wise and modified power-law models predicted a longer durability of nAb response for HPV-16/18 vaccine compared to HPV-6/11/16/18 vaccine. Beyond the differences apparent between the vaccines in terms of immunogenicity and modeled persistence of antibody responses, comparative studies including clinical endpoints would be needed to determine whether differences exist in duration of vaccine-induced protection.

Performance of human chorionic gonadotropin curves in women at risk for ectopic pregnancy: exceptions to the rules

OBJECTIVE To investigate the accuracy of serial hCG to predict outcome of a pregnancy of unknown location in an ethnically and geographically diverse setting. DESIGN Multisite cohort study. SETTING University hospital. PATIENT(S) Women with a pregnancy of unknown location. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Patients were followed until diagnosed with ectopic pregnancy (EP), intrauterine pregnancy (IUP), or miscarriage. To predict outcome, observed hCG level was compared with recommended thresholds to assess deviation from defined normal curves. Predicted outcome was compared with standard of care. Sensitivity, specificity, predictive value, and accuracy were calculated, stratified by diagnosis. RESULT(S) The final diagnosis of 1,005 patients included 179 EPs, 259 IUPs, and 567 miscarriages. The optimal balance in sensitivity and specificity used the minimal expected 2-day increase in hCG level of 35%, and the minimal 2-day decrease in hCG level of 36%-47% (depending on the level) achieving 83.2% sensitivity, 70.8% specificity to predict EP. However, 16.8% of EPs and 7.7% of IUPs would be misclassified solely using serial hCG levels. Consideration of a third hCG and early ultrasound decreased IUP misclassification to 2.7%. CONCLUSION(S) Solely using serial hCG values can result in misclassification. Clinical judgment should trump prediction rules and continued surveillance with a third hCG may be prudent, especially when initial values are low or when values are near suggested thresholds.

Development of a Multiple Marker Test for Ectopic Pregnancy

OBJECTIVE: Many serum markers have been proposed to aid in the identification of an ectopic pregnancy, but few have been validated. Most studies have been limited by sample size and design. The goal of this study was to assess putative markers to identify which can be optimally combined. METHODS: We conducted a case–control study using sera from 100 patients with ectopic pregnancy and 100 patients with intrauterine pregnancy who presented to three urban academic centers between September 2000 and April 2009 with first-trimester pain or bleeding. Samples were analyzed for 12 promising biomarkers. Classification tree analysis was used to examine markers simultaneously with the goal of optimizing the accuracy of ectopic pregnancy diagnosis, and validation was performed using bootstrapping. RESULTS: Six of the 12 markers were differentially expressed between those with ectopic pregnancy and intrauterine pregnancy (P<.001) with fair diagnostic properties (area under the curve greater than 0.6) when examined individually (inhibin A, progesterone, activin A, vascular endothelial growth factor [VEGF], pregnancy-specific &bgr;-1-glycoprotein, and pregnancy-associated plasma protein-A). Six additional markers were found to have limited value. Using a two-step diagnostic algorithm with four markers (progesterone, VEGF, inhibin A, activin A), we diagnosed 42% of the sample with perfect specificity and 98% (93–100%) sensitivity. Overall, a single ectopic pregnancy was misclassified, achieving 99% (96–100%) accuracy. CONCLUSION: Evaluating a large number of biomarkers simultaneously demonstrates that most of the putative markers of ectopic pregnancy are not useful. However, a select few can distinguish ectopic pregnancy from intrauterine pregnancy with superior accuracy as part of a multiple marker test. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00194168. LEVEL OF EVIDENCE: II

Vaginal smooth muscle cell apoptosis is increased in women with pelvic organ prolapse

To compare the smooth muscle content and apoptosis of the vagina in women with and without anterior vaginal wall prolapse. Vaginal tissues were sampled in women with (n = 6) or without (n = 6) anterior vaginal wall prolapse undergoing hysterectomy. Smooth muscle of the vagina was studied by immunohistochemistry. Digital image analysis was used to determine the fractional area of smooth muscle in the histologic cross-sections. Apoptosis was assessed by TUNEL assay. The fractional area of non-vascular smooth muscle in the vagina of women with anterior vaginal wall prolapse was significantly decreased compared to women without prolapse (0.36 ± 0.12 vs. 0.16 ± 0.12 P = 0.021) and the apoptotic index was significantly higher compared to women without prolapse (0.04 ± 0.01 vs. 0.02 ± 0.03, P = 0.041). The fraction of smooth muscle in the vagina is significantly decreased and the rate of apoptosis is higher in women with anterior vaginal wall prolapse compared to women without prolapse.

Prophylactic and antinociceptive effects of coenzyme Q10 on diabetic neuropathic pain in a mouse model of type 1 diabetes.

Background:Oxidative stress is a key factor implicated in the development of diabetic neuropathy. This study evaluates the prophylactic and antinociceptive effects of the antioxidant coenzyme Q10 (CoQ10) on diabetes-induced neuropathic pain in a diabetic mouse model. Methods:Total 56 mice with type 1 diabetes induced by streptozotocin were used, 20 normal mice were used as control. Mechanical and thermal nociceptive behavioral assays were applied to evaluate diabetic neuropathic pain. Tissue lipid peroxidation, immunohistochemistry, reverse transcription, and polymerase chain reaction were used to evaluate the molecular mechanisms of CoQ10. Data are presented as mean ± SEM. Results:CoQ10 administration was associated with reduced loss of body weight compared with nontreated diabetic mice, without affecting blood glucose levels. Low dose and long-term administration of CoQ10 prevented the development of neuropathic pain. Treatment with CoQ10 produced a significant dose-dependent inhibition of mechanical allodynia and thermal hyperalgesia in diabetic mice. Dorsal root ganglia, sciatic nerve, and spinal cord tissues from diabetic mice demonstrated increased lipid peroxidation that was reduced by CoQ10 treatment. CoQ10 administration was also noted to reduce the proinflammatory factors in the peripheral and central nervous system. Conclusions:The results of this study support the hypothesis that hyperglycemia induced neuronal oxidative damage and reactive inflammation may be pathogenic in diabetic neuropathic pain. CoQ10 may be protective by inhibiting oxidative stress and reducing inflammation by down-regulating proinflammatory factors. These results suggest that CoQ10 administration may represent a low-risk, high-reward strategy for preventing or treating diabetic neuropathy.

Risk Factors Associated with the Rupture of Tubal Ectopic Pregnancy

Objective: To identify risk factors that may lead to the rupture of ectopic pregnancies. Study Design: A retrospective chart review was performed on patients with ectopic pregnancies at the University of Miami/Jackson Memorial Hospital between 1/1/1995 and 3/1/2002. 738 patients were identified with ectopic pregnancies. Women with tubal rupture were compared to those without rupture. Variables analyzed were demographic data, patient-related risk factors (history of pelvic surgery, bilateral tubal ligation, history of pelvic inflammatory disease, previous ectopic pregnancy, intrauterine device use) and β-human chorionic gonadotropin (βhCG) measurement. Results: There were 439 (59%) cases with a ruptured and 299 (41%) cases with an unruptured ectopic pregnancy. Multivariate logistic regression analysis revealed that previous ectopic pregnancy (OR 2.88; 95% CI 1.92, 4.33) and βhCG level ≧5,000 mIU/ml (OR 1.85; 95% CI 1.12, 3.06) were the only significant risk factors for tubal rupture. Conclusion: Patients with βhCG levels ≧5,000 mIU/ml and patients with a history of a previous ectopic pregnancy are significantly more likely to experience a tubal rupture.

A disintegrin and metalloprotease protein-12 as a novel marker for the diagnosis of ectopic pregnancy

OBJECTIVE To evaluate the performance of a novel biomarker, a disintegrin and metalloprotease-12 (ADAM-12), to differentiate an ectopic pregnancy (EP) from normal intrauterine pregnancies (IUPs). DESIGN Case-control study. SETTING Three urban academic centers. PATIENT(S) Women who were seen in the emergency department with pain or bleeding in the first trimester of pregnancy. INTERVENTION(S) Sera from women with diagnosed EP or IUP were evaluated via proteomics and an ADAM-12 dissociation-enhanced lanthanide fluoroimmunoassay. MAIN OUTCOME MEASURE(S) Differences between groups, area under the receiver operating curve, sensitivity, and specificity. RESULT(S) Via a proteomics evaluation, we found a statistically significant decrease in ADAM-12 in the sera of patients with EP, which we confirmed in a larger group of 199 patients (median IUP 18.6 ng/mL versus median EP 2.5 ng/mL with good discrimination between the groups as assessed by receiver operating characteristics [area under the curve = 0.82]). At a low cut-point, the sensitivity was 70% and specificity 84%, but, at a higher cut-point optimizing sensitivity, the ADAM-12 test demonstrated a sensitivity of 97%. CONCLUSION(S) ADAM-12 is a promising marker for the diagnosis of EP in women with symptoms in the first trimester, validating the proteomics findings. Further studies in additional patient populations and in combination with other biomarkers are needed.

Normal Vulvovaginal, Perineal, and Pelvic Anatomy with Reconstructive Considerations

A thorough insight into the female genital anatomy is crucial for understanding and performing pelvic reconstructive procedures. The intimate relationship between the genitalia and the muscles, ligaments, and fascia that provide support is complex, but critical to restore during surgery for correction of prolapse or aesthetic reasons. The external female genitalia include the mons pubis, labia majora and minora, clitoris, vestibule with glands, perineal body, and the muscles and fascia surrounding these structures. Through the perineal membrane and the perineal body, these superficial vulvar structures are structurally related to the deep pelvic muscle levator ani with its fascia. The levator ani forms the pelvic floor with the coccygeus muscle and provides vital support to all the pelvic organs and stability to the perineum. The internal female genital organs include the vagina, cervix, uterus, tubes, and ovaries with their visceral fascia. The visceral fascia also called the endopelvic fascia, surrounds the pelvic organs and connects them to the pelvic walls. It is continuous with the paraurethral and paravaginal fascia, which is attached to the perineal membrane. Thus, the internal and external genitalia are closely related to the muscles and fascia, and work as one functioning unit.

Uterosacral ligament smooth muscle cell apoptosis is increased in women with uterine prolapse.

Purpose: The purpose of this study was to compare the smooth muscle content and apoptosis of the uterosacral ligament in women with and without uterine prolapse. Study Design: Uterosacral ligaments were sampled in women with (n = 9) or without (n = 9) uterine prolapse undergoing hysterectomy. Smooth muscle of the uterosacral ligament was identified by immunohistochemistry. Digital image analysis was used to determine the fractional area of smooth muscle in the histologic cross sections. Apoptosis was assessed by terminal deoxynucelotidyl-transferase-mediated dUTP nick-end-labeling method. Results: The fractional area of nonvascular smooth muscle in the uterosacral ligament of women with uterine prolapse was significantly decreased compared to women without prolapse (0.32 + 0.12 vs. 0.42 + 0.03, P = .02) and the apoptotic index was significantly higher compared to women without prolapse (0.20 + 0.06 vs. 0.08 + 0.04, P < .01). Conclusion: The fraction of smooth muscle in the uterosacral ligaments is significantly decreased, and the rate of apoptosis is higher in women with uterine prolapse compared to women without prolapse.

Diabetic neuropathic pain development in type 2 diabetic mouse model and the prophylactic and therapeutic effects of coenzyme Q10

UNLABELLED The early onset of type 2 diabetes mellitus (DM), driven by increasing obesity, is associated with peripheral neuropathy. Here, we characterize diabetic neuropathic pain in New Zealand obese diabetic mice (NZO/HILtJ) as a polygenic model of obesity with type 2 diabetes and investigate the role of coenzyme Q10 (CoQ10) in the prevention and treatment of diabetic neuropathic pain. Since the overexpression of mitogen-activated protein kinase (MAPK), nuclear factor-κB proteins (NF-Kb), toll-like receptor 4 (TLR4) and downstream cytokines (such as CCL2, CXCL10) are considered important factors contributing to the development of neuropathic pain, the expression of these factors and the inhibitory effects of CoQ10 were evaluated. NZO/HILtJ mice spontaneously developed type 2 DM and increased body mass with diabetic neuropathic pain. CoQ10 treatment decreased pain hypersensitivity and long-term supplementation prevented the development of diabetic neuropathic pain but did not attenuate diabetes. Spinal cord, blood serum, liver tissue, and dorsal root ganglia (DRG) from diabetic mice demonstrated increased lipid peroxidation, which was decreased by CoQ10 treatment. The percentage of positive neurons of p65 (the activated marker of NF-KB) and MAPK in DRG were significantly higher in DM mice compared to controls. However, CoQ10 treatment significantly decreased p65 and MAPK positive neurons in the DRG of DM mice. RT-PCR demonstrated that elevated levels of mRNA of CCL2, CXCL10 or TLR4 in the spinal cord of DM mice decreased significantly when DM mice were treated with CoQ10. CONCLUSION This model may be useful in understanding the mechanisms of neuropathic pain in type 2 DM induced neuropathic pain and may facilitate preclinical testing of therapies. CoQ10 may decrease oxidative stress in the central and peripheral nervous system by acting as an anti-oxidant and free-radical scavenger. These results suggest that CoQ10 might be a reasonable preventative strategy for long-term use and using CoQ10 treatment may be a safe and effective long-term approach in the treatment of diabetic neuropathy.