Anterior obturator artery perforator (aOAP) flap: A last-resort treatment option for sexual dysfunction in lichen sclerosus et atrophicus.

INTRODUCTION: Lichen sclerosus et atrophicus is an inflammatory, scarring dermatosis of the female anogenital area and may lead to pain and sexual dysfunction. In select cases which are refractory to conservative therapy, surgery may provide significant symptom improvement. The objective of this study was to expand the range of surgical treatment options for these patients by presenting the operative outcomes of a specialised reconstructive method using the anterior obturator artery perforator (aOAP) flap. METHODS: A retrospective cohort study was conducted on sexual outcomes following the excision of affected vulvovestibular tissue by skinning vulvectomy and subsequent single-stage reconstruction using the aOAP flap. Additional procedures, such as the Omega-Domed (OD) flap, scar surgery and clitoral re-exposure, were performed when indicated. RESULTS: Between 2014 and 2022, a total of 61 patients were surgically treated and retrospectively included in this study. Vulvectomy and subsequent reconstruction with bilateral aOAP flaps were performed in 53 (87%) cases. There was a significant reduction in the prevalence of dyspareunia and inability to have sexual intercourse at the 1-year follow-up compared to baseline (p < 0.001). There were several minor, reversible complications that required secondary intervention. CONCLUSIONS: The outcomes of this study indicate a substantial improvement in sexual function, evidenced by a significant reduction in dyspareunia and an increased ability to engage in sexual intercourse. Altered tissue quality in patients with lichen sclerosus et atrophicus and long-term cortisone application may predispose this patient population to a higher risk of minor post-operative complications. CLINICAL TRIAL REGISTRATION NUMBER: DRKS00033261.

The value of surgical staging in patients with apparent early stage epithelial ovarian carcinoma.

OBJECTIVE: The value of surgical staging of apparent early stage epithelial ovarian carcinoma (EOC) is unclear. The aim of this study was to evaluate the importance of surgical staging on the stage of disease and treatment plan. MATERIAL AND METHODS: All patients with apparent stage I EOC undergoing staging from 01/01/2005 to 30/06/2017 in all Danish hospitals and in the Radboud University Hospital Nijmegen, the Netherlands, were evaluated to identify the pathological findings responsible for upstaging and changes in treatment plans. RESULTS: We included 1234 patients with apparent stage I EOC. The staging steps often missed were the biopsy from the right diaphragmatic surface (missed in 96.9% of all patients) and lymph node (LN) sampling or lymphadenectomy (missed in 65.5% of all patients). Upstaging occurred in 393 patients (31.8%) due to microscopic spread to both ovaries (0.8%); ovarian surface (5.8%); positive cytology (10.0%); fallopian tubes (3.1%), ovary (1.5%) and/or uterus serosa (1.2%); pelvic peritoneum (4.3%); LNs (4.7%); omentum (3.7%); abdominal peritoneum (0.6%) and right diaphragmatic surface (2.6%). Of the 393 upstaged patients, 138 (35.1%) had an altered treatment plan due to metastases found by surgical staging. CONCLUSION: Staging was incomplete in most patients, mainly because a biopsy of the diaphragm was omitted. However, surgical staging led to adjuvant treatment in 35.1% of the upstaged patients. Peritoneal biopsies (para-colic gutters and right diaphragm) were of little value, since few patients had an adjustment of treatment plan due to these biopsies. Omitting these biopsies, in the absence of peritoneal abnormalities, is justifiable.

The influence of unilateral oophorectomy on the age of menopause.

OBJECTIVE: To determine the age of menopause after premenopausal unilateral oophorectomy (UO) and to establish whether UO at a young age leads to menopause at a younger age than if UO occurs at an older age. METHODS: A cohort of 28 731 women, of whom 17 781 (62%) were menopausal, was investigated. Information on menopause was obtained from self-reported questionnaires. Surgical data were obtained from the National Patient Register to avoid recollection bias. Age of menopause after UO/not UO was determined using Kaplan-Meier curves. Cox regression was used to identify factors of importance for early menopause. RESULTS: UO was performed in 1148 women. Women with UO after the age of 45 years, premenopausal hysterectomy, bilateral oophorectomy and cancer were excluded, leaving 236 in the analysis. Menopause occurred 1.8 years earlier after UO compared to women with two intact ovaries (mean 49.5 vs. 51.3 years), and younger age at UO was significantly linearly correlated to younger age at menopause. UO (hazard ratio 1.23) and smoking (hazard ratio 1.12) significantly decreased the age of menopause. CONCLUSIONS: Premenopausal unilateral oophorectomy significantly reduces the age of menopause by 1.8 years. Younger age at UO leads to significantly younger age at menopause.

Prospective investigation of serum anti-Müllerian hormone concentration in ovulatory intrauterine insemination patients: a preliminary study.

This preliminary prospective study investigated serum anti-Müllerian hormone (AMH) through correlations to other basal parameters (123 patients) and according to ovarian response to 75 IU recombinant follicle-stimulating hormone (rFSH)/day (62 patients) in ovulatory patients' first rFSH treatment cycle before intrauterine insemination. Mean age of the patients was 33 years. Serum AMH significantly correlated to age (r=-0.38), antral follicle count (AFC) (r=0.68), ovarian volume (r=0.40), FSH (r=-0.31), (P<0.001) and cycle length (r=0.26, P=0.004). Serum AMH median (interquartile range; IQR) was 8.5 pmol/l (1.9-15.1) in hyporesponders (one mature follicle) versus 10.7 (7.3-17.3) in normal responders (2-3 follicles, with a maximum of two follicles 18 mm and no need for dose reduction) and 13.4 (4.4-24.2) in hyperresponders (>2-3 mature follicles or dose reduction). There was a significant trend over response groups for body weight (P=0.005), body mass index (P=0.035), AFC (P=0.031) and FSH (P=0.001). Serum AMH median (IQR) was 10.6 pmol/l (6.9-18.2) in the 23 patients who achieved an ongoing pregnancy versus 10.5 (5.9-17.2) in the 100 non-pregnant women. Serum AMH may not be the best marker of the ovarian response in these patients.

Individual versus standard dose of rFSH in a mild stimulation protocol for intrauterine insemination: a randomized study.

BACKGROUND: Controlled ovarian stimulation (COS) and intrauterine insemination (IUI) are often used as the first-line treatment for subfertile couples. To minimize the variability in ovarian response in patients' first treatment cycle, we recently developed a recombinant follicle-stimulating hormone (rFSH) dosage nomogram. The nomogram has now been tested. METHODS: Multicentre randomized controlled trial (RCT) including 228 ovulatory patients scheduled for COS and IUI. Patients were randomized to 'individual' (50-100 IU rFSH/day, n = 113) or 'standard' (75 IU rFSH/day, n = 115) dose. 'Individual' dose was prescribed according to the nomogram, which was based on patients' body weight and antral follicle count. The primary end-point was the proportion of patients with two to three follicles > or = 14 mm (maximum two follicles > or = 18 mm) on the day of hCG (leading follicle = 18 mm). Primary analysis was made by intention-to-treat. RESULTS: In the 'individual' group, 79/113 (70%) of the patients developed two to three follicles versus 64/115 (56%) in the 'standard' group [absolute difference = 14.3 percentage points; 95% confidence interval (CI) 2-26, P = 0.03; absolute difference = 14.4; 95% CI 2-27, P = 0.02, when adjusting for centre]. Among patients with two to three follicles, the proportion of patients with two follicles was 46/79 (58%) in the 'individual' group versus 34/64 (53%) in the 'standard' group, P = 0.54. Ongoing pregnancy rate was 23/113 (20%) in the 'individual' group and 21/115 (18%) in the 'standard' group and the rate of multiple gestations was 1/113 (1%) versus 5/115 (4%), P = 0.21. CONCLUSIONS: This RCT is the first to clinically test a dosage nomogram in ovulatory IUI patients' first rFSH treatment cycle. Dosing according to the nomogram was superior to standard dosing. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00374634.

Age determination enhanced by embryonic foot bud and foot plate measurements in relation to Carnegie stages, and the influence of maternal cigarette smoking.

BACKGROUND: Reliable age determination of first-trimester human embryos and fetuses is an important parameter for clinical use and basic science. Age determination by ultrasound or morphometric parameters of embryos 4-6 weeks post conception (p.c.) have been questioned, and more accurate methods are required. Data on whether and how maternal smoking and alcohol consumption influence embryonic and fetal foot growth is also lacking. METHODS: Embryonic tissue from 102 first-trimester legal abortions (aged 35-69 days p.c.) were collected. All women answered a questionnaire concerning smoking and drinking habits, and delivered a urine sample for cotinine analysis. Embryonic age was evaluated by vaginal ultrasound measurements and by post-termination foot length and compared with the Carnegie stages. RESULTS: Foot bud and foot plate were defined and measured as foot length in embryos aged 35-47 days p.c. (range 0.8-2.1 mm). In embryos and fetuses aged 41-69 days p.c., heel-toe length was measured (range 2.5-7.5 mm). We found a significant linear correlation between foot length and age. Morphology of the feet was compared visually with the Carnegie collection, and we found that the mean ages of the two collections correlated well. Foot length was independent of gender, Environmental Tobacco Smoke, maternal smoking and alcohol consumption. CONCLUSION: Foot length correlated linearly to embryonic and foetal age, and was unaffected by gender, ETS, maternal smoking and alcohol consumption.

Biochemical pregnancy after fertilization of an oocyte aspirated from a heterotopic autotransplant of cryopreserved ovarian tissue: case report.

Autotransplantation of frozen/thawed ovarian tissue in women undergoing cancer therapy has so far led to the birth of two healthy babies. In both cases, it can be discussed whether the fertilized oocyte originated from the transplant or from the native ovary. We now present a biochemical pregnancy achieved after heterotopical autotransplantation of cryopreserved ovarian cortical tissue and hence the unquestionable proof that pregnancy can occur after transplantation of cryopreserved ovarian tissue. A woman diagnosed with Hodgkin's lymphoma had ovarian tissue cryopreserved at the age of 28, before receiving chemotherapy and radiation therapy that rendered her amenorrhoeic. After complete remission, she had autotransplantation of ovarian tissue to the remaining ovary, to the right pelvic wall and to a midline subperitoneal pocket on the lower abdominal wall. The transplanted tissue resumed hormone secretion and follicles developed in all three locations. Three times during 8 months, when follicles could not be visualized in other locations, oocytes were aspirated from the subperitoneal autotransplanted tissue on the lower abdominal wall. Twice, an oocyte was retrieved, fertilized by intracytoplasmatic sperm injection (ICSI) and transferred to the woman's uterus. One of the treatments resulted in a positive pregnancy test 14 days after transfer. Clinical pregnancy, however, was not achieved. In conclusion, heterotopic autotransplantation of cryopreserved ovarian tissue can sustain follicle development. The oocytes of aspirated mature follicles are capable of fertilization after ICSI, and the resulting embryo is competent of producing hCG at detectable levels.

Prevention of injuries in young female players in European team handball. A prospective intervention study.

Young female players in European handball have a very high injury incidence, up to 50 injuries per 1000 hours of game. More than half of these injuries happen without any external cause. The aim of the study was to investigate the effect of an intervention programme designed to reduce the number of injuries in young female players in European handball, with special emphasis on injuries in the lower extremities. The programme was created using elite athlete training programmes and those designed for rehabilitation of injured athletes with functional instability of their ankles and rupture of the anterior cruciate ligament. It included the use of an ankle disk for 10-15 min at all practice sessions, for one 10-month season (August 1995-May 1996). Twenty-two teams participated in the study, and were randomly assigned to the intervention or control group. Eleven teams with 111 players were randomised to the intervention group and 11 teams with 126 players to the control group. Data were analysed using a t-test for continuous variables, chi2-analysis and Fisher's exact test for dichotomous variables and multivariate methods to determine odds-ratios. The results indicated that using the intervention programme decreased the numbers of both traumatic and overuse injuries significantly. The differences in injuries between the groups were 80% during games and 71% during practice. In addition, the players in the control group had a 5.9 times higher risk of acquiring an injury than the players in the intervention group.

Identification and characterization of a pro-tumor necrosis factor-alpha-processing enzyme from the ADAM family of zinc metalloproteases.

Tumor necrosis factor-alpha (TNF) is initially expressed as a 26-kDa membrane-bound precusor protein (pro-TNF) that is shed proteolytically from the cell surface, releasing soluble 17-kDa TNF. We have identified human ADAM 10 (HuAD10) from THP-1 membrane extracts as a metalloprotease that specifically clips a peptide substrate spanning the authentic cleavage site between Ala76 and Val77 in pro-TNF. To confirm that HuAD10 has TNF processing activity, we cloned, expressed, and purified an active, truncated form of HuAD10. Characterization of recombinant HuAD10 (rHuAD10) suggests that this enzyme has many of the properties (i.e. substrate specificity, metalloprotease activity, cellular location) expected for a physiologically relevant TNF-processing enzyme.

Inhibition of human immunodeficiency virus type 1 infectivity by secretory leukocyte protease inhibitor occurs prior to viral reverse transcription.

Infection of monocytes with human immunodeficiency virus type 1(Ba-L) (HIV-1(Ba-L)) is significantly inhibited by treatment with the serine protease inhibitor, secretory leukocyte protease inhibitor (SLPI). SLPI does not appear to act on virus directly, but rather the inhibitory activity is most likely due to interaction with the host cell. The current study was initiated to investigate how SLPI interacts with monocytes to inhibit infection. SLPI was found to bind to monocytes with high affinity to a single class of receptor sites (approximately 7,000 receptors per monocyte, K(D) = 3.6 nmol/L). The putative SLPI receptor was identified as a surface protein with a molecular weight of 55 +/- 5 kD. A well-characterized function of SLPI is inhibition of neutrophil elastase and cathepsin G. However, two SLPI mutants (or muteins) that contain single amino acid substitutions and exhibit greatly reduced protease inhibitory activity still bound to monocytes and retained anti-HIV-1 activity. SLPI consists of two domains, of which the C-terminal domain contains the protease inhibiting region. However, when tested independently, neither domain had potent anti-HIV-1 activity. SLPI binding neither prevented virus binding to monocytes nor attenuated the infectivity of any virus progeny that escaped inhibition by SLPI. A polymerase chain reaction (PCR)-based assay for newly generated viral DNA demonstrated that SLPI blocks at or before viral DNA synthesis. Therefore, it most likely inhibits a step of viral infection that occurs after virus binding but before reverse transcription. Taken together, the unique antiviral activity of SLPI, which may be independent of its previously characterized antiprotease activity, appears to reside in disruption of the viral infection process soon after virus binding.

Injuries in young female players in European team handball.

The purpose of this study was to examine the nature, extent and severity of sports injuries in young female players in European team handball and to identify the etiological factors involved in the injuries. Twenty-two teams with 217 players, aged 16-18 years, participated in the study. A very high injury incidence during games was observed, with 40.7 injuries/1000 hours of game. Backplayers had the highest incidence (54.8/1000 hours), which is five times higher than any previously recorded injury incidence in players in European team handball. We found that 92.9% of injuries were traumatic and 7.1% were from overuse. One-hundred and twenty-four of the 211 injuries were traumatic injuries of the lower extremities. Of these 63 (51%) were without contact with an opponent. The study confirmed that European team handball is a sport that has a very high injury rate, especially regarding young female players. Field position and earlier injuries are major risk factors, with an earlier injury being the single highest risk factor and with backplayers having a significantly higher number of injuries than players in other field positions.

[Laparoscopic extraction of a displaced Olmed screw]. / Laparoskopisk fjernelse af displaceret Olmed-skrue.

Intrapelvic migration of hip screws is a rare complication to internal fixation of hip fractures. In this case the screw had migrated through the acetabulum and into the pelvic cavity. The screw was identified and removed with a laparoscopic procedure.

Solution conformation of the extracellular domain of the human tumor necrosis factor receptor probed by Raman and UV-resonance Raman spectroscopy: structural effects of an engineered PEG linker.

The solution structure of the Escherichia coli-expressed extracellular domain, residues 12-172, of the human 55 kDa type I tumor necrosis factor receptor (TNFR) has been probed by Raman (514.5 nm) and ultraviolet-resonance Raman (244 nm) excitations. The Raman spectra have been collected from both the free TNFR domain and an engineered "dumbbell-like" derivative, consisting of two mutant receptor moieties linked by a 20 kDa polyethylene glycol (PEG) tether. The results demonstrate a TNFR secondary structure which is rich in beta-sheet and deficient in alpha-helix, consistent with the reported X-ray crystal structure of baculovirus expressed receptor complexed with factor beta [Banner, D. W., D'Arcy, A., Janes, W., Gentz, R., Schoenfeld, H.-J., Broger, C., Loetscher, H., & Lesslauer, W. (1993) Cell 73, 431-445]. Conversely, the solution structure of TNFR differs from the crystal structure in its distribution of disulfide rotamers and in the orientation of its unique indole side chain (tryptophan-107). These differences are attributed, respectively, to N-terminal truncation and factor binding in the TNFR crystal structure. The tryptophan configuration, which is easily monitored in both Raman and UVRR spectra, is proposed as a potential signal of receptor/factor recognition and binding. Application of the Raman probes to the engineered TNFR dumbbell, which is of interest as a potential therapeutic, shows that TNFR moieties of the dumbbell exhibit secondary structures and side chain environments which are indistinguishable from those of the native, wild-type moiety. The results suggest that the PEGylated dumbbell may function as an effective TNFR drug delivery system without the consequence of a deleterious antigenic response.

Potent inhibitory effects of glial derived neurotrophic factor against kainic acid mediated seizures in the rat.

Recently messenger RNA (mRNA) for glial derived neurotrophic factor (GDNF), a recently discovered member of the TGF-beta superfamily, was shown to increase in the hippocampus after kainic acid-induced seizures. The possibility that exogenous recombinant human (rh) GDNF may have anticonvulsant properties was investigated using a model of temporal lobe epilepsy in the rat. rhGDNF, vehicle or inactive rhGDNF were injected intracerebroventricularly 1 h before peripheral administration of kainic acid. rhGDNF suppressed kainic acid-induced tonic-clonic convulsions when compared to animals treated with vehicle or inactive rhGDNF. The inhibition of kainic acid-induced seizure activity by rhGDNF also prevented the associated neuronal cell loss in hippocampal, thalamic and amygdaloid regions. These results suggest that rhGDNF should be evaluated in other seizure and acute neural disorders that are associated with excitotoxic processes.

DNA functional groups required for formation of open complexes between Escherichia coli RNA polymerase and the lambda PR promoter. Identification via base analog substitutions.

Synthetic 75-base pair promoters bearing base changes and/or base analog substitutions at selected positions were constructed. Using both abortive initiation and run-off transcription assays, the interaction of these altered promoters with Escherichia coli RNA polymerase was studied in order to determine the involvement of DNA functional groups in promoter recognition. Two adjacent thymines in the -35 region were identified whose 5-methyl groups play a crucial role. Additionally, the combined results from several substitution experiments showed that functional groups in the major groove of the strongly conserved T-A base pair at the -7 position are probable sites of direct interaction with RNA polymerase.

Adenosine cyclic 3',5'-monophosphate dependent protein kinase: a new fluorescence displacement titration technique for characterizing the nucleotide binding site on the catalytic subunit.

We determined the dissociation constant (Kd) of a series of nucleotides for the bovine skeletal muscle type II catalytic subunit by displacing lin-benzoadenosine 5'-diphosphate (lin-benzo-ADP) with increasing concentrations of competing nucleotide. The Kd of each nucleotide was calculated from the decreases in the fluorescence polarization of lin-benzo-ADP that accompany its displacement from the catalytic subunit. We found that modifications of the adenine moiety reduce nucleotide affinity for the enzyme. The effect was most pronounced with modifications at position 6 of the base. Replacement of the 3'-hydroxyl group of ribose with a hydrogen increased the affinity of the nucleotide; addition of phosphate to the 2'- or 3'-hydroxyl groups, on the other hand, decreased nucleotide affinity. MgATP and MgADP exhibited Kd's of about 10 microM. AMP, which contains a negatively charged alpha-phosphate, bound with reduced affinity (643 microM). Adenosine, which lacks a charged alpha-phosphate, bound with a higher affinity (32 microM). To learn more about the nature of the alpha-phosphate binding site, a series of uncharged and positively charged derivatives of the 5'-position on the ribose moiety was prepared. The uncharged derivatives bound with much greater affinity than the negatively charged AMP. The Kd's for 5'-tosyladenosine and 5'-iodo-5'-deoxyadenosine were 30 and 32 microM, respectively. Like the negatively charged AMP, positively charged derivatives also bound less tenaciously than the neutral species. The positively charged 5'-amino-5'deoxyadenosine, for example, exhibited a 15-fold higher Kd (506 microM) than the neutral congenors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine cyclic 3',5'-monophosphate dependent protein kinase: interaction of the catalytic subunit and holoenzyme with lin-benzoadenine nucleotides.

The interaction of lin-benzoadenosine di- and triphosphates with the catalytic subunit and type II holoenzymes of adenosine cyclic 3',5'-monophosphate (cAMP) dependent protein kinase has been investigated by steady-state kinetics and fluorescence spectroscopy. lin-Benzo-ADP is a competitive inhibitor of the catalytic subunit with respect to ATP with a Ki (8.0 microM) similar to the Ki for ADP (9.0 microM). This value agrees well with the Kd (9.0 microM) determined by fluorescence polarization titration. Type II holoenzymes from bovine brain and skeletal muscle have Kd values for lin-benzo-ADP of 3.4 microM and 3.5 microM, respectively, and each binds approximately 2 mol/mol of R2C2 tetramer. Furthermore, fluorescence polarization studies indicate that both the catalytic subunit and type II holoenzyme bind lin-benzo-ADP rigidly, so that there is little or no rotation of the lin-benzoadenine portion of the molecule within the nucleotide binding site. lin-Benzo-ATP is a substrate for the phosphotransferase activities of protein kinase with peptides, water, or type II regulatory subunit as phosphoryl acceptors. With Leu-Arg-Arg-Ala-Ser-Leu-Gly as phosphoryl acceptor, the Km for lin-benzo-ATP is 11.3 microM, and that for ATP is 11.9 microM. The Vmax with lin-benzo-ATP is 20% of the Vmax with ATP as the substrate [24.9 +/- 1.8 mumol/(min . mg) vs. 5.0 +/- 1.2 mumol/(min . mg)]. Thus lin-benzo-ATP is the best nucleotide substrate (besides ATP) for the catalytic subunit reported. 1,N6-Etheno-ATP (epsilon ATP), on the other hand, is a poor substrate for the catalytic subunit with a Km of 1.8 mM and a Vmax that is 4% of the Vmax for ATP, making it unsuitable as a fluorescence probe for cAMP-dependent protein kinase.