The severity and frequency distribution of endometriosis subtypes at different ages: a model to understand the natural history of endometriosis based on single centre/single surgeon data.

Background and Objective: to study the natural history of endometriosis. Materials and methods: the analysis of all women (n=2086) undergoing laparoscopy for pelvic pain and endometriosis between 1988 and 2011 at University Hospital Gasthuisberg. Main outcome measures: the severity of subtle, typical, cystic and deep endometriosis in adult women, with or without a pregnancy, as estimated by their pelvic area and their volume. Results: the number of women undergoing a laparoscopy increased up to 28 years of age and decreased thereafter. Between 24 and 44 years, the severity and relative frequencies of subtle, typical, cystic and deep lesions did not vary significantly. The number of women younger than 20 years was too small to ascertain the impression of less severe lesions. The severity of endometriosis lesions was not less in women with 1 or more previous pregnancies or with previous surgery. There was no bias over time since the type and severity of endometriosis lesions remained constant between 1988 and 2011. Conclusions: severity of endometriosis does not increase between 24 and 44 years of age, suggesting that growth is limited by intrinsic or extrinsic factors. Severity was not lower in women with a previous pregnancy. What is new: considering the time needed for lesions to become symptomatic together with the diagnostic delay, the decreasing number of laparoscopies after age 28 is compatible with a progressively declining risk of initiating endometriosis lesions after menarche, the remaining women being progessively less susceptible.

Nonvisualized palpable bowel endometriotic satellites.

STUDY QUESTION: What is the prevalence of laparoscopically nonvisualized palpable satellite bowel nodules at or near the planned stapler site in women undergoing segmental bowel resection for endometriosis? SUMMARY ANSWER: Overall, 13 (25.5%) of 51 patients who underwent resection had nonvisualized palpable satellite lesions as small as 2 mm, including seven (14%) who had nonvisualized palpable lesions at or beyond the planned stapler site. WHAT IS KNOWN ALREADY: Both laparoscopy and laparotomy for bowel resection are standard of care in Europe and the USA. Reoperation rates after laparoscopic bowel procedures are 1-16%. Endometriotic lesions at the stapler margin of bowel resections are associated with increased repeat surgery. Nodules of 0.1 mm to 1 cm in size were not recognized during laparoscopic bowel surgery but were recognized on histological examination. Up to 20 nodules not visualized at laparoscopy have been recognized and excised at laparotomy. Tenderness is found at up to 27 mm from a recognized lesion. The size of a lesion does not always predict its symptoms or behavior. STUDY DESIGN, SIZE, DURATION: This single-arm, observational study focused on the presence of nonvisualized palpable satellite lesions of the bowel. Fifty-one patients scheduled for laparoscopic-assisted bowel resection for deep infiltrating endometriosis with suprapubic incision for placement of the stapler's anvil and removal of the specimen in the course of routine clinical care were included. There were no additional inclusion or exclusion criteria. PARTICIPANTS/MATERIALS, SETTING, METHODS: Laparoscopic-assisted segmental bowel resection for endometriosis was performed in a private referral center on women aged 24-49 years. MAIN RESULTS AND THE ROLE OF CHANCE: Forty-nine (96.1%) of the 51 patients underwent segmental resection of the sigmoid or rectum, and 14 (27.5%) underwent segmental resection of the ileum for large nodule(s) recognized on MRI. Twelve patients underwent both procedures. Eleven (22.4%) of the 49 patients with recognized sigmoid or rectal lesions and 5 (35.7%) of the 14 patients with recognized ileal lesions had nonvisualized, palpable, satellite lesions. All the large lesions and none of the satellite lesions had been recognized preoperatively on MRI. Five (10%) of 49 patients with lesions of the large bowel and 4 (28.6%) of the 14 patients with lesions of the ileum had nonvisualized palpable satellite lesions at or beyond the planned stapler site. Lesions as small as 2 mm were palpable. LIMITATIONS, REASONS FOR CAUTION: This is an observational study. It is not known if the small lesions of this study contributed to the symptoms or were progressive, stable or regressive. This study analyzed lesions in the bowel segment proximal to the primary large bowel lesion, but not in the distal segment as that would have required a change in standard of care surgical technique. This study protocol did not include shaving or disk resection or patients in whom no lesions were visualized. The use of additional techniques for recognition, such as hand-assisted laparoscopy or rectal probes, was not investigated. WIDER IMPLICATIONS OF THE FINDINGS: This study confirms that some nonvisualized satellite lesions as small as 2 mm are palpable and that an increased length of resection can be used to remove lesions recognized by palpation and to avoid lesions at and beyond the stapler site. This may decrease recurrent surgery in 1-16% of the women undergoing surgery for bowel endometriosis. Knowledge of the occurrence of these small lesions may also be particularly useful in plans for repeat surgery or for women with clinically significant bowel symptoms and no visible lesions at laparoscopy. Moreover, small lesions are considered to be important as there is no current technique to determine whether a large primary lesion, smaller lesions, an associated adjacent tissue reaction or a combination of those cause symptoms. STUDY FUNDING/COMPETING INTEREST(S): This CIRENDO cohort was supported by the G4 Group (the University Hospitals of Rouen, Lille, Amiens and Caen) and the ROUENDOMETRIOSE association. No specific funding was received for the study. H.R. reports receiving personal fees from Plasma Surgical Inc., Ethicon Endosurgery, Olympus and Nordic Pharma for presentations related to his experience with endometriosis surgery. D.C.M. reports being given access to Lumenis Surgical CO2 Lasers' lab at a meeting. None of the other authors have conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: N/A.

Correction: Heterogeneity of endometriosis lesions requires individualisation of diagnosis and treatment and a different approach to research and evidence based medicine.

Statistical significance is used to analyse research findings and is together with biased free trials the cornerstone of evidence based medicine. However traditional statistics are based on the assumption that the population investigated is homogeneous without smaller hidden subgroups. The clinical, inflammatory, immunological, biochemical, histochemical and genetic-epigenetic heterogeneity of similar looking endometriosis lesions is a challenge for research and for diagnosis and treatment of endometriosis. The conclusions obtained by statistical testing of the entire group are not necessarily valid for subgroups. The importance is illustrated by the fact that a treatment with a beneficial effect in 80% of women but with exactly the same but opposite effect, worsening the disease in 20%, remains statistically highly significant. Since traditional statistics are unable to detect hidden subgroups, new approaches are mandatory. For diagnosis and treatment it is suggested to visualise individual data and to pay specific attention to the extremes of an analysis. For research it is important to integrate clinical, biochemical and histochemical data with molecular biological pathways and genetic-epigenetic analysis of the lesions.

Heterogeneity of endometriosis lesions requires individualisation of diagnosis and treatment and a different approach to research and evidence based medicine.

Statistical significance is used to analyse research findings and is together with biased free trials the cornerstone of evidence based medicine. However traditional statistics are based on the assumption that the population investigated is homogeneous without smaller hidden subgroups. The clinical, inflammatory, immunological, biochemical, histochemical and genetic-epigenetic heterogeneity of similar looking endometriosis lesions is a challenge for research and for diagnosis and treatment of endometriosis. The conclusions obtained by statistical testing of the entire group are not necessarily valid for subgroups. The importance is illustrated by the fact that a treatment with a beneficial effect in 80% of women but with exactly the same but opposite effect, worsening the disease in 20%, remains statistically highly significant. Since traditional statistics are unable to detect hidden subgroups, new approaches are mandatory. For diagnosis and treatment it is suggested to visualise individual data and to pay specific attention to the extremes of an analysis. For research it is important to integrate clinical, biochemical and histochemical data with molecular biological pathways and genetic-epigenetic analysis of the lesions.

Infection as a potential cofactor in the genetic-epigenetic pathophysiology of endometriosis: a systematic review.

BACKGROUND: The genetic-epigenetic theory postulates that endometriosis is triggered by a cumulative set of genetic-epigenetic (GE) incidents. Pelvic and upper genital tract infection might induce GE incidents and thus play a role in the pathogenesis of endometriosis. Thus, this article aims to review the association of endometriosis with upper genital tract and pelvic infections. METHODS: Pubmed, Scopus and Google Scholar were searched for 'endometriosis AND (infection OR PID OR bacteria OR viruses OR microbiome OR microbiota)', for 'reproductive microbiome' and for 'reproductive microbiome AND endometriosis', respectively. All 384 articles, the first 120 'best match' articles in PubMed for 'reproductive microbiome' and the first 160 hits in Google Scholar for 'reproductive microbiome AND endomytriosis' were hand searched for data describing an association between endometriosis and bacterial, viral or other infections. All 31 articles found were included in this manuscript. RESULTS: Women with endometriosis have a significantly increased risk of lower genital tract infection, chronic endometritis, severe PID and surgical site infections after hysterectomy. They have more colony forming units of Gardnerella, Streptococcus, Enterococci and Escherichia coli in the endometrium. In the cervix Atopobium is absent, but Gardnerella, Streptococcus, Escherichia, Shigella, and Ureoplasma are increased. They have higher concentrations of Escherichia Coli and higher concentrations of bacterial endotoxins in menstrual blood. A Shigella/Escherichia dominant stool microbiome is more frequent. The peritoneal fluid of women with endometriosis contains higher concentrations of bacterial endotoxins and an increased incidence of mollicutes and of HPV viruses. Endometriosis lesions have a specific bacterial colonisation with more frequently mollicutes (54%) and both high and medium-risk HPV infections (11%). They contain DNA with 96% homology with Shigella. In mice transplanted endometrium changes the gut microbiome while the gut microbiome influences the growth of these endometriosis lesions. CONCLUSIONS: Endometriosis is associated with more upper genital tract and peritoneal infections. These infections might be co-factors causing GE incidents and influencing endometriosis growth.

The Stone Cold Truth: The Effect of Concrete Encasement on the Rate and Pattern of Soft Tissue Decomposition.

This study provides a descriptive analysis of taphonomic changes observed in the soft tissue of ten pigs (Sus scrofa) after being encased in Quickrete (®) concrete and excavated at monthly or bimonthly intervals over the course of 2 years. The best method of subject excavation was investigated. Rate and pattern of decomposition were compared to a nonencased control subject. Results demonstrate subjects interred in concrete decomposed significantly slower than the control subject (p < 0.01), the difference being observable after 1 month. After 1 year, the encased subject was in the early stage of decomposition with purging fluids and intact organs present, versus complete skeletonization of the control subject. Concrete subjects also display a unique decomposition pattern, exhibiting a chemically burned outer layer of skin and a common separation of the dermal and epidermal layers. Results suggest using traditional methods to estimate postmortem interval on concrete subjects may result in underestimation.

Lemonade from lemons: the taphonomic effect of lawn mowers on skeletal remains.

This study provides a descriptive analysis of the taphonomic changes produced by passing over skeletonized remains (n = 4, Sus scrofa) with three common lawn mowers. Two skeletons were mowed over with a riding lawn mower set at multiple blade heights (10.16, 7.62, 5.08 cm) and one each with a rotary mower (9.53, 6.35 cm) and a mulching mower (6.35 cm). Results show that different types of common lawn mowers will produce different patterns of bone dispersal and fragmentation rates. Overall, skeletal elements projecting upward from the surface frequently exhibited a sheared morphology characterized by a smooth, flat, cut surface (7.0-7.6% of elements). The push mowers yielded a higher frequency of undamaged bone than the riding mower (54.8-61.2% vs. 17.7%), and the riding mower created more catastrophic damage to skeletal elements. Additionally, each mower produced a distinct dispersal pattern of skeletal fragments. The dispersal patterns have been identified as "bull's-eye" (riding), circular (mulching), and discontinuous rectangle (rotary).

Geographic variation in the taphonomic effect of vulture scavenging: the case for Southern Illinois.

The taphonomic effect of vulture scavenging has been previously documented in central Texas (J Forensic Sci, 2009, 54, 524). This study reports on the behavioral differences between two species of vultures (Coragyps atratus, Cathartes aura) observed over a period of 1 year at the Complex for Forensic Anthropology Research in Southern Illinois. The decomposition of six research subjects and two control subjects was observed. Compared with the previous findings of vulture activity, the authors observed a severe delay in the time of first arrival (up to 28 days), decreased feeding time on remains (14-40 min), a less voracious feeding rate (7 days to 2 months to skeletonization), and a completely different feeding pattern of vultures in Southern Illinois. Additionally, no characteristic markings were observed on skeletal elements of research subjects. This study suggests the taphonomic effects of scavengers varies with climate and regions and may affect decomposition rates and patterns.

An ultraviolet-optical flare from the tidal disruption of a helium-rich stellar core.

The flare of radiation from the tidal disruption and accretion of a star can be used as a marker for supermassive black holes that otherwise lie dormant and undetected in the centres of distant galaxies. Previous candidate flares have had declining light curves in good agreement with expectations, but with poor constraints on the time of disruption and the type of star disrupted, because the rising emission was not observed. Recently, two 'relativistic' candidate tidal disruption events were discovered, each of whose extreme X-ray luminosity and synchrotron radio emission were interpreted as the onset of emission from a relativistic jet. Here we report a luminous ultraviolet-optical flare from the nuclear region of an inactive galaxy at a redshift of 0.1696. The observed continuum is cooler than expected for a simple accreting debris disk, but the well-sampled rise and decay of the light curve follow the predicted mass accretion rate and can be modelled to determine the time of disruption to an accuracy of two days. The black hole has a mass of about two million solar masses, modulo a factor dependent on the mass and radius of the star disrupted. On the basis of the spectroscopic signature of ionized helium from the unbound debris, we determine that the disrupted star was a helium-rich stellar core.

Conduction Properties Of Decellularized Nerve Biomaterials.

The purpose of this study is to optimize poly(3,4,-ethylenedioxythiophene) (PEDOT) polymerization into decellular nerve scaffolding for interfacing to peripheral nerves. Our ultimate aim is to permanently implant highly conductive peripheral nerve interfaces between amputee, stump, nerve fascicles and prosthetic electronics. Decellular nerve (DN) scaffolds are an FDA approved biomaterial (Axogen ) with the flexible tensile properties needed for successful permanent coaptation to peripheral nerves. Biocompatible, electroconductive, PEDOT facilitates electrical conduction through PEDOT coated acellular muscle. New electrochemical methods were used to polymerize various PEDOT concentrations into DN scaffolds without the need for a final dehydration step. DN scaffolds were then tested for electrical impedance and charge density. PEDOT coated DN scaffold materials were also implanted as 15-20mm peripheral nerve grafts. Measurement of in-situ nerve conduction immediately followed grafting. DN showed significant improvements in impedance for dehydrated and hydrated, DN, polymerized with moderate and low PEDOT concentrations when they were compared with DN alone (a ≤ 0.05). These measurements were equivalent to those for DN with maximal PEDOT concentrations. In-situ, nerve conduction measurements demonstrated that DN alone is a poor electro-conductor while the addition of PEDOT allows DN scaffold grafts to compare favorably with the "gold standard", autograft (Table 1). Surgical handling characteristics for conductive hydrated PEDOT DN scaffolds were rated 3 (pliable) while the dehydrated models were rated 1 (very stiff) when compared with autograft ratings of 4 (normal). Low concentrations of PEDOT on DN scaffolds provided significant increases in electro active properties which were comparable to the densest PEDOT coatings. DN pliability was closely maintained by continued hydration during PEDOT electrochemical polymerization without compromising electroconductivity.

An analysis of secular change in the human mandible over the last century.

In light of several recent investigations that have identified notable secular change in cranial size and morphology over the last century, the present study addresses its possible effects in the mandible in U.S. populations. Standard measurements of 407 mandibles from the Terry (Smithsonian) and Hamann-Todd (Cleveland Museum of Natural History) Collections, which are primarily composed of individuals living in the early 20th century, were compared with those of 595 mandibles from the Forensic Anthropology Database (Tennessee), which is primarily composed of individuals living from the later part of the century. The t-tests between the two temporally-different samples by sex and race showed statistically significant decreases in mandibular body width and bigonial breadth as well as significant increases in mandibular body length in nearly all subgroups. White males showed the greatest amount of change, and Black females, the least. Overall, these findings support the conclusion that the mandible is transforming into a longer, narrower, more gracile bone, paralleling many of the morphological shifts seen in the cranium. Factors involved likely include changes in diet, medical care, and dental practices.

Müllerianosis.

Müllerianosis may be defined as an organoid structure of embryonic origin; a choristoma composed of müllerian rests--normal endometrium, normal endosalpinx, and normal endocervix--singly or in combination, incorporated within other normal organs during organogenesis. A choristoma is a mass of histologically normal tissue that is "not normally found in the organ or structure in which it is located" (Choristoma, 2006). Müllerian choristomas are a subset of non-müllerian choristomas found throughout the body. Histologically, endometrial-müllerianosis and endometriosis are both composed of endometrial glands and stroma, but there the similarity ends. Their pathogenesis is different. Sampson faced the same difficulty with pathogenesis and nomenclature when he wrote: "The nomenclature of misplaced endometrial or müllerian lesions is a difficult one to decide upon." "The term müllerian would be inclusive and correct, but unfortunately it suggests an embryonic origin." Sampson then divided "misplaced endometrial or müllerian tissue" into "four or possibly five groups, according to the manner in which this tissue reached its ectopic location" (Sampson, 1925). Sampson's classification of heterotopic or misplaced endometrial tissue is based on pathogenesis: 1) "direct or primary endometriosis" [adenomyosis]; "a similar condition occurs in the wall of the tube from its invasion by the tubal mucosa" [endosalpingiosis]; 2) "peritoneal or implantation endometriosis;" 3) "transplantation endometriosis;" 4) "metastatic endometriosis;" and 5) "developmentally misplaced endometrial tissue. (I admit the possibility of such a condition, but have never been able to appreciate it.)" (Sampson, 1925). It is precisely this condition "developmentally misplaced endometrial tissue," [müllerianosis] that is the subject of this review.

Comparing human skeletal muscle architectural parameters of cadavers with in vivo ultrasonographic measurements.

The purpose of this study was to document and compare the architectural parameters (fibre bundle length, angle of pennation) of human skeletal muscle in cadaveric specimens and live subjects. The medial (MG) and lateral (LG) gastrocnemius, and posterior (PS) and anterior (AS) soleus were examined bilaterally in 5 cadavers (mean age 72.6, range 65-83 y) and 9 live subjects (mean age 76.3, range 70-92 y). Data were obtained from direct measurement of cadaveric specimens and from ultrasonographic scans of the live subjects. In cadaveric muscle, fibre bundles were isolated; their length was measured in millimetres and pennation angles were recorded in degrees. In live muscle, similar measurements were taken from ultrasonographic scans of relaxed and contracted muscle. For the scans of relaxed muscle, subjects were positioned prone with the foot at a 90 degrees angle to the leg, and for scans of contracted muscle, subjects were asked to sustain full plantarflexion during the scanning process. Fibre bundle length and angle of pennation were compared at matched locations in both groups. It was found that the relationship between cadaveric and in vivo values for fibre length and angle of pennation varied between muscle parts. The cadaveric architectural parameters did not tend to lie consistently towards either extreme of relaxation or contraction. Rather, within MG, PS and AS, cadaveric fibre bundle lengths lay between those for relaxed and contracted in vivo muscle. Similarly both the anterior and posterior cadaveric fibre angles of pennation lay between the in vivo values within LG and PS. In summary, architectural characteristics of cadaveric muscle differ from both relaxed and contracted in vivo muscle. Therefore, when developing models of skeletal muscle based on cadaveric studies, the architectural differences between live and cadaveric tissue should be taken into consideration.

Comparing methods to identify general internal medicine clinic patients with chronic heart failure.

OBJECTIVES: Identification of patients with left ventricular systolic dysfunction is the first step in identifying which patients may benefit from clinical practice guidelines. The purpose of this study was to develop and validate a computerized tool using clinical information that is commonly available to identify patients with left ventricular systolic dysfunction (LVSD). METHODS: We performed a cross-sectional study of patients seen in a Department of Veterans Affairs General Internal Medicine Clinic who had echocardiography or radionuclide ventriculography performed as part of their clinical care. RESULTS: We identified 2246 subjects who had at least one cardiac imaging study. A total of 778 (34.6%) subjects met study criteria for LVSD. Subjects with LVSD were slightly older than subjects without LVSD (70 years vs 68 years, P =.00002) but were similar with regard to sex and race. Subjects with LVSD were more likely to have prescriptions for angiotensin-converting enzyme (ACE) inhibitors, carvedilol, digoxin, loop diuretics, hydralazine, nitrates, and angiotensin II receptor antagonists. Of the variables included in the final predictive model, ACE inhibitors, loop diuretics, and digoxin exerted the greatest predictive power. Discriminant analysis demonstrated that models containing pharmacy information were consistently more accurate (75% accurate [65% sensitivity, 81% specificity]) than those models that contained only International Classification of Diseases, 9th revision (ICD-9), codes, including ICD-9 codes for congestive heart failure (72% accurate [80% sensitivity, 68% specificity]). CONCLUSIONS: We demonstrated that an automated, computer-driven algorithm identifying LVSD permits simple, rapid, and timely identification of patients with congestive heart failure by use of only routinely collected data. Future research is needed to develop accurate electronic identification of heart failure and other common chronic conditions.

Regional variations in health status.

CONTEXT: Knowledge about variations in the health status of patients seeking primary care in different parts of the United States is limited. OBJECTIVE: To examine regional variations in the physical and mental health of patients receiving primary care in the largest integrated health care system in the United States which is operated by the Department of Veteran Affairs (VA). STUDY DESIGN AND SETTING: We performed a mailed, cross sectional survey of 54,844 patients who were enrolled in seven VA General Internal Medicine clinics. RESULTS: Among the 30,690 patients who returned an initial set of screening questionnaires, the prevalence of common chronic conditions varied by as much as 60% among the seven clinics. Moreover, patients' general health (measured by the SF-36) also varied significantly in a pattern that mirrored the observed differences in the prevalence of chronic conditions. After adjustment for important comorbid illnesses and sociodemographic factors, geographic site accounted for a small percentage of the explained variance in patient assessed health status. CONCLUSIONS: The substantial differences in the health of patients enrolled in different VA primary clinics have important implications for the evaluation of clinical performance and health outcomes. Most of these differences can be attributed to sociodemographic and comorbid factors.

Surface modification of neural recording electrodes with conducting polymer/biomolecule blends.

The interface between micromachined neural microelectrodes and neural tissue plays an important role in chronic in vivo recording. Electrochemical polymerization was used to optimize the surface of the metal electrode sites. Electrically conductive polymers (polypyrrole) combined with biomolecules having cell adhesion functionality were deposited with great precision onto microelectrode sites of neural probes. The biomolecules used were a silk-like polymer having fibronectin fragments (SLPF) and nonapeptide CDPGYIGSR. The existence of protein polymers and peptides in the coatings was confirmed by reflective microfocusing Fourier transform infrared spectroscopy (FTIR). The morphology of the coating was rough and fuzzy, providing a high density of bioactive sites for interaction with neural cells. This high interfacial area also helped to lower the impedance of the electrode site and, consequently, to improve the signal transport. Impedance spectroscopy showed a lowered magnitude and phase of impedance around the biologically relevant frequency of 1 kHz. Cyclic voltammetry demonstrated the intrinsic redox reaction of the doped polypyrrole and the increased charge capacity of the coated electrodes. Rat glial cells and human neuroblastoma cells were seeded and cultured on neural probes with coated and uncoated electrodes. Glial cells appeared to attach better to polypyrrole/SLPF-coated electrodes than to uncoated gold electrodes. Neuroblastoma cells grew preferentially on and around the polypyrrole/CDPGYIGSR-coated electrode sites while the polypyrrole/CH(3)COO(-)-coated sites on the same probe did not show a preferential attraction to the cells. These results indicate that we can adjust the chemical composition, morphology, electronic transport, and bioactivity of polymer coatings on electrode surfaces on a multichannel micromachined neural probe by controlling electrochemical deposition conditions.

Surface characterization of porous, biocompatible protein polymer thin films.

Genetically engineered protein polymer coatings are intended to improve the performance of implantable neural prosthetic devices. To facilitate device integration with tissue, three-dimensionally structured protein polymer films were deposited on the devices using electrostatic atomization and gas-evolution foaming. Periodic features and the length-scale dependence of the surface roughness were identified in topographic data collected using scanning probe microscopy. Using the power spectral density of surface data, the influence of process parameters on the surface roughness of protein polymer thin films was examined. Details of surface topography are known to influence biological behavior, and the method presented was capable of quantifying the evolution of surface features at biologically relevant length scales. This study provides a means for the quantitative exploration of the effects of topography on the performance of these devices and on biocompatibility in general.