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.

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.

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.

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.

Insulin-like growth factor II signaling in neoplastic proliferation is blocked by transgenic expression of the metalloproteinase inhibitor TIMP-1.

Insulin-like growth factor (IGF) II is overexpressed in many human cancers and is reactivated by, and crucial for viral oncogene (SV40 T antigen, [TAg])-induced tumorigenesis in several tumor models. Using a double transgenic murine hepatic tumor model, we demonstrate that tissue inhibitor of metalloproteinase 1 (TIMP-1) blocks liver hyperplasia during tumor development, despite TAg-mediated reactivation of IGF-II. Because the activity of IGFs is controlled by IGF-binding proteins (IGFBPs), we investigated whether TIMP-1 overexpression altered the IGFBP status in the transgenic liver. Ligand blotting showed that IGFBP-3 protein levels were increased in TIMP-1-overexpressing double transgenic littermates, whereas IGFBP-3 mRNA levels were not different, suggesting that TIMP-1 affects IGFBP-3 at a posttranscriptional level. IGFBP-3 proteolysis assays demonstrated that IGFBP-3 degradation was lower in TIMP-1-overexpressing livers, and zymography showed that matrix metalloproteinases (MMPs) were present in the liver homogenates and were capable of degrading IGFBP-3. As a consequence of reduced IGFBP-3 proteolysis and elevated IGFBP-3 protein levels, dissociable IGF-II levels were significantly lower in TIMP-1-overexpressing animals. This decrease in bioavailable IGF-II ultimately resulted in diminished IGF-I receptor signaling in vivo as evidenced by diminished receptor kinase activity and decreased tyrosine phosphorylation of the IGF-I receptor downstream effectors, insulin receptor substrate 1 (IRS-1), extracellular signal regulatory kinase (Erk)-1, and Erk-2. Together, these results provide evidence that TIMP-1 inhibits liver hyperplasia, an early event in TAg-mediated tumorigenesis, by reducing the activity of the tumor-inducing mitogen, IGF-II. These data implicate the control of MMP-mediated degradation of IGFBPs as a novel therapy for controlling IGF bioavailability in cancer.

Direct imaging of the diacetylene solid-state monomer-polymer phase transformation.

The solid-state phase transformation from 1,6-di(N-carbazolyl)-2-4-hexadiyne (DCHD) diacetylene monomer to polymer has been studied dynamically by low-dose selected area electron diffraction and high-resolution electron microscopy. The total exposure required to induce polymerization is five orders of magnitude smaller than the critical dose for electron beam damage. The phase transformation is quasi-homogeneous, with the lattice parameters changing continuously as a function of beam dose. Characteristic streaking that develops in the selected area electron diffraction patterns in the [200] reciprocal directions during the intermediate stages of the transformation provides information about the defect-mediated mechanisms of this reaction.

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.

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.

Inhibition of SV40 T antigen-induced hepatocellular carcinoma in TIMP-1 transgenic mice.

The potential of tissue inhibitors of metalloproteinases (TIMPs) to inhibit neoplastic progression has been postulated from studies of genetically manipulated cells. To investigate whether the TIMP-1 expressed in a host tissue suppresses cancer in vivo and to identify the affected stages, we developed transgenic mice with constitutive overexpression or reduction of TIMP-1 in the liver. In double transgenic experiments, the TIMP-1 lines were crossed with a second transgenic line which expresses the Simian Virus 40t/T antigen (TAg). This viral oncogene leads to heritable development of hepatocellular carcinomas with a 100% incidence. Effects of TIMP-1 coexpression on the TAg-induced neoplasms were determined at the tissue and cellular level. Here, we report that overexpression of hepatic TIMP-1 blocked the development of TAg-induced hepatocellular carcinomas. High TIMP-1 levels inhibited not only the later stages in tumor development (growth and angiogenesis), but also events associated with tumor initiation (altered hepatocyte cytology and tissue architecture). We further show that an antisense-mediated reduction of TIMP-1 resulted in a more rapid tumor initiation and progression. These data demonstrate that intrinsic TIMP-1 levels contribute to a tissue's susceptibility to viral oncogene-induced tumorigenesis.

Host TIMP-1 overexpression confers resistance to experimental brain metastasis of a fibrosarcoma cell line.

Within the tumor-stromal microenvironment a disrupted balance between matrix metalloproteinases (MMPs) and their inhibitors compromises the integrity of the extracellular matrix and promotes malignancy. Tissue inhibitors of metalloproteinases (TIMPs) have been linked to tumor suppression in studies of genetically altered tissue culture cells and in analyses of clinical specimens in situ. We generated transgenic mice as a model system to test the relationship between TIMP-1 levels in a host organ and susceptibility to experimentally targeted metastasis. Ectopically overexpressed TIMP-1 in the brain resulted in a tissue microenvironment with elevated protein levels of this natural MMP inhibitor. Metastatic challenge provided by lacZ-tagged fibrosarcoma cells permitted high-resolution analysis of metastatic load and pattern. We found that elevated host TIMP-1 imposed resistance to experimental metastasis of fibrosarcoma: In TIMP-1 overexpressing mice, brain metastases were significantly reduced by 75% compared to wild-type littermates. Our findings demonstrate that ectopic TIMP-1 expression efficiently exerts a suppressive effect on metastasizing tumor cells.

Clinical prediction rules for computed tomographic scanning in senile dementia.

The role of computed tomography (CT) of the head in evaluating patients with dementing illnesses remains a controversial issue. Several prediction rules to guide the selective application of CT in the evaluation of dementia have recently been proposed in the medical literature. The present authors examine the value of four such rules through a validation study performed in an outpatient geriatric assessment unit. The rules were assessed in terms of their diagnostic sensitivities, specificities, misclassification rates, and information contents. Prediction rule sensitivities ranged from 12.5% to 87.5%, specificities from 37.2% to 77.9%, and misclassification rates from 23.5% to 60.8%. Of the four prediction rules examined, one emerged as significantly more sensitive than the others, and also served to reduce diagnostic uncertainty a full order of magnitude more than the others, as determined by an information content analysis. Disadvantages to this rule, however, were found in its more complex nature and the assessment of a very high rate of misclassification. Through a critique of existing strategies, this study purports to determine the potential for establishing a useful clinical prediction rule to guide selective CT scanning in the diagnostic evaluation of dementia.

Carotid artery disease in NIDDM diabetes.

A prospective study of 135 controls, 286 non-insulin-dependent diabetic patients, and 31 subjects with an elevated fasting plasma glucose was performed to assess the prevalence of high-grade carotid artery stenosis. The carotid artery evaluation was performed using an ultrasonic duplex scanner. When those patients with an elevated fasting plasma glucose and non-insulin-dependent diabetes were considered together, the prevalence was 8.2% as compared with 0.7% for the controls (P = 0.0007). Those risk factors found to be significantly related to the higher prevalence of carotid disease in the combined groups of patients included age, ratio of systolic blood pressure to diastolic blood pressure, plasma cholesterol, and cigarette smoking. These findings may be an explanation for the greater incidence of stroke in patients with diabetes mellitus.

Progression of lower-extremity arterial occlusive disease in type II diabetes mellitus.

The prevalence of lower-extremity arterial occlusive disease (LEAOD), the progression of LEAOD, and the incidence of new LEAOD were determined by noninvasive method in 410 volunteers between the ages of 50 and 70 yr; 252 individuals had type II (non-insulin-dependent) diabetes, 158 were control subjects. LEAOD was monitored with the ankle/arm systolic blood pressure index in combination with Doppler arterial velocity waveform analysis. LEAOD was much more prevalent in the type II patients (22%, 55 of 252) than in the control subjects (3%, 4 of 158) (P less than .00001). The prevalence of risk factors for LEAOD was much higher in the type II patients, including elevated triglyceride, depressed high-density lipoprotein (HDL) cholesterol, hypertension, smoking, and elevated systolic blood pressure. In type II diabetic patients the incidence of new LEAOD over a 2-yr period (14%, 28 of 197) was lower than the incidence of LEAOD progression (87%, 45 of 52). Type II patients with LEAOD also had a high incidence of mortality (22%, 12 of 55) compared with those without LEAOD (4%, 8 of 197) (P less than .0005). A risk score including smoking history, duration of diabetes, depressed HDL cholesterol, total cholesterol, elevated systolic blood pressure, and low obesity index is related to LEAOD. After accounting for the effect of all of the risk factors, we suggest that type II diabetes contributes additional risk for LEAOD.

Amino acid substitutions at the subunit interface of dimeric Escherichia coli alkaline phosphatase cause reduced structural stability.

The consequences of amino acid substitutions at the dimer interface for the strength of the interactions between the monomers and for the catalytic function of the dimeric enzyme alkaline phosphatase from Escherichia coli have been investigated. The altered enzymes R10A, R10K, R24A, R24K, T59A, and R10A/R24A, which have amino acid substitutions at the dimer interface, were characterized using kinetic assays, ultracentrifugation, and transverse urea gradient gel electrophoresis. The kinetic data for the wild-type and altered alkaline phosphatases show comparable catalytic behavior with k(cat) values between 51.3 and 69.5 s(-1) and Km values between 14.8 and 26.3 microM. The ultracentrifugation profiles indicate that the wild-type enzyme is more stable than all the interface-modified enzymes. The wild-type enzyme is dimeric in the pH range of pH 4.0 and above, and disassembled at pH 3.5 and below. All the interface-modified enzymes, however, are apparently monomeric at pH 4.0, begin assembly at pH 5.0, and are not fully assembled into the dimeric form until pH 6.0. The results from transverse urea gradient gel electrophoresis show clear and reproducible differences both in the position and the shape of the unfolding patterns; all these modified enzymes are more sensitive to the denaturant and begin to unfold at urea concentrations between 1.0 and 1.5 M; the wild-type enzyme remains in the folded high mobility form beyond 2.5 M urea. Alkaline phosphatase H370A, modified at the active site and not at the dimer interface, resembles the wild-type enzyme both in ultracentrifugation and electrophoresis studies. The results obtained suggest that substitution of a single amino acid at the interface sacrifices not only the integrity of the assembled dimer, but also the stability of the monomer fold, even though the activity of the enzyme at optimal pH remains unaffected and does not appear to depend on interface stability.

Sodium lactate and hypertonic sodium chloride induce equivalent panic incidence, panic symptoms, and hypernatremia in panic disorder.

BACKGROUND: Although experimental induction of panic by infusion of 0.5 mol/L sodium lactate in persons with panic disorder was described three decades ago, the mechanism underlying this observation remains unclear. Here we asked if the rapid administration of the large sodium load contained in the 0.5-mol/L sodium lactate infusion might be involved in panic induction. METHODS: We compared in panic disorder and healthy subjects behavioral, electrolyte, endocrine, and acid-base responses to three double-blind randomly ordered equal volume 20-min infusions: 0.5 mol/L sodium lactate, hypertonic saline (3% sodium chloride), and normal saline placebo. RESULTS: Sodium lactate (0.5 mol/L) and hypertonic saline produced the same high incidence of panic and equivalent increases in panic symptoms, serum sodium, and plasma vasopressin in the panic disorder subjects. Neither hypertonic infusion increased cortisol or adrenocorticotropin. No normal subject experienced panic in any condition. The 0.5-mol/L sodium lactate infusion induced alkalosis, whereas hypertonic saline and normal saline induced a mild acidosis. CONCLUSIONS: Hypertonic sodium solution containing either chloride or lactate anion induces panic in panic disorder. The large sodium loads delivered by hypertonic saline and 0.5 mol/L sodium lactate may be involved in the mechanism of panic induction.

Circadian temperature rhythms in young adult and aged men.

The core body temperatures of ten healthy young adult and eight healthy aged men were recorded continuously for 14-24 hours using rectal thermometers and analog tape recorders. Aged subjects had significantly higher temperatures at the nadir of the temperature curve compared to the young subjects. Cosinor analysis of the data revealed that, while all subjects' data significantly fit an idealized cosine function of 24 hours periodicity, the peak to trough amplitude of the rhythm was significantly lower in the aged group. No group differences in the 24-hour mean temperature, the mean temperature during the sleep period time, the mesor, or the acrophase were found. These data are in essential agreement with previously reported data but expand upon those findings and demonstrate that the age-related changes in amplitude of the temperature rhythm are not confined to subjects studied under isolated laboratory environments.