Surgical management of pelvic organ prolapse.

Despite pelvic organ prolapse being a universal problem experienced in nearly 50% of parous women, the surgical management of vaginal prolapse remains an enigma to many, with wide variation in the rates and types of intervention performed. As part of the 6th International Consultation on Incontinence (ICI) our committee, charged with producing an evidence-based report on the surgical management of prolapse, produced a pathway for the surgical management of prolapse. The 2017 ICI surgical management of prolapse evidence-based pathway will be presented and summarized. Weaknesses of the data and pathway will be discussed and avenues for future research proposed.

Error adjustments for file linking methods using encrypted unique client identifier (eUCI) with application to recently released prisoners who are HIV+.

Incarceration provides an opportunity to test for HIV, provide treatment such as highly active anti-retroviral therapy, as well as link infected persons to comprehensive HIV care upon their release. A key factor in assessing the success of a program that links released individuals to care is the time from release to receiving care in the community (linkage time). To estimate the linkage time, records from correction systems are linked to Ryan White Clinic data using encrypted Unique Client Identifier (eUCI). Most of the records that were linked using eUCI belong to the same individual; however, in some cases, it may link records incorrectly, or not identify records that should have been linked. We propose a Bayesian procedure that relies on the relationships between variables that appear in either of the data sources, as well as variables that exists in both to identify correctly linked records among all linked records. The procedure generates K datasets in which each pair of linked records is identified as a true link or a false link. The K datasets are analyzed independently, and the results are combined using Rubin's multiple imputation rules. A small validation dataset is used to examine different statistical models and to inform the prior distributions of the parameters. In comparison with previously proposed methods, the proposed method utilizes all of the available data and is both flexible and computationally efficient. In addition, this approach can be applied in other file linking applications.

Estimating energy expenditure in mice using an energy balance technique.

OBJECTIVE: To compare, in mice, the accuracy of estimates of energy expenditure (EE) using an energy balance technique (TEEbal: food energy intake and body composition change) vs indirect calorimetry (TEEIC). SUBJECTS: In 32 male C57BL/6J mice, EE was estimated using an energy balance (caloric intake minus change in body energy stores) method over a 37-day period. EE was also measured in the same animals by indirect calorimetry. These measures were compared. RESULTS: The two methods were highly correlated (r(2)=0.87: TEEbal=1.07*TEEIC-0.22, P<0.0001). By Bland-Altman analysis, TEEbal estimates were slightly higher (4.6±1.5%; P<0.05) than TEEIC estimates (Bias=0.55 kcal per 24 h). CONCLUSION: TEEbal can be performed in 'home cages' and provides an accurate integrated long-term measurement of EE while minimizing potentially confounding stress that may accompany the use of indirect calorimetry systems. The technique can also be used to assess long-term energy intake.

Robust estimation of causal effects of binary treatments in unconfounded studies with dichotomous outcomes.

The estimation of causal effects has been the subject of extensive research. In unconfounded studies with a dichotomous outcome, Y, Cangul, Chretien, Gutman and Rubin (2009) demonstrated that logistic regression for a scalar continuous covariate X is generally statistically invalid for testing null treatment effects when the distributions of X in the treated and control populations differ and the logistic model for Y given X is misspecified. In addition, they showed that an approximately valid statistical test can be generally obtained by discretizing X followed by regression adjustment within each interval defined by the discretized X. This paper extends the work of Cangul et al. 2009 in three major directions. First, we consider additional estimation procedures, including a new one that is based on two independent splines and multiple imputation; second, we consider additional distributional factors; and third, we examine the performance of the procedures when the treatment effect is non-null. Of all the methods considered and in most of the experimental conditions that were examined, our proposed new methodology appears to work best in terms of point and interval estimation.

Increased morbidity in combined abdominal sacrocolpopexy and abdominoplasty procedures.

INTRODUCTION AND HYPOTHESIS: This study was performed to determine whether abdominoplasty combined with abdominal sacrocolpopexy (ASC + A) increases perioperative morbidity compared with ASC alone. We hypothesized that patients undergoing combined procedures would have increased complications. METHODS: This was a multicenter, retrospective cohort study of all women undergoing ASC + A from 2002 to 2010 at Washington Hospital Center and Johns Hopkins University. We selected two women undergoing ASC alone for comparison with each ASC + A patient. Baseline demographics, surgical data, length of hospitalization, and perioperative complications were recorded. The primary outcome was any major complication within 6 weeks of surgery, including intraoperative complications, pulmonary embolism (PE), deep venous thrombosis (DVT), cardiac compromise, intensive care unit (ICU) admission, reoperation, and readmission. Surgical data and minor complications were also compared. RESULTS: Twenty-six ASC + A patients and 52 ASC patients were identified. There were no significant differences in baseline characteristics between groups. Patients with ASC + A had longer operating times (337 vs 261 min, p < 0.01), more intravenous fluid administration intraoperatively (4,665 vs 3181 ml, p < 0.01), and longer hospital stays (3.7 vs 2.7 days, p < 0.01). Major complications occurred in 23 % of the ASC + A group compared with 12 % of the ASC group (p = 0.20). The ASC + A group had greater declines in hematocrit levels and higher rates of PE, ICU admission, and blood transfusion, all of which were statistically significant. CONCLUSIONS: ASC + A increases length of stay and perioperative complications, such as PE, ICU admission, and blood transfusion, compared with ASC alone. Surgeons should consider recommending interval abdominoplasty due to increased morbidity risk with a combined procedure.

Peroxisome proliferator-activated receptor α (PPARα) activation advances locomotor activity and feeding daily rhythms in mice.

Peroxisome proliferator-activated receptors (PPARs) are key mediators of energy homeostasis, and lipid and glucose metabolism that exhibit circadian expression. PPAR activating drugs are used clinically as lipid and glucose-lowering drugs. We evaluated the effect of long-term (11 weeks) PPARα and PPARγ activation using bezafibrate and rosiglitazone, respectively, on metabolism, locomotor activity and feeding rhythms of non-obese mice. We found that bezafibrate, but not rosiglitazone, led to no weight gain and a slight weight loss with reduced epididymal fat pads. Although rosiglitazone had a minor effect on 24-h food intake rhythm, bezafibrate treatment was accompanied by increased amplitude and an advanced acrophase of the 24-h feeding rhythm. Similarly, unlike rosiglitazone, bezafibrate treatment was accompanied by a significantly advanced acrophase of locomotor activity rhythm under constant darkness conditions. As disrupted circadian rhythms lead to obesity, PPARα activation can serve as a clinical target for the modulation of both circadian rhythms and metabolism.

Spontaneous caloric restriction associated with increased leptin levels in obesity-resistant αMUPA mice.

BACKGROUND: αMUPA mice carry as a transgene the cDNA encoding urokinase-type plasminogen activator, a member of the plasminogen/plasmin system that functions in fibrinolysis and extracellular proteolysis. These mice spontaneously consume less food when fed ad libitum and live longer compared with wild-type (WT) control mice. αMUPA mice are obesity resistant and they share many similarities with calorically restricted animals. However, extensive metabolic characterization of this unique transgenic model has never been performed. METHOD: Metabolism of αMUPA mice was analyzed by measuring hormone, lipid and glucose levels in the serum, as well as gene and protein expression levels in the liver, hypothalamus and brainstem. RESULTS: αMUPA mice were found to be leaner than WT mice mainly because of reduced fat depots. Serum analyses showed that αMUPA mice have high levels of the anorexigenic hormones insulin and leptin, and low levels of the orexigenic hormone ghrelin. Analyses of brain neuropeptides showed that the transcript of the anorexigenic neuropeptide Pomc is highly expressed in the brainstem, whereas the expression of the orexigenic neuropeptides Npy, Orexin and Mch is blunted in the hypothalamus of αMUPA mice. In addition, adenosine monophosphate (AMP)-activated protein kinase (AMPK) levels were higher in the liver and lower in the hypothalamus, thus promoting simultaneously central reduction in appetite and peripheral loss of fat. The levels of SIRT1 were low in the liver, but high in the hypothalamus, a feature that αMUPA mice share with calorically restricted animals. CONCLUSION: Taken together, αMUPA mice exhibit a unique metabolic phenotype of low-calorie intake and high leptin levels, and could serve as a model for both spontaneous calorie restriction and resistance to obesity.

Effects of chronic weight perturbation on energy homeostasis and brain structure in mice.

Maintenance of reduced body weight in lean and obese human subjects results in the persistent decrease in energy expenditure below what can be accounted for by changes in body mass and composition. Genetic and developmental factors may determine a central nervous system (CNS)-mediated minimum threshold of somatic energy stores below which behavioral and metabolic compensations for weight loss are invoked. A critical question is whether this threshold can be altered by environmental influences and by what mechanisms such alterations might be achieved. We examined the bioenergetic, behavioral, and CNS structural responses to weight reduction of diet-induced obese (DIO) and never-obese (CON) C57BL/6J male mice. We found that weight-reduced (WR) DIO-WR and CON-WR animals showed reductions in energy expenditure, adjusted for body mass and composition, comparable (-10-15%) to those seen in human subjects. The proportion of excitatory synapses on arcuate nucleus proopiomelanocortin neurons was decreased by ∼50% in both DIO-WR and CON-WR mice. These data suggest that prolonged maintenance of an elevated body weight (fat) alters energy homeostatic systems to defend a higher level of body fat. The synaptic changes could provide a neural substrate for the disproportionate decline in energy expenditure in weight-reduced individuals. This response to chronic weight elevation may also occur in humans. The mouse model described here could help to identify the molecular/cellular mechanisms underlying both the defense mechanisms against sustained weight loss and the upward resetting of those mechanisms following sustained weight gain.

Testing treatment effects in unconfounded studies under model misspecification: logistic regression, discretization, and their combination.

Logistic regression is commonly used to test for treatment effects in observational studies. If the distribution of a continuous covariate differs between treated and control populations, logistic regression yields an invalid hypothesis test even in an uncounfounded study if the link is not logistic. This flaw is not corrected by the commonly used technique of discretizing the covariate into intervals. A valid test can be obtained by discretization followed by regression adjustment within each interval.

Specific biologic effects of intestinal glucagon-like materials.

It has been demonstrated that gastrointestinal extracts contain substances which react immunologically with antibodies prepared to pancreatic glucagon. These extracts have been termed intestinal GLI for glucagon-like immunoreactivity, or enteroglucagon. To determine whether GLI has specific biological effects, studies were designed using the criterion of effect with antiglucagon antibodies. These antibodies did not cross-react with either secretin or pancreozymin. Rat intestinal extracts were prepared and filtered on Sephadex G-50 columns eluted in 0.02 M ammonium carbonate buffer pH 8.8. Two peaks of GLI (I, II) were consistently found, and the in vitro effects of these peaks on two biological systems were tested: (a) immunoreactive insulin (IRI) release by rat pancreas pieces, and (b) free fatty acid (FFA) release and 3',5'-cyclic adenosine monophosphate (cAMP) levels in adipose tissue. Both GLI peaks increased IRI release in the absence of glucose and also enhanced the glucose effects. Antiglucagon antibody suppressed only peak II GLI activity. Both peaks increased FFA release and cAMP levels in adipose tissue. Only peak II GLI activity was suppressed by antibody. These findings support a specific IRI-releasing and lipolytic action for Peak II GLI. Hypotheses are presented concerning the structure and possible physiologic role of peak II GLI.

Studies on the biological activity of porcine proinsulin.

The biological activity of purified porcine proinsulin was investigated in rats. In vivo studies revealed that proinsulin produced a hypoglycemic response similar to insulin but of lesser magnitude. Hypophysectomized and adrenalectomized animals proved to be more sensitive to proinsulin than normal. In vitro studies with rat hemidiaphragm were consistent with the in vivo findings. No competition with insulin action could be demonstrated. Experiments were carried out to determine whether proinsulin is converted to intermediate forms or insulin as a requisite to its biological activity. Labeled proinsulin injected in vivo or incubated in vitro remained intact by a variety of techniques (Sephadex column chromatography and polyacrylamide-gel electrophoresis). An inhibitory action of Kunitz pancreatic trypsin inhibitor on proinsulin action in vitro was confirmed. No clarification of this effect could be ascertained.

Complications of treatment of obstetric fistula in the developing world: gynatresia, urinary incontinence, and urinary diversion.

OBJECTIVE: To provide a comprehensive review of the pathophysiology, evaluation, and treatment of gynatresia and urinary incontinence, 2 conditions that can arise following the repair of obstetric fistulas. The article discusses relevant issues with respect to urinary diversion in the treatment of obstetrical fistula and associated urinary incontinence. METHODS: A review was conducted of the existing literature and of the expert recommendations issued at the Gates Institute fistula meeting held in July 2005 at the Johns Hopkins Bloomberg School of Public Health. RESULTS: Gynatresia and urinary incontinence develop in approximately 10% and 16% of patients, respectively, after the first repair. Urinary diversion may be necessary when fistulas cannot be closed vaginally or in cases of severe urinary incontinence following successful closure. Gynatresia, urinary incontinence, and urinary diversion are all associated with morbidity, and they require surgical and nonsurgical expertise for proper management. CONCLUSIONS: Closing the anatomical fistula is not always sufficient, and treatment paradigms must shift toward the prevention and repair of gynatresia and urinary incontinence at the time of the primary operation.

Estimation of causal effects of binary treatments in unconfounded studies with one continuous covariate.

The estimation of causal effects in nonrandomized studies should comprise two distinct phases: design, with no outcome data available; and analysis of the outcome data according to a specified protocol. Here, we review and compare point and interval estimates of common statistical procedures for estimating causal effects (i.e. matching, subclassification, weighting, and model-based adjustment) with a scalar continuous covariate and a scalar continuous outcome. We show, using an extensive simulation, that some highly advocated methods have poor operating characteristics. In many conditions, matching for the point estimate combined with within-group matching for sampling variance estimation, with or without covariance adjustment, appears to be the most efficient valid method of those evaluated. These results provide new conclusions and advice regarding the merits of currently used procedures.

Chemotherapy of pancreatic adenocarcinoma: initial report on two transplantable models in the Syrian hamster.

Experimental evaluation of chemotherapy of pancreatic cancer has been limited by the lack of suitable animal models, which have only recently become available. The present study is the first report on the chemosensitivity of two transplantable animal models of pancreatic adenocarcinoma. The single-agent antitumor activity of 5-fluorouracil, cyclophosphamide, mitomycin C (MMC), methotrexate, actinomycin D, vincristine, and two dose levels of Adriamycin (ADR) were tested against established palpable tumors of well-differentiated pancreatic ductal adenocarcinoma (WD PaCa), a solid tumor model of the Syrian hamster. None of the agents or dosages of ADR were effective against palpable WD PaCa tumors. ADR, MMC, streptozotocin, and the combination of 5-fluorouracil, ADR, and MMC were similarly ineffective when administered 1 week after WD PaCA implantation, while tumors were still nonpalpable. The behavior of poorly differentiated pancreatic ductal adenocarcinoma (PD PaCa), an ascitic model of the Syrian hamster, was studied for comparison. In vivo, with survival as the end point, PD PaCa is markedly sensitive to ADR, perhaps weakly sensitive to MMC, and resistant to streptozotocin. In vitro clonogenic assays from cultured PD PaCa and WD PaCa confirmed the pattern of response seen in vivo. The data suggest that these recently developed pancreatic cancer models can be profitably used and compared, both in vivo and in vitro, as examples of relatively chemotherapy resistant (WD PaCa) and more sensitive (PD PaCa) tumor models.

Schedule-dependent interaction of alpha-difluoromethylornithine and cis-diamminedichloroplatinum(II) against human and hamster pancreatic cancer cell lines.

The interaction of cis-diamminedichloroplatinum (cisplatin) and alpha-difluoromethylornithine (DFMO) has been previously shown by us to be roughly additive in enhancing the growth-inhibitory effects of cisplatin and by another group of investigators to be antagonistic. Since two different schedules of administration were used, we sought to investigate systematically the role of schedule dependence in the interaction of cisplatin and DFMO in a panel of pancreatic adenocarcinoma cell lines (PANC-1, of human origin, and WD PaCa and PD PaCa, both of hamster origin). Dose-effect relationships of single drug alone and in combination were analyzed by the median-effect principle and by the combination indices for the quantitation of synergism or antagonism with the aid of a microcomputer. Pre-cisplatin administration of DFMO for 2 or 5 to 6 days at concentrations of 50 or 100 micrograms/ml (0.21 or 0.42 mM) was found to antagonize the effects of cisplatin to various degrees in the cell lines. In contrast, whenever post-cisplatin DFMO was administered, marked enhancement, which was synergistic in most instances, of cisplatin's inhibition of colony formation was found. Thus, the interaction of cisplatin and DFMO is felt to be schedule dependent with deleterious effects found only when DFMO is administered prior to and not following cisplatin. Furthermore, the combination shows promise as an approach to overcoming drug resistance in pancreatic cancer.

Inhibition of growth of human or hamster pancreatic cancer cell lines by alpha-difluoromethylornithine alone and combined with cis-diamminedichloroplatinum(II).

A major problem in the therapy of pancreatic adenocarcinoma is its inherent resistance to most chemotherapeutic agents. Previously, we have reported that the four pancreatic cancer cell lines studied here have elevated levels of ornithine decarboxylase, a growth-regulating enzyme, and further that the degree of elevation tends to parallel the degree of chemoresistance. On the basis of these prior findings, we investigated the effects of alpha-difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase, alone and in combination with cis-diamminedichloroplatinum(II) (cisplatin), to which two of the four cell lines display relative resistance. The cell lines studied were: two of human origin, PANC-1 and COLO-357; and two of hamster origin, WD PaCa and PD PaCa. Colony formation (clonogenic) assays were used to evaluate drug effects. Cells were exposed continuously to DFMO in medium. For the combined treatments, cells were exposed to cisplatin for 1 hr, washed, and then plated in DFMO-containing medium. The inhibitory effects of DFMO were predominantly cytostatic, were reversible by putrescine, and were roughly additive when combined with cisplatin. Our panel of cell lines responded heterogeneously to DFMO, with PANC-1 and WD PaCa showing the most sensitivity. The combination of DFMO and cisplatin appears to be a promising experimental approach to overcoming drug resistance in pancreatic cancer.

Association of negatively-charged phospholipids with low-density lipoprotein (LDL) increases its uptake and the deposition of cholesteryl esters by macrophages.

LDL, the major carrier of cholesterol in blood, is poorly metabolized by macrophages. In contrast, macrophages can recognize and endocytose anionic phospholipids such as phosphatidylserine, phosphatidylglycerol and cardiolipin. Since macrophages can take up large amounts of these phospholipids, experiments were performed to ascertain whether pre-incubation of native LDL with negatively-charged phospholipids would enhance the metabolism of LDL by macrophages. When 125I-LDL was incubated with cardiolipin liposomes for 18 h at 37 degrees C before addition to macrophages, an approx. 40-fold increase of LDL metabolism by these cells was observed. Similar results were found when LDL was pre-incubated with phosphatidylserine or phosphatidylglycerol; however, pre-incubation of LDL with phosphatidylcholine liposomes did not lead to an increase of LDL metabolism. The macrophage uptake of LDL pre-incubated with cardiolipin was reduced to approx. 40% of control values in the presence of dextran sulfate and fucoidin, inhibitors of anionic phospholipid uptake. Cytochalasin D, an inhibitor of phagocytosis, reduced the lysosomal degradation of LDL pre-incubated with cardiolipin to approx. 10% of control values. When the LDL-cardiolipin mixture was chromatographed on agarose gel, two peaks containing LDL were observed in the elution profile: the first peak appeared at the void volume and the second peak was detected just ahead of native LDL. The LDL in both peaks was much more extensively metabolized by macrophages than was native LDL; the LDL in the first peak was metabolized at a rate that was 8 times the second peak. The results demonstrate that negatively-charged phospholipids can form a complex with LDL which facilitates its phagocytosis by macrophages.

Dietary fish oil normalize dyslipidemia and glucose intolerance with unchanged insulin levels in rats fed a high sucrose diet.

The aim of this study was to investigate the relationship between the lipid-lowering effects of fish oils and concomitant consequences on glucose tolerance and insulin sensitivity in an experimental animal model of hypertriglyceridemia induced by high sucrose intake. To achieve this goal, male Wistar rats were fed a semi-synthetic sucrose rich diet (SRD) (w/w: 62.3% sucrose, 8% corn oil, 17% protein) for 90 days. At the time, a well established and permanent hypertriglyceridemia accompanied by glucose intolerance was present. After that, one half of the animals continued on the SRD up to 120 days. The other half received an SRD in which the source of fat was substituted by cod liver oil (w/w 7% CLO plus 1% corn oil) from day 90 to 120 (SRD+CLO). Control rats were fed a semi-synthetic diet (CD) (w/w: 62.5% corn starch, 8% corn oil, 17% protein) throughout the 120 days experimental period. Results obtained after the experimental period show that the hypertriglyceridemia and glucose intolerance ensuing long term feeding normal rats with a sucrose-rich diet could be completely reversed mediating no change in circulating insulin levels by shifting the source of fat in the diet from corn oil to cod liver oil. These findings suggest that manipulation of dietary fats may play a role in the management of the lipid disorders associated with glucose intolerance and insulin resistance.

Iron-ascorbate-phospholipid mediated modification of low density lipoprotein.

LDL can be oxidized by a variety of agents to form a modified lipoprotein which is capable of being avidly metabolized by macrophages. While previous in vitro studies have focused exclusively on the oxidation of LDL, other lipids found in the atheroma are also subject to oxidation and its lipoperoxide byproducts may contribute to the process of LDL modification. To examine the relationship between the oxidation of phospholipids and the subsequent modification of LDL, we incubated 250 microM phosphatidylcholine with 10 microM ferrous sulfate and 50 microM ascorbic acid in 10 mM Tris (pH 7.0). After 18 h at 37 degrees C, significant amounts of thiobarbituric acid reactive substances (TBARS) were formed. The inclusion of LDL (100 micrograms protein/ml) elevated the TBARS and increased the electrophoretic mobility of the lipoprotein. LDL treated with iron and ascorbate in the absence of phosphatidylcholine did not result in the modification of this lipoprotein. LDL that was incubated with phosphatidylcholine, iron and ascorbate was found to be metabolized by macrophages to a far greater extent than native LDL or LDL treated with phosphatidylcholine alone. Probucol (10 microM) inhibited the LDL modification process. These results demonstrate that while iron and ascorbate cannot oxidize LDL directly, the addition of phosphatidylcholine to these initiators of lipid peroxidation can mediate and lead to the modification of LDL.