Management and outcomes of obturator hernias: a systematic review and meta-analysis.

PURPOSE: Obturator Hernia (OH) is a rare type of abdominal wall hernia. It usually occurs in elderly women with late symptomatic presentation, increasing mortality rates. Surgery is the standard of care for OH, and laparotomy with simple suture closure of the defect is commonly used. Given the rarity of this disease, large studies are lacking, and data to drive management are still limited. This systematic review and meta-analysis aimed to describe current surgical options for OHs, with a focus on comparing the effectiveness and safety of mesh use with primary repair. METHODS: PubMed, EMBASE, and Cochrane were searched for studies comparing mesh and non-mesh repair for OH. Postoperative outcomes were assessed by pooled analysis and meta-analysis. Statistical analysis was performed using RevMan 5.4. RESULTS: One thousand seven hundred and sixty studies were screened and sixty-seven were thoroughly reviewed. We included 13 observational studies with 351 patients surgically treated for OH with mesh or non-mesh repair. One hundred and twenty (34.2%) patients underwent mesh repair and two hundred and thirty-one (65.81%) underwent non-mesh repair. A total of 145 (41.3%) underwent bowel resection, with the majority having a non-mesh repair performed. Hernia recurrence was significantly higher in patients who underwent hernia repair without mesh (RR 0.31; 95% CI 0.11-0.94; p = 0.04). There were no differences in mortality (RR 0.64; 95% CI 0.25-1.62; p = 0.34; I2 = 0%) or complication rates (RR 0.59; 95% CI 0.28-1.25; p = 0.17; I2 = 50%) between both groups. CONCLUSION: Mesh repair in OH was associated with lower recurrence rates without an increase in postoperative complications. While mesh in clean cases is more likely to offer benefits, an overall recommendation regarding its use in OH repair cannot be made due to potential bias across studies. Given that many OH patients are frail and present emergently, the decision to use mesh is complex and should consider the patient's clinical status, comorbidities, and degree of intraoperative contamination.

Taking the sweetness out of the 'Share a Coke' marketing campaign: the influence of personalized labelling on elementary school children's bottled drink choices.

BACKGROUND: Drink personalization (featuring names on bottle labels) has been used by soft drink companies to make their drinks attractive to children, potentially increasing consumption. To date, no publically available research has evaluated the influence of personalization on children's drink choices. OBJECTIVES: To determine (i) whether personalizing bottled drinks influences children's drink choices; (ii) whether it is comparably effective in promoting healthy and unhealthy drinks and (iii) whether drink choices are affected by self-esteem, body mass index and parental factors. METHODS: Children aged 8-13 years (N = 404) were randomly assigned to one of three drink labeling conditions: Prime Healthy, Prime Unhealthy and Control. All participants selected one beverage from 12 options, comprising six healthy and unhealthy drinks. RESULTS: Personalizing healthy drinks increased choice of healthy drinks (OR, 2.21; 95% CI, 1.24-4.00), and personalizing unhealthy drinks reduced choice of healthy drinks (OR, 0.35; 95% CI, 0.15-.0.75). Higher self-esteem predicted choosing own-named drinks (OR = 1.08, 95% CI, 1.00-1.18; p = .049). CONCLUSIONS: Children's drink choices are influenced by personalizing drink bottles. Tighter regulation of this marketing strategy for soft drinks may reduce children choice of these drinks. Personalization may also be used to encourage children to choose healthy drinks.

Anatomical integration and rich-club connectivity in euthymic bipolar disorder.

BACKGROUND: Although repeatedly associated with white matter microstructural alterations, bipolar disorder (BD) has been relatively unexplored using complex network analysis. This method combines structural and diffusion magnetic resonance imaging (MRI) to model the brain as a network and evaluate its topological properties. A group of highly interconnected high-density structures, termed the 'rich-club', represents an important network for integration of brain functioning. This study aimed to assess structural and rich-club connectivity properties in BD through graph theory analyses. METHOD: We obtained structural and diffusion MRI scans from 42 euthymic patients with BD type I and 43 age- and gender-matched healthy volunteers. Weighted fractional anisotropy connections mapped between cortical and subcortical structures defined the neuroanatomical networks. Next, we examined between-group differences in features of graph properties and sub-networks. RESULTS: Patients exhibited significantly reduced clustering coefficient and global efficiency, compared with controls globally and regionally in frontal and occipital regions. Additionally, patients displayed weaker sub-network connectivity in distributed regions. Rich-club analysis revealed subtly reduced density in patients, which did not withstand multiple comparison correction. However, hub identification in most participants indicated differentially affected rich-club membership in the BD group, with two hubs absent when compared with controls, namely the superior frontal gyrus and thalamus. CONCLUSIONS: This graph theory analysis presents a thorough investigation of topological features of connectivity in euthymic BD. Abnormalities of global and local measures and network components provide further neuroanatomically specific evidence for distributed dysconnectivity as a trait feature of BD.

Decision landscapes: visualizing mouse-tracking data.

Computerized paradigms have enabled gathering rich data on human behaviour, including information on motor execution of a decision, e.g. by tracking mouse cursor trajectories. These trajectories can reveal novel information about ongoing decision processes. As the number and complexity of mouse-tracking studies increase, more sophisticated methods are needed to analyse the decision trajectories. Here, we present a new computational approach to generating decision landscape visualizations based on mouse-tracking data. A decision landscape is an analogue of an energy potential field mathematically derived from the velocity of mouse movement during a decision. Visualized as a three-dimensional surface, it provides a comprehensive overview of decision dynamics. Employing the dynamical systems theory framework, we develop a new method for generating decision landscapes based on arbitrary number of trajectories. This approach not only generates three-dimensional illustration of decision landscapes, but also describes mouse trajectories by a number of interpretable parameters. These parameters characterize dynamics of decisions in more detail compared with conventional measures, and can be compared across experimental conditions, and even across individuals. The decision landscape visualization approach is a novel tool for analysing mouse trajectories during decision execution, which can provide new insights into individual differences in the dynamics of decision making.

Differences in the metabolism and pharmacokinetics of two structurally similar PPAR agonists in dogs: involvement of taurine conjugation.

1. The metabolism and pharmacokinetics of two structurally similar PPAR agonists, MRL-I, (2R)-7-[3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy]-2-ethyl-3,4-dihydro-2H-benzopyran-2-carboxylic acid, and MRL-II, (2R)-7-[3-[2-chloro-4-(2,2,2,-trifluoroethoxy)phenoxy]propoxy]-3,4-dihydro-2-methyl-2H-benzopyran-2-carboxylic acid, in dogs were investigated. 2. MRL-I was absorbed rapidly in dogs and exhibited linear pharmacokinetics over the dose range examined, 1-25mgkg(-1). In contrast, the pharmacokinetics of MRL-II were non-linear following both intravenous and oral administration. 3. The acyl glucuronide (AG) conjugate was the only radioactive component detected in bile from dogs dosed with [14C]MRL-I, whereas bile from dogs dosed with [14C]MRL-II contained varying amounts of both the AG and taurine conjugates. The percentages of the acyl glucuronide and taurine conjugates of [14C]MRL-II in dog bile were dose dependent. A higher percentage of radioactivity was associated with the taurine conjugate (about 41%) following intravenous administration at 0.2mgkg(-1) than at 0.9mgkg(-1) (about 14%) or oral administration at 5 mgkg(-1) (about 6%). The decrease in the percentage of radioactivity associated with the taurine conjugate at 0.9 mgkg(-1) was accompanied by a concomitant increase in the amount of the acyl glucuronide. 4. MRL-I, but not MRL-II, was subject to significant enterohepatic recirculation in dogs. Continuous collection of bile resulted in an 11-fold decrease in the terminal half-life of MRL-I in plasma (1.5 versus 16.6 h), and a 2.4-fold increase in its plasma clearance (4.0 versus 1.7 ml min(-1) kg(-1)) after intravenous administration at 1 mg kg(-1). 5. Collectively, the data suggest that the presence and subsequent saturation of the taurine conjugation pathway might have contributed to the non-linear pharmacokinetics of MRL-II in the dog.

Identification of novel metabolites of pioglitazone in rat and dog.

1. Four new metabolites of pioglitazone were identified by liquid chromatography-mass spectrometry (LC-MS/MS) as being formed by hydroxylation (M-VII and M-VIII), opening of the thiazolidinedione ring (M-X) and by desaturation of the terminal ethyl side chain or tether ethoxy moiety (M-IX), respectively. The structure of one of the hydroxylated metabolites (M-VII) was confirmed by chemical modification using the Jones reaction. 2. Oxidative cleavage of the thiazolidinedione ring is a novel pathway not previously reported for pioglitazone. 3. The hydroxylated M-VII was detected in incubations with rat, dog and human liver and kidney microsomes, and in plasma from rats and dogs dosed orally with [(3)H]pioglitazone. 4. The carboxylic acid derivative of M-VII (M-V) and its taurine conjugate were the major radioactive components in dog bile.

Correolide and derivatives are novel immunosuppressants blocking the lymphocyte Kv1.3 potassium channels.

The voltage-gated potassium channel, Kv1.3, is specifically expressed on human lymphocytes, where it controls membrane potential and calcium influx. Blockade of Kv1.3 channels by margatoxin was previously shown to prevent T cell activation and attenuate immune responses in vivo. In the present study, a triterpene natural product, correolide, was found to block Kv1.3 channels in human and miniswine T cells by electrophysiological characterization. T cell activation events, such as anti-CD3-induced calcium elevation, IL-2 production, and proliferation were inhibited by correolide in a dose-dependent manner. More potent analogs were evaluated for pharmacokinetic profiles and subsequently tested in a delayed-type hypersensitivity (DTH) response to tuberculin in the miniswine. Two compounds were dosed orally, iv, or im, and both compounds suppressed DTH responses, demonstrating that small molecule blockers of Kv1.3 channels can act as immunosuppressive agents in vivo. These studies establish correolide and its derivatives as novel immunosuppressants.

Administration of a nonpeptidyl growth hormone secretagogue, L-163, 255, changes somatostatin pattern, but has no effect on patterns of growth hormone-releasing factor in the hypophyseal-portal circulation of the conscious pig.

The activity of the growth hormone secretagog, L-163,255, on growth hormone (GH), growth hormone-releasing factor (GRF), and somatostatin (SRIF) levels was evaluated in a porcine model of hypophyseal portal blood (HPB) collection. Young, castrated pigs had HPB and jugular blood collected for approximately 300 min. The blood collection was divided into discrete periods: baseline (BL) approximately 180 min; GH response period (RSP) approximately 90 min; and positive control period following a GRF bolus, 30 min. RSP was divided into a dominant response period (DOM) and a tail (TL). The spontaneous relationship between HPB GRF and SRIF and peripheral GH during BL has been reported (Proc Soc Exp Biol Med 217:188-196, 1998). The apex of the GH pulse resulting from L-163,255 administration was nonrandomly associated (P < 0.05) with descending periods of SRIF troughs. Frequency and amplitude of GRF and SRIF pulses, and frequency and depth of SRIF troughs were not different between BL and the beginning of DOM (the 20-30 min of GH increase). GH AUC was significantly greater (P < 0.05) for DOM compared to BL and TL, and for TL compared to BL. GRF AUC tended to be greater (P < 0.1) for RSP compared to BL, but the majority of the increase was in the TL period. There were no significant differences in the SRIF AUCs between the sampling periods. Furthermore, in a separate experiment, fos activity (a marker of neuronal activation) in the hypothalamus of pigs was examined after either L-163,255 (1x or 4x), isotonic saline (control), or hypertonic saline (positive control) administration. There were no differences in fos activity in the GRF, SRIF, or CRH immunopositive neurons between L-163,255 treatment and control. The pituitaries of the L-163,255-treated pigs showed marked fos activation compared to the controls. In conclusion, L-163,255 in pigs has its primary effect at the level of the anterior pituitary.

Hypophyseal-portal concentrations of growth hormone-releasing factor and somatostatin in conscious pigs: relationship to production of spontaneous growth hormone pulses.

A method of collecting hypophyseal portal blood (HPB) in conscious pigs was used to show the relationship between GRF and somatostatin (SRIF) concentration and peripheral GH response. Six male castrate pigs (approximately 63 kg body weight) had HPB and jugular blood collected individually for an average of 175 min each. Twenty-seven spontaneous GH pulses were detected in the 1050 min of total HPB collection. Of the associations examined, the only significant finding was that GH pulse maxima occurred nonrandomly within periods of SRIF descent (63%; P = 0.005). Although 48% (13/27) of GH pulse maxima were associated with an ascent in portal GRF concentration, these associations were not determined to be nonrandom (P = 0.14). Only 7 of 27 (26%) GH pulse maxima were associated with an ascent in portal GRF concentration and a descent in SRIF concentration occurring simultaneously. A saline infusion given approximately 120 min after beginning blood collection resulted in an increase in SRIF pulse frequency and a decrease in GH-AUC and GRF-AUC. The cause of this saline effect is unknown, but it may have been related to acclimation of the pigs to the blood collection procedure. These data show the complexity of the relationship between SRIF and GRF concentrations and GH secretion and may indicate a close relationship with SRIF in GH pulse generation in the pig. In addition, these data support the hypothesis that, in the pig, mediation of GH release cannot be explained simply by antagonism between GRF and SRIF.

Synthesis and biological activities of phenyl piperazine-based peptidomimetic growth hormone secretagogues.

A new class of potent, orally active phenyl piperazine-based GH secretagogues have been discovered from attempts to mimic the arrangement of the phenyl substituent in the spiroindanyl piperidine and spiroindoline sulfonamide privileged structures of 4 and 1, respectively. The best of these compounds, 18 (EC50 = 2.8 nM) is nearly as potent as MK-0677 for releasing GH from rat pituitary cells.

Growth hormone secretagogue increases muscle strength during remobilization after canine hindlimb immobilization.

Twenty-two beagles were divided into two equal groups, and the right hindlimb of each animal was immobilized at 105 degrees of knee flexion by external fixation. After 10 weeks of fixation, the device was removed, allowing free mobility for the following 5 weeks. Each day throughout the 15 weeks, one group received a growth hormone secretagogue (treatment) at a dose of 5 mg/kg, and the other received a lactose placebo (control). At weeks 0, 10, and 15, strength as indicated by maximum isometric extension torque was measured in the right hindlimb, biopsies of the vastus lateralis muscle were taken, and the dogs were weighed. Weekly blood samples were analyzed for insulin-like growth factor-1, blood urea nitrogen, and creatine phosphokinase. Between weeks 0 and 10, tetanic torque declined by about 60% (p < 0.001) in both groups, with no significant difference between the groups (p > 0.7). Between weeks 10 and 15, tetanic torque in the treated group increased by 0.81 Nm; this was significantly greater than the increase of 0.25 Nm in the placebo group (p < 0.05). The diameters of slow (type-1) and fast (type-2) fibers measured from the vastus lateralis muscle followed the same trend. At all time points, fiber diameter correlated strongly with torque; this argues against nonmuscular causes such as nerve injury for strength loss. The mean levels of insulin-like growth factor-1 increased 100% by week 4 in the treated group and remained elevated by about 60% throughout the experiment. Levels of insulin-like growth factor-1 in the placebo group decreased 30% within week 1 and remained depressed throughout the experiment. Our interpretation of these data suggests that the growth hormone secretagogue elevated levels of serum insulin-like growth factor-1, which in turn increased the size and strength of the quadriceps muscle during remobilization. These data may ultimately have therapeutic application to humans during rehabilitation after prolonged inactivity.

Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo.

The voltage activated K+ channel (Kv1.3) has recently been identified as the molecule that sets the resting membrane potential of peripheral human T lymphoid cells. In vitro studies indicate that blockage of Kv1.3 inhibits T cell activation, suggesting that Kv1.3 may be a target for immunosuppression. However, despite the in vitro evidence, there has been no in vivo demonstration that blockade of Kv1.3 will attenuate an immune response. The difficulty is due to species differences, as the channel does not set the membrane potential in rodent peripheral T cells. In this study, we show that the channel is present on peripheral T cells of miniswine. Using the peptidyl Kv1.3 inhibitor, margatoxin, we demonstrate that Kv1.3 also regulates the resting membrane potential, and that blockade of Kv1.3 inhibits, in vivo, both a delayed-type hypersensitivity reaction and an Ab response to an allogeneic challenge. In addition, prolonged Kv1.3 blockade causes reduced thymic cellularity and inhibits the thymic development of T cell subsets. These results provide in vivo evidence that Kv1.3 is a novel target for immunomodulation.

MK-0677, a potent, novel, orally active growth hormone (GH) secretagogue: GH, insulin-like growth factor I, and other hormonal responses in beagles.

MK-0677, a spiroindoline sulfonamide, is a novel, orally active GH secretagogue. The effects of MK-0677 on serum GH and other hormones after oral and iv single dose administrations in beagles were evaluated. After oral administration in a balanced eight-dog crossover study, treatment with MK-0677 significantly increased peak GH concentrations, with a 5.3-fold increase (mean +/- SEM, 10.5 +/- 1.9 ng/ml) at the 0.25 mg/kg dose, a 9.0-fold increase (18.0 +/- 3.3 ng/ml) at the 0.50 mg/kg dose, and a 15.8-fold increase (31.6 +/- 5.8 ng/ml) at the 1.0 mg/kg dose. Total GH release, expressed as the area under the curve, showed similar significant increases over the effect of the water placebo. A single oral 1 mg/kg dose in three dogs induced a mean GH peak of 27.6 +/- 1.5 ng/ml at 120 min, and GH levels remained elevated up to 360 min after treatment. Insulin-like growth factor I (IGF-I) levels were significantly increased by 30% at 480 min after treatment. Cortisol levels were increased 2.4-fold over pretreatment levels. After i.v. administration, compared to the saline control group which had a mean (+/- SEM) serum GH peak of 3.8 +/- 0.7 ng/ml, MK-0677 at 0.25 mg/kg significantly increased (P < 0.05) peak GH concentrations 20.4-fold (77.4 +/- 13.7 ng/ml). Total GH release, expressed as the area under the curve, showed a similar increase. The mean peak GH level was recorded 10 min after treatment, with GH levels elevated up to 180 min after treatment. IGF-I levels were significantly elevated by 25% 360 min after the administration of MK-0677. Cortisol levels were increased 2.3-fold over pretreatment levels. Insulin and glucose levels were higher, LH and PRL levels were unaltered, and T4 levels were marginally lower; the levels of each of these hormones remained within the normal ranges for dogs throughout the experiment. In summary, MK-0677 is a potent GH secretagogue that induces an immediate, large, long lasting increase in GH levels when administered orally or i.v. In contrast to GH-releasing peptide-6 and benzolactam secretagogues, GH levels were elevated up to 360 min after treatment, and this was associated with a significant increase in IGF-I levels. Cortisol levels were increased; however, the increases were modest compared to those in GH.

Transorbital approach to the porcine pituitary.

A transorbital approach to the pituitary gland is described in domestic swine weighing between 40 and 70 kg. A transpalpebral eye exenteration is performed and the optic canal is enlarged caudally, using a bone drill. An operating microscope is used to improve visualization of the surgical site as the pituitary stalk and anterior pituitary are exposed to the level of the optic chiasm. This approach exposes the pituitary sufficiently to perform either a hypophyseal stalk transection or a hypophysectomy or to implant cannulas for hypothalamic-hypophyseal portal blood sampling. This technique has been performed in more than 50 pigs without major complications. Postoperative recovery has been rapid and uneventful. The transorbital approach is a significant refinement of the frontal craniotomy and cerebral elevation technique previously described in the pig, and results in shortened surgery time, minimal brain manipulation, and greatly decreased morbidity.

Formation of eosinophilic and monocytic intradermal inflammatory sites in the dog by injection of human RANTES but not human monocyte chemoattractant protein 1, human macrophage inflammatory protein 1 alpha, or human interleukin 8.

Equilibrium binding studies on canine mononuclear and granulocytic cells allow the identification of a single high affinity receptor for the human C-C chemokine RANTES (dissociation constant, 14 +/- 8 pM), that, in contrast to the human RANTES receptor, has no affinity for human macrophage inflammatory protein 1 alpha (hMIP-1 alpha). A single intradermal injection of hRANTES in dog resulted in eosinophil- and macrophage-rich inflammatory sites within 4 h. Cell infiltration peaked at 16-24 h after hRANTES injection. There was histological evidence of intravascular activation of eosinophils at 4 h, although eosinophils in the vasculature and interstitium contained apparently intact granules. Monocytes were the predominant cells adherent to venular endothelium at 16-24 h. Human MIP-1 alpha elicited no response in canine dermis, whereas monocyte chemoattractant protein 1 caused mild perivascular cuffing with monocytes. In contrast, human interleukin 8 induced a neutrophilic dermal infiltrate that was maximal by 4 h after challenge. This provides the first direct evidence in vivo that RANTES has significant proinflammatory activity and, in addition, could be a mediator in atopic pathologies characterized by eosinophilic and monocytic inflammatory responses.

Indomethacin attenuates exercise-induced proteinuria in hypertensive miniature swine.

Exercise-induced proteinuria may be increased in hypertensives. The mechanisms underlying the increased proteinuria are not known, and it has not been determined whether animal models of hypertension exhibit a similar response. We investigated whether indomethacin (Indo) altered exercise-induced proteinuria in normal and hypertensive deoxycorticosterone acetate (DOCA) Yucatan miniature swine (YMS). Five normal and four DOCA YMS underwent 30 min of treadmill exercise at 80% of maximal heart rate. Cumulative (exercise + recovery) albumin excretion in the DOCA YMS was 25-fold (P < 0.01) greater than observed in the normal YMS. Indo had no effect on resting or exercise-induced proteinuria in the normal YMS. However, Indo decreased the slightly elevated proteinuria at rest, and normalized the exaggerated exercise-induced proteinuria in the DOCA YMS. The antiproteinuric effect of Indo in the DOCA YMS was not associated with altered exercise, recovery blood pressure, or glomerular filtration rate. Thus hypertensive DOCA YMS exhibit an exaggerated exercise-induced proteinuria. It is suggested that eicosanoids are involved in this abnormal renal proteinuric response to exercise.