The postpartum abdomen: psychology, surgery and quality of life.

PURPOSE: The postpartum abdomen presents significant challenges to the surgeon. It is anatomically complex, with often substantial symptomatic divarication of the rectus abdominis, affecting all anterior abdominal wall layers. This may lead to profound functional sequelae, and often, of more importance to patients, a significant physical deformity. The complex interplay of functional/physical symptoms can result in reduced quality of life (QoL) as well as negative body image/self-esteem. Postpartum women may seek abdominoplasty to address the whole scope of these concerns. Whilst techniques have evolved achieving such goals operatively, the impact of such surgery on QoL/mental health has yet to be established. METHODS: We perform a comprehensive review of potential options of validated patient-reported outcome measures (PROMs) for consideration of use in postpartum women seeking abdominoplasty; in addition to discussing current driving factors for seeking surgery and associated ethics. RESULTS: Pressure on postpartum women to return their abdominal wall contour to a pre-pregnant state is high. This poses important ethical considerations for surgeons. There are several well-established/validated PROMs used in body contouring in massive weight loss/bariatric population groups, including Body-Q and Body-QoL scales, but none yet specific to postpartum women. CONCLUSION: PROMs use to enable establishment of the true value of abdominoplasty in postpartum women, not just in terms of functional/physical restoration, but also in terms of delivering a positive impact on patients' mental health and QoL, are important. Further research is needed to determine if those already developed are appropriate or whether a postpartum-specific PROM would be beneficial.

Anesthesia modifies subthreshold critical slowing down in a stochastic Hodgkin-Huxley-like model with inhibitory synaptic input.

The dynamics of a stochastic type-I Hodgkin-Huxley-like point neuron model exposed to inhibitory synaptic noise are investigated as a function of distance from spiking threshold and the inhibitory influence of the general anesthetic agent propofol. The model is biologically motivated and includes the effects of intrinsic ion-channel noise via a stochastic differential equation description as well as inhibitory synaptic noise modeled as multiple Poisson-distributed impulse trains with saturating response functions. The effect of propofol on these synapses is incorporated through this drug's principal influence on fast inhibitory neurotransmission mediated by γ-aminobutyric acid (GABA) type-A receptors via reduction of the synaptic response decay rate. As the neuron model approaches spiking threshold from below, we track membrane voltage fluctuation statistics of numerically simulated stochastic trajectories. We find that for a given distance from spiking threshold, increasing the magnitude of anesthetic-induced inhibition is associated with augmented signatures of critical slowing: fluctuation amplitudes and correlation times grow as spectral power is increasingly focused at 0 Hz. Furthermore, as a function of distance from threshold, anesthesia significantly modifies the power-law exponents for variance and correlation time divergences observable in stochastic trajectories. Compared to the inverse square root power-law scaling of these quantities anticipated for the saddle-node bifurcation of type-I neurons in the absence of anesthesia, increasing anesthetic-induced inhibition results in an observable exponent <-0.5 for variance and >-0.5 for correlation time divergences. However, these behaviors eventually break down as distance from threshold goes to zero with both the variance and correlation time converging to common values independent of anesthesia. Compared to the case of no synaptic input, linearization of an approximating multivariate Ornstein-Uhlenbeck model reveals these effects to be the consequence of an additional slow eigenvalue associated with synaptic activity that competes with those of the underlying point neuron in a manner that depends on distance from spiking threshold.

Factors influencing completion of multi-dose vaccine schedules in adolescents: a systematic review.

BACKGROUND: Completion of multiple dose vaccine schedules is crucial to ensure a protective immune response, and maximise vaccine cost-effectiveness. While barriers and facilitators to vaccine uptake have recently been reviewed, there is no comprehensive review of factors influencing subsequent adherence or completion, which is key to achieving vaccine effectiveness. This study identifies and summarises the literature on factors affecting completion of multi-dose vaccine schedules by adolescents. METHODS: Ten online databases and four websites were searched (February 2014). Studies with analysis of factors predicting completion of multi-dose vaccines were included. Study participants within 9-19 years of age were included in the review. The defined outcome was completion of the vaccine series within 1 year among those who received the first dose. RESULTS: Overall, 6159 abstracts were screened, and 502 full texts were reviewed. Sixty one studies were eligible for this review. All except two were set in high-income countries. Included studies evaluated human papillomavirus vaccine, hepatitis A, hepatitis B, and varicella vaccines. Reported vaccine completion rates, among those who initiated vaccination, ranged from 27% to over 90%. Minority racial or ethnic groups and inadequate health insurance coverage were risk factors for low completion, irrespective of initiation rates. Parental healthcare seeking behaviour was positively associated with completion. Vaccine delivery in schools was associated with higher completion than delivery in the community or health facilities. Gender, prior healthcare use and socio-economic status rarely remained significant risks or protective factors in multivariate analysis. CONCLUSIONS: Almost all studies investigating factors affecting completion have been carried out in developed countries and investigate a limited range of variables. Increased understanding of barriers to completion in adolescents will be invaluable to future new vaccine introductions and the further development of an adolescent health platform. PROSPERO reg# CRD42014006765.

Channel-noise-induced critical slowing in the subthreshold Hodgkin-Huxley neuron.

The dynamics of a spiking neuron approaching threshold is investigated in the framework of Markov-chain models describing the random state-transitions of the underlying ion-channel proteins. We characterize subthreshold channel-noise-induced transmembrane potential fluctuations in both type-I (integrator) and type-II (resonator) parametrizations of the classic conductance-based Hodgkin-Huxley equations. As each neuron approaches spiking threshold from below, numerical simulations of stochastic trajectories demonstrate pronounced growth in amplitude simultaneous with decay in frequency of membrane voltage fluctuations induced by ion-channel state transitions. To explore this progression of fluctuation statistics, we approximate the exact Markov treatment with a 12-variable channel-based stochastic differential equation (SDE) and its Ornstein-Uhlenbeck (OU) linearization and show excellent agreement between Markov and SDE numerical simulations. Predictions of the OU theory with respect to membrane potential fluctuation variance, autocorrelation, correlation time, and spectral density are also in agreement and illustrate the close connection between the eigenvalue structure of the associated deterministic bifurcations and the observed behavior of the noisy Markov traces on close approach to threshold for both integrator and resonator point-neuron varieties.

Free ferulic acid uptake in lactating cows.

Ferulic acid (FRA), a phenolic compound with antioxidant and anticancer activities, naturally occurs in plants as a lignin precursor. Many veins of research have been devoted to releasing FRA from the lignin complex to improve digestibility of ruminant feeds. Thus, the objective of this research was to investigate the transfer of a given dosage of the free form of FRA into the milk of dairy cattle. Six mid- to late-lactation Holstein cows at the Cornell Research Farm (Harford, NY) were given 14-d adaptation to diet and stall position. Ad libitum access to a total mixed ration based on haylage and maize silage (31.1% neutral detergent fiber containing 5.52 mg of FRA/g) was provided during the study. A crossover design was implemented so that each cow alternated weekly between FRA-dosed and control. On d 1, jugular cannulas and urine catheters were placed in all cows. On d 2, FRA-dosed cows received a single dosage of 150 g of pure FRA powder at 0830 h via their fistula (n=4) or a balling gun for nonfistulated cows (n=2). Plasma, urine, feces, feed, orts, milk, and rumen fluid were sampled intensively for the next 36 h and analyzed for FRA concentration. On d 8, the cows crossed over and the experiment was repeated. When compared with the control, FRA administration did not have an effect on dry matter intake, milk yield, milk fat yield, milk protein yield, somatic cell count, or neutral detergent fiber content of orts and feces. The concentration of FRA in the feces did not change as a result of FRA dosage. As expected, FRA concentration increased dramatically upon FRA dosage and decreased over time until returning to basal levels in rumen fluid (4 h after dosage), plasma (5.5 h after dosage), urine (10 h after dosage), and milk (14 h after dosage). Baseline values for FRA in urine and rumen fluid were variable among cows and had an effect on FRA concentration in FRA-dosed cows. From this study, it is observed that orally ingested FRA can be transported into the milk and that the physiological transfer of FRA occurs from rumen to milk within 6.5 h or the first milking after dosage. Ferulic acid may affect the functionality of milk due to its antioxidant, anticancer, and antibacterial activities. Future research will be required to elucidate whether FRA in milk is bioavailable and bioactive, and to evaluate the complete sensory and microbiological effects of increased FRA and FRA degradation products in milk.

Improvements in compliance with medical force protection measures by simplification of the anti-malarial chemoprophylaxis regime.

OBJECTIVES: Medical Force Protection (MFP) is important in keeping service personnel "fit to fight." It is particularly important for overseas deployment, where personnel are exposed to a range of infectious diseases. We report a full audit cycle assessing compliance with medical force protection measures, on an exercise in Belize. METHODS: An anonymous questionnaire was administered to personnel four weeks after returning from an Infantry Overseas Training Exercise (OTX) in Belize in two successive years (OTX 1 & 2). RESULTS: Compliance with physical MFP measures (mosquito nets, insecticide soak of kit and personal insect repellent usage) was excellent on both exercises. Antimalarial chemoprophylaxis compliance with a regime of weekly chloroquine and daily proguanil was poor (30%) during OTX 1. Revision of the regime to weekly chloroquine alone following review of antimalarial policies increased compliance on OTX 2 to 67%. CONCLUSION: Simplification of dosage regimes, consistency of information provided between different medical briefs and emphasis of the threat from malaria in Belize significantly improved compliance with antimalarial chemoprophylaxis.

International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.

BACKGROUND: HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. OBJECTIVE: The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. METHODS: The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. RESULTS: The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

Thermal injuries to autologous breast reconstructions and their donor sites--literature review and report of six cases.

Breast reconstruction using autologous techniques has now become the gold standard. In recent years the focus has been on maintaining excellent cosmesis whilst minimising the incidence of partial or complete flap loss and donor site morbidity. However, an area which is frequently overlooked is the sequelae resulting from denervation of these flaps and their donor sites which can potentially lead to thermal injury. We report on six patients who sustained burns following free autologous breast reconstruction using either a DIEP or a muscle sparing TRAM. Four of the burns were confined to the flap skin paddle and two to the abdominal donor site. To prevent such thermal injuries all patients undergoing flap reconstruction should be educated regarding the vulnerability of the flap and its donor site as well as means of protecting these susceptible areas during daily activities.

Multiplexed assays by high-content imaging for assessment of GPCR activity.

G-protein-coupled receptors (GPCR) participate in many disease pathways and represent the largest family of therapeutic targets. Thus, great investments are made to discover drugs modulating GPCR-mediated events. Among functional assays for screening GPCRs, the Transfluor imaging assay is based on redistribution of cytosolic beta-arrestin to an activated GPCR and has become widely used in high-content screening. However, assessing Transfluor alone has limitations: relying on a single mechanistic step of beta-arrestin redistribution during GPCR activation, providing no information on the stimulated GPCR's intracellular fate, and using only a single fluorescent color (green fluorescent protein). Taking full advantage of high-content imaging to screen approximately 2000 compounds, the authors multiplexed the Transfluor assay with an immunofluorescence-based quantification of GPCR internalization. This approach identified and classified 377 compounds interfering with agonist-induced activation of the Transfluor assay, receptor internalization, or both. In addition, a subset of compounds was analyzed for their performance across imaging, cell-based calcium release (fluorometric imaging plate reader [FLIPR]), and biochemical receptor binding assays (scintillation proximity assay). This indicated that the imaging assays have even better predictive power for direct inhibition of receptor binding than the FLIPR assay. In conclusion, compounds inducing unique responses can suggest novel mechanisms of action and be used as tools to study GPCR activation and internalization.

Successful stent-graft placement for the treatment of a superior gluteal artery pseudoaneurysm in a patient following complex pelvic surgery.

Aneurysms of the gluteal arteries are rare and were previously managed with open surgical procedures. Recently percutaneous embolisation techniques have helped reduce morbidity and mortality. A case is presented of a 63-year-old man who presented with haemorrhage and had developed a superior gluteal artery aneurysm following treatment for an invasive squamous cell carcinoma in the sacral area. There was concern that embolisation of the aneurysm might compromise the survival of the myocutaneous buttock rotation flaps that had been used for reconstruction. To overcome this, an endovascular stent was deployed to successfully close off the aneurysm whilst at the same time maintaining blood flow through the superior gluteal artery. Aneurysms in larger peripheral vessels have been managed with stents. However, this is the first reported case of this method of treatment being used in the management of gluteal artery aneurysms.

Going beyond a mean-field model for the learning cortex: second-order statistics.

Mean-field models of the cortex have been used successfully to interpret the origin of features on the electroencephalogram under situations such as sleep, anesthesia, and seizures. In a mean-field scheme, dynamic changes in synaptic weights can be considered through fluctuation-based Hebbian learning rules. However, because such implementations deal with population-averaged properties, they are not well suited to memory and learning applications where individual synaptic weights can be important. We demonstrate that, through an extended system of equations, the mean-field models can be developed further to look at higher-order statistics, in particular, the distribution of synaptic weights within a cortical column. This allows us to make some general conclusions on memory through a mean-field scheme. Specifically, we expect large changes in the standard deviation of the distribution of synaptic weights when fluctuation in the mean soma potentials are large, such as during the transitions between the "up" and "down" states of slow-wave sleep. Moreover, a cortex that has low structure in its neuronal connections is most likely to decrease its standard deviation in the weights of excitatory to excitatory synapses, relative to the square of the mean, whereas a cortex with strongly patterned connections is most likely to increase this measure. This suggests that fluctuations are used to condense the coding of strong (presumably useful) memories into fewer, but dynamic, neuron connections, while at the same time removing weaker (less useful) memories.

Developmental and nutritional regulation of the prepubertal bovine mammary gland: II. Epithelial cell proliferation, parenchymal accretion rate, and allometric growth.

It is well documented that elevated nutrient intake prior to puberty reduces prepubertal mammary development in the bovine. The companion paper demonstrated that age at harvest is a primary determinant of parenchymal (PAR) mass and that any effects of elevated energy intake on mechanisms regulating mammary development are dwarfed by this effect of time. Therefore, it is hypothesized that while causing a decrease in prepubertal PAR mass, elevated nutrient intake will have no effect on growth characteristics of the mammary gland. The objectives of this experiment were to evaluate the effects of increased nutrient intake from early in life on 1) mammary epithelial cell proliferation, 2) mammary PAR DNA accretion rates, and 3) the dynamics of prepubertal allometric PAR growth. Holstein heifers (n = 78) were fed from 45 kg of body weight either elevated (E) or restricted (R) levels of nutrients to support 950 (E) or 650 (R) g/d of body weight gain. Six heifers per treatment were harvested at 50-kg increments from 100 to 350 kg of body weight. Heifers on the E plane of nutrition had higher plasma leptin and less PAR DNA than their body weight-matched R-intake cohorts. Despite this reduction in PAR DNA, treatment did not negatively influence mammary epithelial cell proliferation or the PAR DNA accretion rate. Dynamics of allometric and isometric mammary growth were also unaffected by the level of nutrient intake, as was exit from allometric growth. This work represents the first demonstrating that the level of nutrient intake and the concomitant increase in plasma leptin have no measurable influence on 1) the rate of PAR DNA accretion, 2) mammary epithelial cell proliferation, or 3) total PAR mass and, by default, the local or systemic controls that coordinate these processes.

Long term follow-up of c-myc, p53 and proliferation measurements in malignant melanoma.

AIMS: We report a prospective study examining the prognostic significance of the c-myc oncoprotein, p53 tumour suppressor gene and proliferation rate measurements in malignant melanoma. METHODS: Flow cytometry (FCM) was used to measure the expression of c-myc, p53 and proliferation parameters in patients who had received an injection of the thymidine analogue bromodeoxyuridine prior to surgery. RESULTS: Sixty-seven patients had successful FCM measurements of the three parameters. c-myc was detected in 97% of patients with a median cell positivity of 62%. The median p53 positivity was 13%. The median potential doubling time (T(pot)) of the tumours wasf 9.4 days. In univariate analysis, each of the parameters showed an association with survival in metatstatic disease with rapid proliferation (p=0.006) or overexpression of c-myc (p=0.038) related to poor survival whereas increased positivity for p53 predicted better survival (p=0.013). CONCLUSIONS: These data indicate that laser cytometric technology can be used to obtain quantitative data on oncoproteins expression and cell proliferation rates in clinical samples of malignant melanoma.

Use of the vertical rectus abdominis myocutaneous flap after abdominoplasty.

A vertical rectus abdominis myocutaneous flap was used to provide cover for a recurrent angiosarcoma in the abdominal skin. Of note, the patient had 9 years previously undergone formal abdominoplasty to allow closure following excision of the primary tumour. This flap is normally reliant on myocutaneous perforators originating from the deep epigastric system, which are divided during abdominoplasty. Despite this, the flap survived well, implying that a new blood supply had formed during the intervening years. This flap can, therefore, be considered a possible option in reconstructive cases where other options are limited, despite a preceding abdominoplasty. In the future because of the increasingly common occurrence of abdominoplasty in young females, this procedure may need to be considered.

The sleep cycle modelled as a cortical phase transition.

We present a mean-field model of the cortex that attempts to describe the gross changes in brain electrical activity for the cycles of natural sleep. We incorporate within the model two major sleep modulatory effects: slow changes in both synaptic efficiency and in neuron resting voltage caused by the ∼90-min cycling in acetylcholine, together with even slower changes in resting voltage caused by gradual elimination during sleep of somnogens (fatigue agents) such as adenosine. We argue that the change from slow-wave sleep (SWS) to rapid-eye-movement (REM) sleep can be understood as a first-order phase transition from a low-firing, coherent state to a high-firing, desychronized cortical state. We show that the model predictions for changes in EEG power, spectral distribution, and correlation time at the SWS-to-REM transition are consistent not only with those observed in clinical recordings of a sleeping human subject, but also with the on-cortex EEG patterns recently reported by Destexhe et al. [J. Neurosci.19(11), (1999) 4595-4608] for the sleeping cat.

Cisplatin, fluorouracil, and leucovorin induction chemotherapy followed by concurrent cisplatin chemoradiotherapy for organ preservation and cure in patients with advanced head and neck cancer: long-term follow-up.

PURPOSE: The poor functional outcome in patients with advanced head and neck squamous cell carcinoma (HNSCC) with surgery and radiation has led to alternative approaches to advanced disease. We conducted a phase II study of induction chemotherapy followed by concurrent chemoradiotherapy for organ preservation in patients with advanced resectable and unresectable (nasopharyngeal) tumors. PATIENTS AND METHODS: Forty-two patients with stage III to IV resectable HNSCC and nasopharyngeal tumors received induction chemotherapy with two courses of cisplatin (20 mg/m2/d continuous infusion [CI]), fluorouracil (800 mg/m2/d CI), and leucovorin (500 mg/m2/d CI; PFL) for 4 days followed by concurrent therapy with cisplatin (100 mg/m2/d on days 1 and 22) and approximately 70 Gy of external-beam radiotherapy. RESULTS: Response to induction chemotherapy included partial response rate of 52% and complete response rate of 24%. The most common grade 3 or 4 toxicity was neutropenia (59%). After cisplatin chemoradiotherapy the complete response rate was 67%. Toxicities of cisplatin chemoradiotherapy consisted of grade 3 or 4 mucositis (79%) and neutropenia (51%). At a median follow-up of 71.5 months, 43% of the patients are still alive and disease-free. The 5-year progression-free survival (PFS) rate was 60%, and the 2- and 5-year overall survival (OS) rates were 67% and 52%, respectively. Three patients died of second primaries. Late complications of treatment included xerostomia and hoarseness. One patient had persistent dysphagia and required laser epiglotectomy 108 months after treatment. CONCLUSION: Induction chemotherapy with PFL followed by concurrent cisplatin chemoradiotherapy is well tolerated and results in a good likelihood of organ preservation and excellent PFS and OS.

Hereditary haemorrhagic telangiectasia: state of the art.

Hereditary haemorrhagic teleangiectasia (HHT) or Rendu-Osler-Weber disease is a genetic autosomal-dominant disorder characterised by the presence of vascular telangiectases in mucocutaneous tissues, visceral organs and the Central Nervous System. Pulmonary arteriovenous malformations have a variable incidence rate ranging between 15-33%, and the safest treatment is transcatheter embolotherapy. Haemmorrhages from the gastrointestinal tract occur in 10-40% of patients with HHT localized in duodenum and colon and can be treated with endoscopy and laser coagulation, but this procedure is not efficacious for vascular anomalies in small intestine since this site cannot be easily reached. The prevalence of cerebrovascular malformations in hereditary haemorrhagic telangiectasia patients is 5-27%, and there are several types described including telangiectasias, cavernous angiomas, arteriovenous malformations, and aneurysms. Cerebrovascular malformations can be treated by: neurovascular surgery, embolization, and stereotactic radiosurgery, but the appropriate course of action for dealing with asymptomatic cerebrovascular malformations is still debated. The most common symptom in HHT patients is epistaxis, which can sometimes be so profuse that it requires multiple transfusions and iron supplementation. Nose bleeds begin before 10 years of age and become more severe in later decades. A multitude of different treatments are available, tailored to the severity of epistaxis. These include: hormonal therapy with oestrogens, application of fibrine tissue sealant, laser coagulation, embolization and septal dermoplasty using Saunder's technique. Aim of this study is to review diagnostic and therapeutic techniques, since continuous growth and danger of these arteriovenous malformations require early diagnosis, adequate treatment, prolonged follow-up and screening of the family.

Magnetic resonance imaging of ethyl-nitrosourea-induced rat gliomas: a model for experimental therapeutics of low-grade gliomas.

Human low-grade gliomas represent a population of brain tumors that remain a therapeutic challenge. Preclinical evaluation of agents, to test their preventive or therapeutic efficacy in these tumors, requires the use of animal models. Spontaneous gliomas develop in models of chemically induced carcinogenesis, such as in the transplacental N-ethyl-N-nitrosourea (ENU) rat model. However, without the ability to detect initial tumor formation, multiplicity or to measure growth rates, it is difficult to test compounds for their interventional or preventional capabilities. In this study Fisher-334 rats, treated transplacentally with ENU, underwent magnetic resonance imaging (MRI) examination in order to evaluate this approach for detection of tumor formation and growth. ENU-induced intracranial cerebral tumors were first observable in T2-weighted images beginning at 4 months of age and grew with a mean doubling time of 0.487 +/- 0.112 months. These tumors were found histologically to be predominately mixed gliomas. Two therapeutic interventions were evaluated using MRI, vitamin A (all-trans retinol palmitate, RP), as a chemopreventative agent and the anti-angiogenic drug SU-5416. RP was found to significantly delay the time to first tumor observation by one month (P = 0.05). No differences in rates of tumor formation or growth rates were observed between control and RP-treated groups. MRI studies of rats treated with SU-5416 resulted in reduction in tumor growth rates compared to matched controls. These results show that MRI can be used to provide novel information relating to the therapeutic efficacy of agents against the ENU-induced tumor model.