Low- and high-volume blood-flow restriction treadmill walking both improve maximal aerobic capacity independently of blood volume.

AIM: Assess the effect of low- and high-volume blood flow restriction training (BFR) on maximal aerobic capacity (VO2 max) and determine if alteration in VO2 max is mediated through changes in hemoglobin mass (Hbmass) and blood volume. METHODS: Participants' Hbmass (CO-rebreathe), single, and double-leg VO2 max and blood volume regulating hormonal responses (renin and copeptin) were measured before and after BFR training. Training consisted of treadmill walking either (1) twice-daily for 4week (CON and BFRHV ) or (2) twice-weekly for 6week (BFRLV ). Each session consisted of five intervals (3 min, 5% incline, 5 km/h, 100% of lowest occlusion pressure), with 1 min of standing rest between sets. RESULTS: VO2 max increased using both training exposures, in as quickly as 2-weeks (BFRLV baseline to 4week: +315 ± 241 mL (8.7%), p = 0.02; BFRHV baseline to 2week: +360 ± 261 mL (7.9%), p < 0.01), for the BFRLV and BFRHV groups, with no change in CON. Single- and double-leg VO2 max improved proportionately (single/double-leg VO2 max ratio: BFRLV 78 ± 4.9-78 ± 5.8%, BFRHV 79 ± 6.5-77 ± 6.5%), suggesting that the mechanism for increased VO2 max is not solely limited to central or peripheral adaptations. Hbmass remained unchanged across groups (CON: +10.2 ± 34 g, BFRLV : +6.6 ± 42 g, BFRHV : +3.2 ± 44 g; p = 0.9), despite a significant release of blood volume regulating hormones after initial BFR exposure (renin +20.8 ± 21.9 ng/L, p < 0.01; copeptin +22.0 ± 23.8 pmol/L, p < 0.01), which was blunted following BFRHV training (renin: +13.4 ± 12.4 ng/L, p = 0.09; copeptin: +1.9 ± 1.7 pmol/L, p = 0.98). CONCLUSION: BFR treadmill walking increases VO2 max irrespective of changes in Hbmass or blood volume despite a large release of blood volume regulating hormones in response to BFR treadmill walking.

A novel approach for the treatment of Morgagni hernias: robotic transabdominal preperitoneal diaphragmatic hernia repair.

PURPOSE: We introduce a novel approach to the surgical repair of Morgagni hernias (MHs) utilizing the robotic transabdominal preperitoneal repair (rTAPP) approach. Borrowed from our previous and robust experience with rTAPP repairs for hernias of the anterior abdominal wall, this technique boasts the benefits of hernia sac reduction, the use of an uncoated mesh in an extraperitoneal plane, and minimal fixation leading to lower postoperative pain relative to other approaches. METHODS: To evaluate the effectiveness of this novel approach, five consecutive symptomatic Morgagni hernias (MHs) were repaired with the rTAPP approach. The size of the defect, mesh size, length of stay, follow-up imaging, and follow-up complications were documented for comparison. RESULTS: The size of the MH defects ranged from 4 × 6 cm to 5 × 10 cm. LOS was an average of 1.2 days. Two out of the five patients underwent concomitant repair of a lower abdominal hernias (one Spigelian hernia, and one indirect inguinal hernia). Outpatient follow-up from surgery ranged anywhere from 6 months to 4 years, with most patients receiving follow-up after 1 year. Four out of the five patients received follow-up CT scans to confirm the absence of hernia recurrence. One patient experienced an incisional hernia from the midline 12-mm port site which was repaired 1 year after. CONCLUSION: We propose a new technique for a minimally invasive strategy to treat these complex hernias utilizing an rTAPP technique resulting in minimal length of stay and a durable result in long-term follow-up. The benefits of repair, which include minimal postoperative pain, minimal length of stay, and cost-effective prosthetic mesh hidden from the visceral contents, are consistent with the author's experience for rTAPP repairs for hernias of the anterior abdominal wall.

Improving Access for Priority Patient Populations Within Outpatient Specialty Practices.

In an outpatient health care practice, it can be challenging to convert patient demand into completed appointments, even for high-priority patients. One of the barriers to higher conversion rates is excessive appointment lag time, which can lead to nonattendance or cancellation for other reasons. In this article, we develop a mechanism for reducing appointment lag time for priority patient populations. We report on a pilot program with 12 practices, split into pilot and control groups, and involving 11001 patients requesting new appointments. The results of the pilot show that statistically significant improvements to conversion rates can be achieved.

Changes in Physical Activity and Television Viewing From Pre-pregnancy Through Postpartum Among a Socioeconomically Disadvantaged Perinatal Adolescent Population.

STUDY OBJECTIVE: Adolescent pregnancy contributes to accelerated trajectories of adiposity and cardiometabolic diseases. Two potentially low-cost prevention strategies include promoting physical activity (PA) and limiting television (TV) viewing. Few studies have explored these behavior patterns in perinatal adolescents. This study sought to characterize PA and TV viewing in a socioeconomically disadvantaged perinatal adolescent population. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: A cross-sectional, retrospective, 10-item survey was used to explore behavior patterns in 79 predominantly Black (86%) postpartum adolescents. MAIN OUTCOME MEASURES: Outcomes included self-reported changes in PA from pre-pregnancy through pregnancy, and 7-day recall of PA and TV viewing in postpartum. RESULTS: The majority of adolescents (66%) reported being active on ≥3 days/week in pre-pregnancy; however, many reported low PA (≤2 days/wk) in their first (59%), second (66%), and third (54%) trimesters. Adolescents who reported being active on ≥5 days/wk in pre-pregnancy (19%) experienced first trimester PA decline, which subsequently plateaued. This group remained the most active throughout pregnancy. In postpartum, over half (54%) of all adolescents reported low PA and irrespective of PA, spent considerable time watching TV (median = 1680.0 minutes, inerquartile range = 2940). CONCLUSION: Interventions promoting PA coupled with reducing TV viewing during pregnancy and in postpartum may benefit perinatal adolescents. The findings from this study suggest that PA history is a predictor of gestational PA, and low PA and high TV viewing in postpartum underscore the need for behavioral intervention. Conducting a brief assessment of PA history in early gestation may offer important insight.

MRNIP is a replication fork protection factor.

The remodeling of stalled replication forks to form four-way DNA junctions is an important component of the replication stress response. Nascent DNA at the regressed arms of these reversed forks is protected by RAD51 and the tumor suppressors BRCA1/2, and when this function is compromised, stalled forks undergo pathological MRE11-dependent degradation, leading to chromosomal instability. However, the mechanisms regulating MRE11 functions at reversed forks are currently unclear. Here, we identify the MRE11-binding protein MRNIP as a novel fork protection factor that directly binds to MRE11 and specifically represses its exonuclease activity. The loss of MRNIP results in impaired replication fork progression, MRE11 exonuclease-dependent degradation of reversed forks, persistence of underreplicated genomic regions, chemosensitivity, and chromosome instability. Our findings identify MRNIP as a novel regulator of MRE11 at reversed forks and provide evidence that regulation of specific MRE11 nuclease activities ensures protection of nascent DNA and thereby genome integrity.

Simulated participant methodology in paediatric surgical training: Exploring contemporary practices.

Surgical training is long and complex. At the core of clinical practice is communication. Voice is central to relationships of care. Communication and other person-centred competencies are well articulated in surgical training programs. Simulated participant (SP) methodology has seen significant development over its contemporary history. Most commonly in paediatrics SPs portray the roles of parents. However, children and adolescents as SPs are increasingly employed to support the development and assessment of the complex concept of voice. There are specific considerations in all phases of SP-based work, and these are heightened for children and adolescents. This article explores contemporary SP practices in health professional education with a focus on paediatric surgery training.

Activation of RyR2 by class I kinase inhibitors.

BACKGROUND AND PURPOSE: Kinase inhibitors are a common treatment for cancer. Class I kinase inhibitors that target the ATP-binding pocket are particularly prevalent. Many of these compounds are cardiotoxic and can cause arrhythmias. Spontaneous release of Ca2+ via cardiac ryanodine receptors (RyR2), through a process termed store overload-induced Ca2+ release (SOICR), is a common mechanism underlying arrhythmia. We explored whether class I kinase inhibitors could modify the activity of RyR2 and trigger SOICR to determine if this contributes to the cardiotoxic nature of these compounds. EXPERIMENTAL APPROACH: The impact of class I and II kinase inhibitors on SOICR was studied in HEK293 cells and ventricular myocytes using single-cell Ca2+ imaging. A specific effect on RyR2 was confirmed using single channel recordings. Ventricular myocytes were also used to determine if drug-induced changes in SOICR could be reversed using anti-SOICR agents. KEY RESULTS: Class I kinase inhibitors increased the propensity of SOICR. Single channel recording showed that this was due to a specific effect on RyR2. Class II kinase inhibitors decreased the activity of RyR2 at the single channel level but had little effect on SOICR. The promotion of SOICR mediated by class I kinase inhibitors could be reversed using the anti-SOICR agent VK-II-86. CONCLUSIONS AND IMPLICATIONS: Part of the cardiotoxicity of class I kinase inhibitors can be assigned to their effect on RyR2 and increase in SOICR. Compounds with anti-SOICR activity may represent an improved treatment option for patients.

The effects of speed-dependent treadmill training and rhythmic auditory-cued overground walking on balance function, fall incidence, and quality of life in individuals with idiopathic Parkinson's disease: a randomized controlled trial.

OBJECTIVES: The purpose of this single-blinded, randomized controlled study was to examine and compare the immediate and retention effects of progressive speed-dependent treadmill training (SDTT) and rhythmic auditory-cued (RAC) training on balance function, fall incidence, and quality of life (QOL) in individuals with PD. METHODS: Twenty participants (mean age 66.1 yrs) with idiopathic PD were randomized into either SDTT (n = 10) or RAC (n = 10) progressive, interval-based locomotor training for 6 weeks. Measures included the Berg Balance Scale (BBS), Rapid Step-Up Test (RST), Activities-specific Balance Confidence Scale, Parkinson's Disease Questionnaire-39 (PDQ), and the NeuroCom Sensory Organization Test (SOT), Motor Control Test, and Limits of Stability (LOS). Fall incidence was assessed prospectively post-training based on six monthly self-report fall calendars. RESULTS: Significant gains in balance measures were observed post-training in BBS, RST and SOT for the RAC group and in RST, SOT and LOS for the SDTT group. Gains were retained at 3 months post-training in all measures for RAC group, but only the RST for the SDTT group. No clear trend in reduction in fall frequency was evident. CONCLUSION: Externally-cued locomotor training paradigms with progressive speed challenges produced significant improvements in dynamic balance function in persons with PD, with stronger retention of gains in RAC group.

Characterization of a third generation lentiviral vector pseudotyped with Nipah virus envelope proteins for endothelial cell transduction.

Lentiviruses are becoming progressively more popular as gene therapy vectors due to their ability to integrate into quiescent cells and recent clinical trial successes. Directing these vectors to specific cell types and limiting off-target transduction in vivo remains a challenge. Replacing the viral envelope proteins responsible for cellular binding, or pseudotyping, remains a common method to improve lentiviral targeting. Here, we describe the development of a high titer, third generation lentiviral vector pseudotyped with Nipah virus fusion protein (NiV-F) and attachment protein (NiV-G). Critical to high titers was truncation of the cytoplasmic domains of both NiV-F and NiV-G. As known targets of wild-type Nipah virus, primary endothelial cells are shown to be effectively transduced by the Nipah pseudotype. In contrast, human CD34+ hematopoietic progenitors were not significantly transduced. Additionally, the Nipah pseudotype has increased stability in human serum compared with vesicular stomatitis virus pseudotyped lentivirus. These findings suggest that the use of Nipah virus envelope proteins in third generation lentiviral vectors would be a valuable tool for gene delivery targeted to endothelial cells.

Shear waves in viscoelastic wormlike micellar fluids over a broad concentration range.

Low frequency (61 Hz) shear wave speeds have been measured in viscoelastic wormlike micellar (WM) fluids for a concentration range of 20/12-500/300 mM CTAB/NaSAL where CTAB is the surfactant and NaSAL is the salt and the concentration ratio was fixed at 0.6 for all experiments. The birefringent property of the WM fluids was exploited to visually track the the shear pulse using crossed optical polarizing filters and high speed video. Several scalings of shear wave speed as a function of concentration were discovered: c(s) ~ √C for 20-200 mM and c(s) ~ C for higher concentrations, but with a break in the slope at 400 mM CTAB. Over this full concentration range, the shear wave speed varied from 0.08-0.7 m/s. The shear wave speed was also found to be sensitive to the time between fluid synthesis and measurement indicating a long equilibrium time. Further, comparison with elastic and loss moduli obtained from rheology data show that shear wave propagation is dominated by the elastic modulus for this frequency range. Also briefly discussed are potential applications of this fluid in elastography.

The effect of creosote on vitellogenin production in rainbow trout (Oncorhynchus mykiss).

As part of a broader investigation into the effects of creosote treatments on the aquatic biota in pond microcosms, we examined the possible implications for vitellogenin (Vtg) production in Oncorhynchus mykiss [rainbow trout (RT)]. Vtg is the precursor of egg yolk protein and has emerged as a useful biomarker of exposure to estrogenic substances. Our a priori intent was to assess the ability of the creosote treatments (nominal cresoste concentrations were 0, 3, and 10 microl/L immediately after the last subsurface addition) to induce estrogenic responses in RT. The data showed no evidence of an estrogenic response in the treated fish. During the course of the experiment, however, the fish matured and began to produce Vtg, probably in response to endogenous estrogen. A posteriori analysis of the Vtg data from the maturing fish showed that after 28 days, the plasma Vtg concentrations were about 15-fold lower in fish from the creosote-treated microcosms compared with fish from the reference microcosm. Although the experiment design does not permit mechanistic insights, our observation suggests that exposure of female fish to PAH mixtures such as creosote can impair the production of Vtg with possible health implications for embryos and larvae.

Microlinguistic deficits in the narrative discourse of adults with traumatic brain injury.

BACKGROUND: Recent studies of microlinguistic impairments in the narrative discourse of adults with traumatic brain injury (TBI) have applied syntactic analyses, with some noting no deficits and others specific problems with sentence formulation. An alternative approach to examining the microlinguistic dysfunction in the discourse of individuals with TBI is through the use of propositional analysis. The advantage of propositional analysis is that it enables one to assess semantic complexity of utterances apart from sentence structure and grammaticality. AIMS: The present study applied propositional analysis to the story narratives of participants with TBI and participants with no brain injury (NBI). Specifically, the mean number of propositions within a sentence was tallied, in other words the participants' ability to insert multiple ideas into single surface sentences. It was hypothesized that the participants with TBI would produce fewer propositions per sentence because of organizational problems than the participants with NBI, regardless of level of education. METHODS AND PROCEDURES: Two story narratives (retelling and generation) previously elicited from the two participant groups (TBI (n = 53) and NBI (n = 42)) were analysed. For each language sample, the number of propositions was tallied and divided by the number of T-units. The resulting number, the propositional complexity index (PCI), was the average number of predicates per sentence. OUTCOMES AND RESULTS: Results indicated that the group with TBI produced significantly fewer propositions per T-unit. CONCLUSIONS: The present findings are in harmony with the notion that the participants with TBI studied presented with impairments of both micro- and macrolinguistic processes involved with the organization of semantic information in discourse. Clinical implications are discussed.

Structure and reactivity studies of the first tungsten cyanoalkylidene complex.

Alkylidene complex W(CHCMe2Ph)(NAr)[OCMe(CF3)2]2 (Ar = 2, 6 diisopropylphenyl) (4) reacts with one equivalent of acrylonitrile in methylene chloride to afford the tetrameric, cyanoalkylidene complex [W(CHCN)(NAr)[OCMe(CF3)2]2]4 (5) which reacts with excess acetonitrile to give the tetrameric complex [W(N(H)C(CH3)C(CN)C(CH3)N)(NAr)[OCMe(CF3)2]2]4 (6).

An ELISA for brown trout (Salmo trutta) vitellogenin and its use in bioassays for environmental estrogens.

An enzyme linked immunosorbent assay (ELISA) was developed for the detection of the egg yolk precursor vitellogenin (Vg) in plasma of brown trout (Salmo trutta). Purified Vg from a 17 beta-estradiol-induced trout was used as the competing antigen in the ELISA which is based on polyclonal antibodies. The ELISA's performance was optimized and characterized. The assay's working range was (25-500 ng ml-1), its sensitivity was (10.5 ng ml-1), and it had an intra-assay coefficient of variation of less than 10% between 30 and 1000 ng ml-1. The ELISA was used in bioassays for the detection of environmental estrogens, including estrogen mimics, in whole and fractionated industrial waste waters. Those bioassays were based on intraperitoneal (i.p.) injection-, static renewal-, and flow through exposure systems. The response threshold of both bioassays is limited to 1-2 micrograms ml-1 Vg by a low level plasma interference that was regularly detected in plasma from non-induced male fish. The responsiveness of the bioassays was characterized using progressive doses of 17 beta-estradiol. The i.p.-based assay, which was responsive to at least 100 micrograms kg-1 of 17 beta-estradiol, was used to screen extracts of pulp mill effluent and black liquor for estrogenic effects. Neither extract induced Vg in our assay. The i.p. assay was also used to test 4-tert-octylphenol (OP) and the PAH derivative, retene, for estrogenic activity. OP induced Vg in the i.p.-exposed fish; no Vg induction was detected in the retene-exposed fish. The static renewal bioassay, which was responsive to at least 0.1 microgram ml-1 of 17 beta-estradiol over a 15-day exposure period, was used to screen whole pulp mill effluents for estrogenic effects. No Vg induction was detected in the effluent-treated fish.

Stopping female genital mutilation. An update.

PIP: There is widespread consensus among many individuals, countries, and organizations that female genital mutilation (FGM) is a human rights abuse. France, Britain, Sweden, and Switzerland have passed legislation forbidding medical personnel from performing FGM, eighteen African countries have made official statements against FGM, and FGM was an issue in the 1993 World Health Assembly, the 1993 World Human Rights Conference, and the 1994 International Conference on Population and Development. True change, however, depends upon a transformation in the informal economic, social, and political structures which perpetuate women's dependency upon marriage and men. The Research Action Information Network for the Bodily Integrity of Women (RAINBOW) and the Development Law and Policy Unit of the Columbia University School of Public Health introduced the Global Action Against FGM (GAAFGM) Project in June 1994. The project is designed to integrate action against FGM into existing health and human rights programs and to pool available resources against FGM. GAAFGM has also coordinated an interagency working group comprised of international agencies, in-country grassroots organizations, and women's groups, which met for the first time in November 1994. The project should provide considerable information and leadership on the issue. On another front, participants in the most recent preparatory meeting for the upcoming Beijing Conference noted the existence of a strong recognition that FGM is a problem upon which the international community should act. The author notes recent litigation brought by the Egyptian Organization for Human Rights against the grand sheik of Al-Azhar University for issuing a fatwa declaring female circumcision an Islamic duty. In addition, a Ghanaian may be granted refugee status in Canada on the basis of her efforts to avoid mutilation if deported to her country of origin.^ieng

Use of tumour marker immunoreactivity to identify primary site of metastatic cancer.

OBJECTIVES: To determine whether variations in the expression of tumour related antigens can predict the origin of tumours. DESIGN: Immunohistological study of tumour marker expression in primary adenocarcinomas and respective metastatic deposits. Antibodies to the following tumour markers were used: polymorphic epithelial mucin (NCRC-11 and SM3), carcinoembryonic antigen, carcinoembryonic antigen with non-specific antigen co-specificity, CA125, CA19.9, prostate specific antigens, and thyroglobulin. SETTING: Histopathology department of teaching hospital. SUBJECTS: 100 pathology sections of metastatic adenocarcinoma and their related primary tumours. MAIN OUTCOME MEASURES: Concordance of reactivity between primary and metastatic tumours. Reactivity profiles of tumour sites. RESULTS: The correct primary site of origin was predicted in 70% (33/47) of tumours in men and 54% (27/43) tumours in women with antibodies SM3, 288, CA19.9, CA125, and PSA (men only). Specificities ranged from 68% for breast tumour to 98% for prostate tumour. CONCLUSION: Use of tumour markers in patients presenting with metastatic adenocarcinoma of unknown origin can help localise the probable primary sites and reduce the need for extensive and expensive imaging techniques.

Excitatory amino acid-induced convulsions in neonatal rats mediated by distinct receptor subtypes.

We found that N-methyl-D-aspartate (NMDA) was a very potent, systematically active convulsant in the rat in the early period of postnatal development (7-11 days of age). Other receptor subtype-selective excitatory amino acid agonists were then examined for their convulsant effects following i.p. administration to neonatal rats. alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) was the most potent convulsant (ED50 0.6 mg/kg), followed by kainate (ED50 1.5 mg/kg), N-methyl-D-aspartate (NMDA) (ED50 3.1 mg/kg), then quisqualate (ED50 5.1 mg/kg). NMDA-induced convulsions were antagonized in a dose-related manner by prior administration of the NMDA antagonists cis-(+/- )-4-phosphonomethyl-2-piperidine carboxylic acid (CGS19755), cis-(+/- )-4-(2H-tetrazol-5-yl)methyl-piperidine-2-carboxylic acid (LY233053), (+/- )3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), D,L-2-amino-5-phosphonovalerate (D,L-AP5) and MK801. NMDA antagonists did not protect against AMPA- or kainate-induced convulsions. 6,7-Dinitroquinoxaline-2,3-dione (DNQX) selectively prevented the effect of AMPA at doses which had no effect on NMDA or kainate convulsions. Quisqualate-induced convulsions were antagonized by NMDA antagonists or DNQX. The greater sensitivity of neonatal rats to systemically administered excitatory amino acid agonists appears useful for evaluating the selectivity of antagonists acting at ionotropic excitatory amino acid receptors in the central nervous system. Using neonatal rats three pharmacologically distinct excitatory amino acid receptor effects were demonstrated following administration of NMDA, AMPA or kainate.

A comparison of two methods for the computer analysis of arterial blood pressure waveforms.

Two different methods, one analogue and one digital, for the analysis of the arterial blood pressure waveform are described and compared. Little difference was found in the systolic and diastrlic pressures determined by the two methods.