Sleep restriction reduces voluntary isometric quadriceps strength through reduced neuromuscular efficiency, not impaired contractile performance.

Acute sleep restriction (SR) reduces strength through an unknown mechanism. PURPOSE: To determine how SR affects quadriceps contractile function and recruitment. METHODS: Eighteen healthy subjects (9 M, 9F, age 23.8 ± 2.8y) underwent isometric (maximal and submaximal), isokinetic (300-60°·s-1), and interpolated twitch (ITT) assessment of knee extensors following 3d of adequate sleep (SA; 7-9 h·night-1), 3d of SR (5 h·night-1), and 7d of washout (WO; 7-9 h·night-1). RESULTS: Compared to SA (227.9 ± 76.6Nm) and WO (228.19 ± 62.9Nm), MVIC was lesser following SR (209.9 ± 73.9Nm; p = 0.006) and this effect was greater for males (- 9.8 v. - 4.8%). There was no significant effect of sleep or sleep x speed interaction on peak isokinetic torque. Peak twitch torque was greater in the potentiated state, but no significant effect of sleep was noted. Males displayed greater potentiation of peak twitch torque (12 v. 7.5%) and rate of torque development (16.7 v. 8.2%) than females but this was not affected by sleep condition. ITT-assessed voluntary activation did not vary among sleep conditions (SA: 81.8 ± 13.1% v. SR: 84.4 ± 12.6% v. WO 84.9 ± 12.6%; p = 0.093). SR induced a leftward shift in Torque-EMG relationship at high torque output in both sexes. Compared to SA, females displayed greater y-intercept and lesser slope with SR and WO and males displayed lesser y-intercept and greater slope with SR and WO. CONCLUSIONS: Three nights of SR decreases voluntary isometric knee extensor strength, but not twitch contractile properties. Sex-specific differences in neuromuscular efficiency may explain the greater MVIC reduction in males following SR.

Chaos in a ring circuit.

A ring-shaped logic circuit is proposed here as a robust design for a True Random Number Generator (TRNG). Most existing TRNGs rely on physical noise as a source of randomness, where the underlying idealized deterministic system is simply oscillatory. The design proposed here is based on chaotic dynamics and therefore intrinsically displays random behavior, even in the ideal noise-free situation. The paper presents several mathematical models for the circuit having different levels of detail. They take the form of differential equations using steep sigmoid terms for the transfer functions of logic gates. A large part of the analysis is concerned with the hard step-function limit, leading to a model known in mathematical biology as a Glass network. In this framework, an underlying discrete structure (a state space diagram) is used to describe the likely structure of the global attractor for this system. The latter takes the form of intertwined periodic paths, along which trajectories alternate unpredictably. It is also invariant under the action of the cyclic group. A combination of analytical results and numerical investigations confirms the occurrence of symmetric chaos in this system, which when implemented in (noisy) hardware, should therefore serve as a robust TRNG.

Non-epithelial tumors of the larynx: a single institution review.

AIM: Non-epithelial tumors of the larynx are rare and encompass a wide range of pathology. We present the decade-long experience of a single institution to define clinical presentations and outcomes. MATERIAL AND METHODS: This is a ten year retrospective chart review of a tertiary head and neck cancer center. Index patients were identified from a review of a pathology database, and patient demographics, presenting signs and symptoms, treatment modalities, and clinical outcomes were extracted from electronic medical records. Epithelial tumors (squamous cell carcinoma, spindle cell carcinoma, and salivary tumors), granulomas, sarcoidosis, papilloma, and amyloidosis were all excluded. RESULTS: Twenty-four patients with ages ranging from 2months-old to 84years were identified. Malignant lesions (11) included chondrosarcoma (6), Kaposi's sarcoma (2), metastatic melanoma, synovial cell sarcoma, and T cell neoplasm. Six were operated upon endolaryngeally, but four required either upfront or salvage total laryngectomy. Two received adjuvant therapy. Benign lesions (13) included hemangioma (4), granular cell tumor (3), myofibroblastic tumor (2), schwannoma (2), chondroma, and ossifying fibromyxoid tumor. Nine underwent endolaryngeal operations, and four were managed medically or with observation. None have required aggressive open resection or total laryngectomy. CONCLUSION: Treatment approach of non-epithelial tumors of the larynx depends on the site and extent of the tumor, histology, and sensitivity of adjuvant therapy. Benign tumors can be managed without need for aggressive resection thereby sparing laryngeal function.

The effects of scaffold architecture and fibrin gel addition on tendon cell phenotype.

Development of tissue engineering scaffolds relies on careful selection of pore architecture and chemistry of the cellular environment. Repair of skeletal soft tissue, such as tendon, is particularly challenging, since these tissues have a relatively poor healing response. When removed from their native environment, tendon cells (tenocytes) lose their characteristic morphology and the expression of phenotypic markers. To stimulate tendon cells to recreate a healthy extracellular matrix, both architectural cues and fibrin gels have been used in the past, however, their relative effects have not been studied systematically. Within this study, a combination of collagen scaffold architecture, axial and isotropic, and fibrin gel addition was assessed, using ovine tendon-derived cells to determine the optimal strategy for controlling the proliferation and protein expression. Scaffold architecture and fibrin gel addition influenced tendon cell behavior independently in vitro. Addition of fibrin gel within a scaffold doubled cell number and increased matrix production for all architectures studied. However, scaffold architecture dictated the type of matrix produced by cells, regardless of fibrin addition. Axial scaffolds, mimicking native tendon, promoted a mature matrix, with increased tenomodulin, a marker for mature tendon cells, and decreased scleraxis, an early transcription factor for connective tissue. This study demonstrated that both architectural cues and fibrin gel addition alter cell behavior and that the combination of these signals could improve clinical performance of current tissue engineering constructs.

Ionic solutes impact collagen scaffold bioactivity.

The structure of ice-templated collagen scaffolds is sensitive to many factors. By adding 0.5 wt% of sodium chloride or sucrose to collagen slurries, scaffold structure could be tuned through changes in ice growth kinetics and interactions of the solute and collagen. With ionic solutes (sodium chloride) the entanglements of the collagen molecule decreased, leading to fibrous scaffolds with increased pore size and decreased attachment of chondrocytes. With non-ionic solutes (sucrose) ice growth was slowed, leading to significantly reduced pore size and up-regulated cell attachment. This highlights the large changes in structure and biological function stimulated by solutes in ice-templating systems.

Mechanical properties of morcellised bone graft with the addition of hydroxyapatite.

Mixtures of morcellised bone graft (MBG) and hydroxyapatite (HA) are frequently used in revision arthroplasty surgery. However, the changes in the mechanical properties from adding HA to MBG are unknown. This study used a uniaxial compression test to replicate impaction bone grafting and subsequent early postoperative weightbearing to investigate the effect of adding different proportion of HA to MBG. To achieve this aim, human MBG was subjected to increasing impaction forces and the apparent stiffness and creep for each stress level determined. Subsequently, increasing proportions porous and non porous HA were added to the MBG. The major findings were that the apparent stiffness for MBG increased and the associated creep decreased both with the application of increasing stress and with the addition of increasing proportions of HA. In conclusion, greater proportions of HA in the graft mixture improved the mechanical response compared with MBG impacted under the same force. This improvement replicated the properties of pure MBG under high axial stress. This study indicates that graft mixtures of MBG and HA can be tailormade for patients. The need for less impaction force in MBG:HA mixtures to obtain the same properties as pure MBG may decrease the risk of intraoperative fracture.

The effect of ageing and fitness on thermoregulatory response to high-intensity exercise.

There are conflicting reports as to whether ageing causes a decreased thermoregulatory response, or if observed differences in previous studies are related to maximal aerobic capacity or training status. This study hypothesized that thermoregulatory response to severe exercise-heat stress is maintained with ageing when both young and older subjects are well trained. Seven older highly trained (OHT = 51-63 years) cyclists were matched with two groups of young cyclists (19-35 years); one group matched for training status [young highly trained (YHT) participants, n = 7] and another for V ˙ O 2 max [young moderately trained (YMT), n = 7]. Each participant exercised at 70% V ˙ O 2 max in hot (35°C, 40% relative humidity) and thermoneutral (20°C, 40% relative humidity) conditions for 60 min. Final rectal temperature in the thermoneutral and heat (YHT = 39.13 ± 0.33°C, YMT = 39.11 ± 0.38°C, OHT = 39.11 ± 0.51°C) tests were similar between all three groups. %HR(max) (heat test: YHT = 92.5 ± 6.0%, YMT = 91.6 ± 4.4%, OHT = 88.6 ± 5.1%), skin temperature, and cutaneous vascular conductance during cycling in both environments were similar between groups. Lower sweat loss and evaporative heat loss in the heat test in the OHT and YMT groups when compared with the YHT group reflected lower metabolic heat production. The findings of the present study suggest that thermoregulatory response is maintained with age among highly trained subjects.

Intermediate term outcomes associated with the surveillance of ureteropelvic junction obstruction in adults.

PURPOSE: We determined the outcome of minimally symptomatic adult ureteropelvic junction obstruction in a group of patients treated conservatively with an active surveillance regimen. MATERIALS AND METHODS: A total of 27 patients with asymptomatic or minimally symptomatic ureteropelvic junction obstruction were treated conservatively. All patients were evaluated with diuretic renograms. Ureteropelvic junction obstruction was defined by an obstructive pattern of the clearance curve and/or T1/2 greater than 20 minutes. Followup consisted of an office visit and renogram every 6 to 12 months. Cases of greater than 10% loss of relative renal function of the affected kidney, development of pyelonephritis and/or more than 1 episode of acute pain were considered active surveillance failures, and treatment was recommended. RESULTS: Of the 27 patients 6 were lost to followup, leaving 21 (median age 47 years) with sufficient followup for analysis. In the 4 patients (19%) who initially presented with mild pain that led to the diagnosis of ureteropelvic junction obstruction, the pain completely resolved. Ipsilateral relative renal function decreased significantly in 2 patients (9.5%, mean reduction 14%). Pain worsened in 3 patients (14.3%) and de novo pain occurred in 1 (4.7%). Surgical intervention for ureteropelvic junction obstruction was required in 6 patients (29%) at an average of 34 months. In total 15 patients (71%) remained on surveillance with a mean followup of 48 months. CONCLUSIONS: Active surveillance seems to be a reasonable initial option for asymptomatic or mildly symptomatic adult patients with ureteropelvic junction obstruction because only approximately 30% have progression to surgical intervention within 4 years of diagnosis. This strategy offers the advantage of individualizing therapy according to symptoms and renographic findings.

Canine subcutaneous mast cell tumor: characterization and prognostic indices.

Histologic grading schemes for canine cutaneous mast cell tumors (MCTs) were not developed for subcutaneous MCTs. Despite this, subcutaneous MCTs are currently categorized by many as grade II or higher. The aim of this investigation was to assess the pathology and clinical outcome for subcutaneous MCTs to provide a more accurate prognosis. Information on clinical outcome for 306 dogs was obtained from veterinarians and correlated with histologic features. Mean and median follow-up was 842 and 891 days, respectively (range, 3-2,305 days). Only 27 (9%) were confirmed as mast cell-related deaths. Metastasis occurred in 13 (4%), and 24 (8%) had local reoccurrence, even though 171 (56%) cases had incomplete surgical margins. Median survival time was not reached, and the estimated 6-month, 1-, 2-, and 5-year survival probabilities were 95%, 93%, 92%, and 86%, respectively. Dogs were euthanized or died as a result of local tumor reoccurrence, additional MCT development distant to the surgical site, or metastasis. Decreased survival time was linked to mitotic index (number of mitotic figures per 10 high-power fields), infiltrative growth pattern, and presence of multinucleation. Both univariable and multivariable analysis showed mitotic index to be strongly predictive of survival, local reoccurrence, and metastasis. The results of the study indicate that the majority of subcutaneous MCTs have a favorable prognosis, with extended survival times and low rates of reoccurrence and metastasis.

Canine subcutaneous mast cell tumors: cellular proliferation and KIT expression as prognostic indices.

Molecular assays are widely used to prognosticate canine cutaneous mast cell tumors (MCT). There is limited information about these prognostic assays used on MCT that arise in the subcutis. The aims of this study were to evaluate the utility of KIT immunohistochemical labeling pattern, c-KIT mutational status (presence of internal tandem duplications in exon 11), and proliferation markers--including mitotic index, Ki67, and argyrophilic nucleolar organizing regions (AgNOR)--as independent prognostic markers for local recurrence and/or metastasis in canine subcutaneous MCT. A case-control design was used to analyze 60 subcutaneous MCT from 60 dogs, consisting of 24 dogs with subsequent local recurrence and 12 dogs with metastasis, as compared to dogs matched by breed, age, and sex with subcutaneous MCT that did not experience these events. Mitotic index, Ki67, the combination of Ki67 and AgNOR, and KIT cellular localization pattern were significantly associated with local recurrence and metastasis, thereby demonstrating their prognostic value for subcutaneous MCT. No internal tandem duplication mutations were detected in exon 11 of c-KIT in any tumors. Because c-KIT mutations have been demonstrated in only 20 to 30% of cutaneous MCT and primarily in tumors of higher grade, the number of subcutaneous MCT analyzed in this study may be insufficient to draw conclusions on the role c-KIT mutations in these tumors.

Proposal of a 2-tier histologic grading system for canine cutaneous mast cell tumors to more accurately predict biological behavior.

Currently, prognostic and therapeutic determinations for canine cutaneous mast cell tumors (MCTs) are primarily based on histologic grade. However, the use of different grading systems by veterinary pathologists and institutional modifications make the prognostic value of histologic grading highly questionable. To evaluate the consistency of microscopic grading among veterinary pathologists and the prognostic significance of the Patnaik grading system, 95 cutaneous MCTs from 95 dogs were graded in a blinded study by 28 veterinary pathologists from 16 institutions. Concordance among veterinary pathologists was 75% for the diagnosis of grade 3 MCTs and less than 64% for the diagnosis of grade 1 and 2 MCTs. To improve concordance among pathologists and to provide better prognostic significance, a 2-tier histologic grading system was devised. The diagnosis of high-grade MCTs is based on the presence of any one of the following criteria: at least 7 mitotic figures in 10 high-power fields (hpf); at least 3 multinucleated (3 or more nuclei) cells in 10 hpf; at least 3 bizarre nuclei in 10 hpf; karyomegaly (ie, nuclear diameters of at least 10% of neoplastic cells vary by at least two-fold). Fields with the highest mitotic activity or with the highest degree of anisokaryosis were selected to assess the different parameters. According to the novel grading system, high-grade MCTs were significantly associated with shorter time to metastasis or new tumor development, and with shorter survival time. The median survival time was less than 4 months for high-grade MCTs but more than 2 years for low-grade MCTs.

Gender-related differences in the risk factors for repeat stone surgery.

Our objective was to analyze and compare the associations between potential risk factors for nephrolithiasis and repeat stone surgery in male and female patients. We retrospectively analyzed 1970 patients who had stone surgery at our institution in the period from January 2009 to May 2017, were older than 18 years and had at least 12 months of postoperative follow-up. Our definition of surgical recurrence included repeat surgery on the same renal unit or on the opposite renal unit if the original imaging did not demonstrate significant stones on that side. Uni- and multivariate Cox regression models were built for each gender. We also explored the interactions between gender and other patient's characteristics in their effect on the risk of recurrence. Ureteroscopy was the most common treatment modality for both first (83%) and repeat (87%) procedures. Over a mean follow-up of 4.3 years (median 3.8, interquartile range 2.2-6.0), 413 (21.0%) patients had a surgical recurrence. In multivariate analyses, hypertension, diabetes, Caucasian race and younger age (less than 60 years) were significantly associated with the risk of surgical recurrence only in females. Interaction between these characteristics and gender was significant indicating a larger effect on the risk of surgical recurrence in females compared to males. Our study demonstrated a number of differences in the predictors of repeat surgery for nephrolithiasis between males and females. If confirmed by future studies these differences may be helpful for optimizing nephrolithiasis prevention efforts.

Protein kinase G phosphorylates mosquito-borne flavivirus NS5.

Serine/threonine phosphorylation of the nonstructural protein 5 (NS5) is a conserved feature of flaviviruses, but the kinase(s) responsible and function(s) remain unknown. Mass spectrometry was used to compare the phosphorylation sites of the NS5 proteins of yellow fever virus (YFV) and dengue virus (DENV), two flaviviruses transmitted by mosquitoes. Seven DENV phosphopeptides were identified, but only one conserved phosphoacceptor site (threonine 449 in DENV) was identified in both viruses. This site is predicted to be a protein kinase G (PKG) recognition site and is a strictly conserved serine/threonine phosphoacceptor site in mosquito-borne flaviviruses. In contrast, in tick-borne flaviviruses, this residue is typically a histidine. A DENV replicon engineered to have the tick-specific histidine residue at this position is replication defective. We show that DENV NS5 purified from Escherichia coli is a substrate for PKG in vitro and facilitates the autophosphorylation of PKG as seen with cellular substrates. Phosphorylation in vitro by PKG also occurs at threonine 449. Activators and inhibitors of PKG modulate DENV replication in cell culture but not replication of the tick-borne langat virus. Collectively, these data argue that PKG mediates a conserved serine/threonine phosphorylation event specifically for flaviviruses spread by mosquitoes.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 1.

The alarming reduction in drug effectiveness against bacterial infections has created an urgent need for the development of new antibacterial agents that circumvent bacterial resistance mechanisms. We report here a series of DNA gyrase and topoisomerase IV inhibitors that demonstrate potent activity against a range of Gram-positive and selected Gram-negative organisms, including clinically-relevant and drug-resistant strains. In part 1, we present a detailed structure activity relationship (SAR) analysis that led to the discovery of our previously disclosed compound, REDX05931, which has a minimum inhibitory concentration (MIC) of 0.06 µg mL-1 against fluoroquinolone-resistant Staphylococcus aureus. Although in vitro hERG and CYP inhibition precluded further development, it validates a rational design approach to address this urgent unmet medical need and provides a scaffold for further optimisation, which is presented in part 2.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 2.

Building on our previously-reported novel tricyclic topoisomerase inhibitors (NTTIs), we disclose the discovery of REDX07965, which has an MIC90 of 0.5 µg mL-1 against Staphylococcus aureus, favourable in vitro pharmacokinetic properties, selectivity versus human topoisomerase II and an acceptable toxicity profile. The results herein validate a rational design approach to address the urgent unmet medical need for novel antibiotics.

Cell response to plasma electrolytic oxidation surface-modified low-modulus ß-type titanium alloys.

Plasma electrolytic oxidation (PEO) has been demonstrated to be an effective surface treatment for enhancing the osteoconduction and osseointegration of commercially pure α-Ti (CP α-Ti) dental implant materials for clinical application. To explore the feasibility of extending the application of PEO to low-modulus ß-type titanium alloys for load-bearing orthopaedic implants, a thorough understanding of the effect of substrate material on the biological performance of the PEO-treated surface is required. A 10 kW 50 Hz KeroniteTM processing unit was used to modify the surface of low-modulus near ß-Ti13Nb13Zr and ß-Ti45Nb substrates. CP α-Ti and (α + ß)-Ti6Al4V were also used in parallel as reference materials. In vitro culture of foetal human osteoblast (fHOb) cells on PEO-treated low-modulus near ß-Ti13Nb13Zr and ß-Ti45Nb alloys revealed comparable behaviour to that seen with CP α-Ti and (α + ß)-Ti6Al4V with respect to metabolic activity, collagen production, matrix formation and matrix mineralisation. No difference was observed in TNF-α and IL-10 cytokine release from CD14+ monocytes as markers of inflammatory response across samples. Cell interdigitation into the porous structure of the PEO coatings was demonstrated and cell processes remained adherent to the porous structure despite rigorous sonication. This study shows that PEO technology can be used to modify the surface of low-modulus ß-type titanium alloys with porous structure facilitating osseointegration, without impeding osteoblast activity or introducing an untoward inflammatory response.

Effect of scatter material on diode detector performance for in vivo dosimetry.

The accuracy of Scanditronix EDE, EDP10 and EDP20 diodes for entrance dosimetry of complex fields has been assessed using static and dynamic multileaf collimator test fields on phantoms. Specifically, surrounding scatter material size and composition have been investigated. The EDP10 and EDP20 diodes incorporate steel build-up caps. The effect of varying the diameter of the wax scatter discs on the dosimeter response showed a systematic detector under-response for the smaller discs with errors up to 4.1% relative to full scatter conditions. In static fields, all diodes over-respond at a field size of 1 x 1 cm(2). Diodes with non-water-equivalent build-up material exhibit over-response of up to 10.8%. In dynamic fields, diodes over-respond when there is an increased contribution from phantom scatter and under-respond in shielded regions due to low dose rate and beam hardening. For high dose regions, all diodes over-respond with the greatest over-response of 3.8% observed with a 6 mm sliding window field. The EDE diode with a 6 cm scatter disc correlated best with the reference dosimeter. A diode design with minimal non-water-equivalent components and the addition of a 6 cm diameter water-equivalent disc for scatter material is recommended for the in vivo dosimetry of 6 MV complex fields.