Developmental light deprivation transiently reduces the expression of vGluT2 and GluN2B in the rat ventral suprachiasmatic nucleus.

The suprachiasmatic nucleus (SCN) is the most important circadian clock in mammals. The SCN synchronizes to environmental light via the retinohypothalamic tract (RHT), which is an axon cluster derived from melanopsin-expressing intrinsic photosensitive retinal ganglion cells. Investigations on the development of the nonimage-forming pathway and the RHT are scarce. Previous studies imply that light stimulation during postnatal development is not needed to make the RHT functional at adult stages. Here, we examined the effects of light deprivation (i.e., constant darkness (DD) rearing) during postnatal development on the expression in the ventral SCN of two crucial proteins for the synchronization of circadian rhythms to light: the presynaptic vesicular glutamate transporter type 2 (vGluT2) and the GluN2B subunit of the postsynaptic NMDA receptor. We found that animals submitted to DD conditions exhibited a transitory reduction in the expression of vGluT2 (at P12-19) and of GluN2B (at P7-9) that was compensated at older stages. These findings support the hypothesis that visual stimulation during early ages is not decisive for normal development of the RHT-SCN pathway.

Initiating home spirometry for children during the COVID-19 pandemic - A practical guide.

The COVID-19 pandemic has led to a rapid escalation in use of home monitoring and video consultations in children with a variety of chronic respiratory conditions. Our department set up a home spirometry service from scratch once it became evident that we needed to keep patients away from hospital clinics whenever possible. We faced a number of challenges but now have around 400 children using home spirometers. There are a number of portable spirometers available, some with online platforms. The technology, particularly the software/apps interface, has been improved by the companies in response to issues that have arisen. We believe the use of home monitoring is here to stay.

Efficacy and safety of the EMS Swiss LithoClast® Trilogy for PCNL: results of the European multicentre prospective study on behalf of European Section of UroTechnology.

PURPOSE: PCNL requires a lithotrite to efficiently break stones, and some devices include active suction to remove the fragments. We set out to determine the efficacy and safety of the Swiss LithoClast® Trilogy, in a prospective European multicentre evaluation and compared it to published stone clearance rates for Trilogy based on surface area (68.9 mm2/min) and using the 3D calculated stone volume (526.7 mm3/min). METHODS: Ten European centres participated in this prospective non-randomized study of Trilogy for PCNL. Objective measures of stone clearance rate, device malfunction, complications and stone-free rates were assessed. Each surgeon subjectively evaluated ergonomic and device effectiveness, on a 1-10 scale (10 = extremely ergonomic/effective) and compared to their usual lithotrite on a 1-10 scale (10 = extremely effective). RESULTS: One hundred and fifty seven PCNLs using Trilogy were included (53% male, 47% female; mean age 55 years, range 13-84 years). Mean stone clearance rate was 65.55 mm2/min or 945 mm3/min based on calculated 3D volume. Stone-free rate on fluoroscopy screening at the end of the procedure was 83%. Feedback for suction effectiveness was 9.0 with 9.1 for combination and 9.0 for overall effectiveness compared to lithotrite used previously. Ergonomic score was 8.1, the least satisfactory element. Complications included 13 (8.2%) Clavien-Dindo Grade II and 2 (1.3%) Grade III. Probe breakage was seen in 9 (5.7%), none required using a different lithotrite. CONCLUSIONS: We have demonstrated that Trilogy is highly effective at stone removal. From a user perspective, the device was perceived by surgeons to be highly effective overall and compared to the most commonly used previous lithotrite, with an excellent safety profile.

A practical approach and algorithm for intensifying beyond basal insulin in type 2 diabetes.

Despite the availability of long-term data demonstrating the benefits of timely and aggressive intensification of antihyperglycaemic regimens among individuals with type 2 diabetes, intensification beyond basal insulin continues to be suboptimal and a global challenge. This review summarizes the evidence surrounding the various options of advancing glucose-lowering management beyond basal insulin and provides a practical algorithm to assist in optimizing patient care and enhancing glycaemic target achievements.

Primary Ciliary Dyskinesia Due to Microtubular Defects is Associated with Worse Lung Clearance Index.

PURPOSE: Primary ciliary dyskinesia (PCD) is characterised by repeated upper and lower respiratory tract infections, neutrophilic airway inflammation and obstructive airway disease. Different ultrastructural ciliary defects may affect lung function decline to different degrees. Lung clearance index (LCI) is a marker of ventilation inhomogeneity that is raised in some but not all patients with PCD. We hypothesised that PCD patients with microtubular defects would have worse (higher) LCI than other PCD patients. METHODS: Spirometry and LCI were measured in 69 stable patients with PCD. Age at testing, age at diagnosis, ethnicity, ciliary ultrastructure, genetic screening result and any growth of Pseudomonas aeruginosa was recorded. RESULTS: Lung clearance index was more abnormal in PCD patients with microtubular defects (median 10.24) than those with dynein arm defects (median 8.3, p = 0.004) or normal ultrastructure (median 7.63, p = 0.0004). Age is correlated with LCI, with older patients having worse LCI values (p = 0.03, r = 0.3). CONCLUSION: This study shows that cilia microtubular defects are associated with worse LCI in PCD than dynein arm defects or normal ultrastructure. The patient's age at testing is also associated with a higher LCI. Patients at greater risk of obstructive lung disease should be considered for more aggressive management. Differences between patient groups may potentially open avenues for novel treatments.

Lung Clearance Index (LCI) is Stable in Most Primary Ciliary Dyskinesia (PCD) Patients Managed in a Specialist Centre: a Pilot Study.

Primary ciliary dyskinesia is a condition in which abnormal cilia structure or function leads to reduced mucociliary clearance and obstructive lung disease. Twenty-nine patients had lung clearance index (LCI) measured in 2009 and we attempted to perform a 5-year follow-up. Only 12 patients could be re-recruited, but in this small group LCI was stable over the 5 years, which confirms previous data showing that spirometry is also stable in these patients over the medium term. The two patients with the highest LCI in 2009 had since died, despite one having relatively preserved spirometry at the time. These data may be used to inform sample size calculations of future studies.

Performance of Alpine Touring Boots When Used in Alpine Ski Bindings.

Alpine touring (AT) equipment is designed for ascending mountains and snow skiing down backcountry terrain. Skiers have been observed using AT boots in alpine (not made for Alpine Touring) ski bindings. We tested the effect on the retention-release characteristics of AT boots used in alpine bindings. Ten AT ski boots and 5 alpine ski boots were tested in 8 models of alpine ski bindings using an ASTM F504-05 (2012) apparatus. Thirty-one percent of the AT boots released appropriately when used in alpine ski bindings. One alpine binding released appropriately for all alpine and AT boots tested; 2 alpine ski bindings did not release appropriately for any AT boots. Altering the visual indicator settings on the bindings (that control the release torque of an alpine system) had little or no effect on the release torque when using AT boots in alpine ski bindings. Many combinations released appropriately in ski shop tests, but did not release appropriately in the more complex loading cases that simulated forward and backward falls; the simple tests performed by ski shops could produce a "false-negative" test result. These results indicate that using AT boots with alpine ski bindings could increase the likelihood of lower leg injuries.

Total Energy Expenditure of Infants with Congenital Heart Disease Who Have Undergone Surgical Intervention.

Growth failure is often observed in infants with congenital heart disease (CHD); it is unclear, however, whether growth failure is due to increased total energy expenditure (TEE). An observational study of infants with CHD and surgical intervention within the first 30 days of life and healthy infants of similar age was undertaken. TEE was measured using the doubly labeled water method in 3-month-old infants (n = 15 CHD, 12 healthy) and 12-month-old infants (n = 11 CHD, 12 healthy). Multiple linear regression models were fit to examine the association between health status (CHD vs. healthy) and TEE. The accuracy of equations for calculating TEE was also determined. TEE for CHD infants was not significantly different from healthy infants at 3 and 12 months; TEE in CHD infants was 36.4 kcal/day higher (95 % CI -46.3, 119.2; p = 0.37) and 31.7 kcal/day higher, (95 % CI -71.5, 134.8; p = 0.53) at 3 and 12 months, respectively, compared to healthy infants. The 2002 Dietary Reference Intake (DRI) equation and the 1989 Recommended Dietary Allowance equation over-estimated measured TEE to a lesser extent than CHD specific equations; the 2002 DRI yielded the smallest mean difference between calculated versus measured TEE (difference 79 kcal/day). During the first year of life, TEE of infants with CHD and interventional surgery within the first month of life was not different than age-matched healthy infants. When calculating TEE of ≤12-month-old infants with CHD who have undergone surgical intervention, the 2002 DRI equation may be used as a starting point for estimating initial clinical energy intake goals.

Quantification of tibiofemoral shear and compressive loads using a MRI-based EMG-driven knee model.

The purpose of this study is to describe an MRI-based EMG-driven knee model to quantify tibiofemoral compressive and shear forces. Twelve healthy females participated. Subjects underwent 2 phases of data collection: (1) MRI assessment of the lower extremity to quantify muscle volumes and patella tendon orientation and (2) biomechanical evaluation of a drop-jump task. A subject-specific EMG-driven knee model that incorporated lower extremity kinematics, EMG, and muscle volumes and patella tendon orientation estimated from MRI was developed to quantify tibiofemoral shear and compressive forces. A resultant anterior tibial shear force generated from the ground reaction force (GRF) and muscle forces was observed during the first 30% of the stance phase of the drop-jump task. All of the muscle forces and GRF resulted in tibiofemoral compression, with the quadriceps force being the primary contributor. Acquiring subject-specific muscle volumes and patella tendon orientation for use in an EMG-driven knee model may be useful to quantify tibiofemoral forces in persons with altered patella position or muscle atrophy following knee injury or pathology.

Measuring the principal Hugoniot of inertial-confinement-fusion-relevant TMPTA plastic foams.

Wetted-foam layers are of significant interest for inertial-confinement-fusion capsules, due to the control they provide over the convergence ratio of the implosion and the opportunity this affords to minimize hydrodynamic instability growth. However, the equation of state for fusion-relevant foams are not well characterized, and many simulations rely on modeling such foams as a homogeneous medium with the foam average density. To address this issue, an experiment was performed using the VULCAN Nd:glass laser at the Central Laser Facility. The aim was to measure the principal Hugoniot of TMPTA plastic foams at 260mg/cm^{3}, corresponding to the density of liquid DT-wetted-foam layers, and their "hydrodynamic equivalent" capsules. A VISAR was used to obtain the shock velocity of both the foam and an α-quartz reference layer, while streaked optical pyrometry provided the temperature of the shocked material. The measurements confirm that, for the 20-120 GPa pressure range accessed, this material can indeed be well described using the equation of state of the homogeneous medium at the foam density.

Risk profiles of prostate cancers identified from UK primary care using national referral guidelines.

OBJECTIVE: Prostate cancer in the United Kingdom is mainly diagnosed from primary care referrals based on national guidelines published by the Department of Health. Here we investigated the characteristics of cancers detected through the use of these guidelines. METHODS: A prospective two-centre study was established to assess men referred from the primary care based on the UK national guidelines. RESULTS: The overall cancer detection rate was 43% (169 out of 397) with 15% (26 out of 169) of all cancers metastatic at presentation. Amongst 50-69-year-old men these rates were 34% (68 out of 200) and 15% (10 out of 68). Only 21% (25 out of 123) of men with local cancers had low-risk disease. In comparison to a historical cohort from 2001 (n=137) we found no overall differences in rates of metastatic disease, locally advanced tumours, or risk categories. Amongst 50-69-year-old men with local disease, however, we observed an increase in detection of low-risk cancers in a contemporary cohort (P=0.04). This was primarily because of the increased detection of low-stage organ-confined tumours in this group (P=0.02). CONCLUSION: Use of the UK prostate cancer guidelines detects a high proportion of clinically significant cancers. Use of the guidelines does not seem to have led to an overall change in the clinical characteristics of presenting cancers. There may, however, be a specific benefit in detecting more low-risk disease in younger men.

An observational study of skier compliance with posted "slow" signs and ski patrollers.

OBJECTIVES: To examine the efficacy of "slow" signs and patroller presence at "slow" signs to reduce speeds of snowsports participants, compared to a condition where no sign or patroller are present, independent of other factors that may contribute to skier slowing (such as prior knowledge, trail convergence, etc.). DESIGN AND METHODS: Snowsports participant speeds were measured on "more difficult" trails using a radar gun at two ski areas with: (1) no-sign - the usual condition for the trail, and (2) slow-sign - a large "slow" sign was posted in the middle of the trail. At one ski area, a third condition was also tested: (3) slow+patroller - a ski patroller stood at the slow sign. Participant equipment type and estimated ability were also recorded. RESULTS: At one ski area, there was no significant difference in speed between conditions. At the second ski area, the differences in mean (SD) speeds were small but significant for the no-sign, slow-sign, and slow+patroller conditions: 10.9 (3.0), 10.3 (2.9), and 9.8 (2.6)m/s. Effects were driven by non-beginner skiers; on average, beginner skiers and all snowboarders were slower than non-beginner skiers and did not adjust their speed in response to the signage conditions. CONCLUSIONS: Reductions in speed for the slow-sign and slow+patroller conditions compared to the no-sign condition were small (0.5 and 1.1m/s) compared to the variation in chosen skier speed reported in other studies. The small differences in chosen speeds make it unlikely that slow sign and patroller presence alone would produce meaningful reductions in collision likelihood or severity of impacts.

Method to examine how geometry affects the release and retention of alpine touring boot-binding systems.

OBJECTIVES: Develop a method to examine the effects of component geometry and force-deflection on the release process of Tech/Pin alpine touring (AT) ski boots and bindings. DESIGN AND METHODS: For seven AT boots, we measured the critical geometric dimensions of the metal inserts at the toe region of the boots. Binding geometry (including the pins and rocker arms) and the force-angular deflection curves of typical AT bindings were measured. A kinematic model was derived to predict the contact force between the metal inserts of the AT boots and the pins of the AT bindings, dependent on angular displacement of the binding rocker arms. By combining the kinematic model, the force-angular deflection curves, and moment equilibrium, we determined the force and binding rotation angle needed to release the AT boot in a direction normal to the ski. RESULTS: The metal AT boot insert geometry and AT binding pin geometry and dimensions can affect significantly the contact states and kinematics of release. Two load-deflection curves of similar peak loads can result in significantly different maximal forces and angles to release the binding, even when the geometry and dimensions of the binding pins and boot inserts remain unchanged. CONCLUSIONS: The geometry and dimensions of the binding (pins and rocker arm) and the boot inserts define the kinematics of the binding release. The model can be used to test the effects of varying parameters on the release and retention characteristics of Tech/Pin boot-binding systems to optimize the release and retention characteristics.

Examining ski area padding for head and neck injury mitigation.

OBJECTIVES: The injury mitigation capabilities of foam, ski-area padding was examined for headfirst impacts. DESIGN AND METHODS: A custom-made pendulum impactor system was constructed using an instrumented, partial 50th-percentile-male Hybrid-III anthropomorphic testing device (ATD). For each test, the ATD was raised 1.0m, released, and swung into a 20-cm diameter wooden pole. Test trials were conducted with the wooden pole covered by ski area padding (five conditions of various foam types and thicknesses) or unpadded. Linear (linear acceleration and HIC15) and angular (angular velocity, angular acceleration, and BrIC) kinematics were examined and used to estimate the likelihood of severe brain injury. Cervical spine loads were compared to the injury assessment reference values for serious injury. Further tests were conducted to examine the changes produced by the addition of a snowsport helmet. RESULTS: 38 test trials were recorded with a mean (±sd) impact speed of 4.2 (±0.03) m/s. Head, resultant linear acceleration, HIC15, and associated injury likelihoods were tempered by ski area padding at the impact speed tested. Ski area padding did not reduce brain injury likelihood from rotational kinematics (p>0.05 for all comparisons) or reduce the cervical spine compression below injury assessment reference values. The addition of a helmet did not reduce significantly the likelihoods of brain or cervical spine injury. CONCLUSIONS: At the impact speed tested, ski area padding provided limited impact protection for the head (for linear kinematics) but did not protect against severe brain injuries due to rotational kinematics or serious cervical spine injuries.

Multiplane loading of the extensor mechanism alters the patellar ligament force/quadriceps force ratio.

Since the direction of the quadriceps force and location of the patellofemoral contact point likely differ between axial and multiplane loadings, the force and moment balance solutions for a multiplane loading condition may not yield the same patella ligament force/quadriceps force ratio (F(PL)/F(Q) ratio) when compared with an axial loading condition. The purpose of this study was to compare the effects of an axial loading condition and an anatomical, multiplane loading condition on the F(PL)/F(Q) ratio at various knee flexion angles. Ten cadaver knees were used in this investigation. Each was mounted on a custom jig that was fixed to an Instron frame. Quadriceps muscle loads were applied with same resultant force magnitudes under two force directions, as follows: (1) axial loading (central quadriceps tendon loading parallel to the femoral axis), and (2) an anatomically based, multiplane loading condition (individual vasti loaded, taking into consideration physiologic muscle fiber orientation). Patellar ligament tension was measured using a buckle transducer. The patellar ligament force/quadriceps force ratio (F(PL)/F(Q) ratio) was calculated for both loading conditions at 0 deg, 20 deg, 40 deg, and 60 deg of knee flexion. Across the range of knee motion evaluated, the F(PL)/F(Q) ratio for the axial loading condition was significantly greater than the F(PL)/F(Q) ratio for the multiplane loading condition. Our results suggest that loading orientation affects the transfer of forces from the quadriceps tendon to the patellar ligament.

Synergistic antidepressant-like effect of capsaicin and citalopram reduces the side effects of citalopram on anxiety and working memory in rats.

RATIONALE: We have previously shown that in rats, capsaicin (Cap) has antidepressant-like properties when assessed using the forced swimming test (FST) and that a sub-threshold dose of amitriptyline potentiates the effects of Cap. However, synergistic antidepressant-like effects of the joint administration of Cap and the selective serotonin reuptake inhibitor citalopram (Cit) have not been reported. OBJECTIVES: To assess whether combined administration of Cap and Cit has synergistic effects in the FST and to determine whether this combination prevents the side effects of Cit. METHODS: Cap, Cit, and the co-administration of both substances were evaluated in a modified version of the FST (30-cm water depth) conducted in rats, as well as in the open field test (OFT), elevated plus maze (EPM), and Morris water maze (MWM). RESULTS: In line with previous studies, independent administration of Cap and Cit displayed antidepressant-like properties in the FST, while the combined injection had synergistic effects. In the OFT, neither treatment caused significant increments in locomotion. In the EPM, the time spent in the closed arms was lower in groups administered either only Cap or a combination of Cap and Cit than in groups treated with Cit alone. In the MWM, both Cap and the joint treatment (Cap and Cit) improved the working memory of rats in comparison with animals treated only with Cit. CONCLUSION: Combined administration of Cap and Cit produces a synergistic antidepressant-like effect in the FST and reduces the detrimental effects of Cit on anxiety and working memory.

Expression of a zinc finger gene in HTLV-I- and HTLV-II-transformed cells.

Gene products encoded by the human T cell leukemia virus (HTLV) types I and II mediate transformation by the transactivation of cellular genes necessary for proliferation, probably including transcriptional regulatory factors. By searching for factors that may control proliferation, a zinc finger gene (225) was identified that was constitutively expressed in all HTLV-I- or HTLV-II-transformed cell lines examined, whereas in normal T cells it was only transiently expressed after mitogenic stimulation. The 225 gene was also constitutively expressed in two HTLV-I-transformed helper T cell clones, but not in the parental cell lines. Thus this putative cellular transcriptional factor, which was abnormally expressed in retrovirus-infected cells, may have a role in transformation.

Efficacy of Nasal Testosterone Gel (Natesto®) Stratified by Baseline Endogenous Testosterone Levels.

OBJECTIVE: Pharmacokinetic and efficacy data from a phase 3 testosterone nasal gel (TNG) study were stratified by baseline endogenous testosterone level in patients with testosterone deficiency. Total testosterone (TT), LH, and FSH levels, as well as erectile function, mood, and lean body mass for each group were compared. In a subset of patients with very low baseline endogenous testosterone levels (<100 ng/dL), we investigated whether TNG is a suitable treatment option. MATERIALS AND METHODS: Patients with testosterone deficiency (serum TT <300 ng/dL) were treated with TNG for 3 months, followed by safety extension periods of 90 and/or 180 days. Pharmacokinetic parameters were calculated from serum hormone levels on days 30 and 90, along with efficacy measurements, which were analyzed by comparison with baseline values. Baseline and/or predose TT values were used for patient stratification. RESULTS: Prestudy and predose endogenous testosterone concentrations correlated. The maximal concentration of TT was nearly identical across all cohorts at days 30 and 90, whereas the average concentration over 24 hours had a slight positive dependence relative to predose levels. LH levels remained in the normal range but were decreased more in patients with higher starting baseline levels. These findings indicate that TNG works with an active hypothalamic-pituitary-gonadal axis that responds to each dose of TNG throughout the treatment period. Patients with the lowest endogenous testosterone levels received maximum exposure impact from each TNG dose. Patients with severe testosterone deficiency had similar efficacy improvements as the remainder of the study population. CONCLUSION: All testosterone-deficient cohorts were successfully treated with TNG.

Mitogen-induced genes are subject to multiple pathways of regulation in the initial stages of T-cell activation.

The delivery of a mitogenic signal to T cells via any one of several cell surface molecules elicits a variety of intracellular responses, some or all of which regulate subsequent gene expression events. The expression of nine novel mitogen-induced genes in response to various T-cell-activating agents was examined to evaluate the diversity of pathways which regulate such genes. The relative contribution of distinct secondary signals, individually or together, to mitogen-stimulated gene induction and the capability of individual genes to respond to the sometimes divergent signals generated from different cell surface structures is addressed. The activation of T cells with mitogenic monoclonal antibodies directed against the CD2 or CD3 cell surface molecules, or with phytohemagglutinin, induced all nine genes. Thus, stimulation by fully mitogenic agents regardless of cell surface-binding specificity correlated with the expression of all of the genes studied. However, heterogeneous patterns of gene expression, encompassing five regulatory classes, were revealed by the use of phorbol 12-myristate 13-acetate, calcium ionophore, and anti-CD28 monoclonal antibody, agents which mediated only a subset of intracellular events and thus an incomplete mitogenic signal. Interleukin-2 and two novel lymphokines represented one regulatory class that appeared to require unique transcriptional activation signals relative to the other mitogen-induced genes. As demonstrated in the accompanying paper (P. F. Zipfel, S. G. Irving, K. Kelly, and U. Siebenlist, Mol. Cell. Biol. 9:1041-1048, 1989), the immediate transcriptional response of T cells to mitogenic stimulation is quite complex, involving numerous genes beyond those which have been previously described. Furthermore, the discrimination of several regulatory phenotypes among these nine genes suggests that a multiplicity of signaling pathways extends from the cell surface to the level of transcription.

Complexity of the primary genetic response to mitogenic activation of human T cells.

We describe the isolation and characterization of more than 60 novel cDNA clones that constitute part of the immediate genetic response to resting human peripheral blood T cells after mitogen activation. This primary response was highly complex, both in the absolute number of inducible genes and in the diversity of regulation. Although most of the genes expressed in activated T cells were shared with the activation response of normal human fibroblasts, a significant number were more restricted in tissue specificity and thus likely encode or effect the differentiated functions of activated T cells. The activatable genes could be further differentiated on the basis of kinetics of induction, response to cycloheximide, and sensitivity to the immunosuppressive drug cyclosporin A. It is of note that cyclosporin A inhibited the expression of more than 10 inducible genes, which suggests that this drug has a broad genetic mechanism of action.