Anxious and non-anxious adolescents' experiences of non-clinical magnetic resonance imaging research.
Magnetic resonance imaging (MRI) has become a ubiquitous research tool for developmental neuroscientists interested in brain structure and function in children and adolescents. However, ethical concerns are sometimes raised about using MRI with children and adolescents, especially when participants have anxiety. We asked 17 clinically/sub-clinically anxious and 19 non-anxious adolescents about their experiences of taking part in MRI for research purposes. Although the anxious group reported experiencing more anxiety during the scan, these differences had attenuated by the time participants got home. We found no evidence that anxious adolescents would be less likely to choose to have another scan or would feel more nervous during another scan. There was some evidence that more trait anxious adolescents found the MRI study enjoyable. These findings should give ethics committees, clinicians, and parents confidence that so long as researchers exercise appropriate care, MRI research is acceptable to adolescents, including those with clinical anxiety.


Utility of computed tomography and selected MR sequences in the diagnostics of patients with partial epileptic attacks.
Epilepsy is a disease which manifests itself with recurrent dysfunction of the brain. Epilepsy thus becomes a serious social problem and it is therefore necessary to introduce more and more up-to-date methods of its diagnostics. Examinations were performed on 85 patients with partial epileptic attacks. The study group included 43 women and 42 men who had suffered from epilepsy for 2 to 40 years. CT and MR examinations were performed in the interparoxysmal period. In MRI, T1-weighted images before and after contrast administration, T2- and PD-weighted images, and FLAIR images were analyzed. Agreement between the location of lesions in CT and EEG was evaluated with the kappa test and amounted to 0.29. Low compatibility was also found between MR and EEG and amounted to 0.33. However, compatibility between the location in CT and MR reached the level of 0.62. The most common abnormalities were asymmetry of the lateral ventricles (most often temporal horns), cortical scars, mesial temporal sclerosis (MTS), and CNS tumors. T1- and T2-weighted images enabled recognition of most of the focuses, but they failed to visualize some of the degenerative lesions in the hippocampus which were recognizable in coronal FLAIR. No statistically significant correlation was found between the patient age, duration of the disease, and type of lesion and its location. The performed examinations showed that MR is the method of choice in patients with temporal epilepsy. The study protocol should include the FLAIR sequence in the coronal plane, which has high sensitivity in recognizing lesions within the hippocampus.


Treatment of traumatic cervical myelopathy with surgery, prolonged positive-pressure ventilation, and physical therapy in a dog.
A 9-year-old dog was evaluated for traumatic cervical myelopathy after a surgical attempt to realign and stabilize the C2 and C3 vertebrae. The dog could not ventilate spontaneously and was tetraplegic; positive-pressure ventilation (PPV) was maintained. Myelography and computed tomography revealed spinal cord compression with subluxation of the C2 and C3 vertebrae and extrusion of the C2-3 intervertebral disk. Surgically, the protruding disk material was removed and the vertebrae were realigned with screws and wire. For PPV, assist control ventilation in volume control mode and then in pressure control mode was used in the first 6 days; this was followed by synchronized intermittent mandatory ventilation until 33 days after the injury; then only continuous positive airway pressure was provided until the dog could breathe unassisted, 37 days after the injury. Physical therapy that included passive range of motion exercises, neuromuscular electrical stimulation, and functional weight-bearing positions was administered until the dog was discharged 46 days after injury; the dog was severely ataxic and tetraparetic but could walk. Therapy was continued at home, and 1 year later, the dog could run and had moderate ataxia and tetraparesis. Hypoventilation with tetraparesis in traumatic spinal cord injury can be successfully treated with PPV exceeding 30 days, surgery, and physical therapy.


Supervised learning in spiking neural networks with ReSuMe: sequence learning, classification, and spike shifting.
Learning from instructions or demonstrations is a fundamental property of our brain necessary to acquire new knowledge and develop novel skills or behavioral patterns. This type of learning is thought to be involved in most of our daily routines. Although the concept of instruction-based learning has been studied for several decades, the exact neural mechanisms implementing this process remain unrevealed. One of the central questions in this regard is, How do neurons learn to reproduce template signals (instructions) encoded in precisely timed sequences of spikes? Here we present a model of supervised learning for biologically plausible neurons that addresses this question. In a set of experiments, we demonstrate that our approach enables us to train spiking neurons to reproduce arbitrary template spike patterns in response to given synaptic stimuli even in the presence of various sources of noise. We show that the learning rule can also be used for decision-making tasks. Neurons can be trained to classify categories of input signals based on only a temporal configuration of spikes. The decision is communicated by emitting precisely timed spike trains associated with given input categories. Trained neurons can perform the classification task correctly even if stimuli and corresponding decision times are temporally separated and the relevant information is consequently highly overlapped by the ongoing neural activity. Finally, we demonstrate that neurons can be trained to reproduce sequences of spikes with a controllable time shift with respect to target templates. A reproduced signal can follow or even precede the targets. This surprising result points out that spiking neurons can potentially be applied to forecast the behavior (firing times) of other reference neurons or networks.


Impact of left atrial appendage exclusion on left atrial function.
We sought to investigate the short-term and midterm effects of left atrial appendage exclusion on left atrial function. Left atrial appendage exclusion is considered a possible therapeutic option for stroke prevention in patients with atrial fibrillation. Favorable outcomes have encouraged widespread use of left atrial appendage exclusion for cardiac surgical patients-even for patients in sinus rhythm who have stroke risk factors; however, the chronic effects on left atrial function of left atrial appendage exclusion are unclear. Nineteen mongrel dogs (29.7 +/- 5.2 kg) in sinus rhythm were studied. The Doppler signals from the pulmonary venous flow, transmitral flow, and tissue Doppler imaging of mitral annular motion were obtained before and after left atrial appendage exclusion. Dogs were evaluated in the same manner at 7 days (n = 2), 30 days (n = 7), or 90 days (n = 10) after left atrial appendage exclusion. Except for a significant increase in early diastolic transmitral flow velocity after left atrial appendage exclusion (P = .01), no significant differences were found in any parameters related to the transmitral flow and tissue Doppler imaging measurements throughout follow-up. The systolic components of pulmonary venous flow at follow-up revealed a significant reduction relative to baseline (peak systolic velocity P < .0001, systolic velocity-time integral P < .0001), despite the lack of significant changes in left atrial pressure, left ventricular volume, and stroke volume. Left atrial appendage exclusion may affect left atrial reservoir function in the short-term and midterm periods. Further long-term studies with more clinically relevant models are needed.


Does integration of various ion channel measurements improve diagnostic performance in cystic fibrosis?
The diagnosis of cystic fibrosis (CF) may remain inconclusive despite comprehensive evaluation. Determine whether combined ion channel measurements (C-ICMs) obtained from different end-organ epithelia can help diagnose CF. Prospective enrollment of (1) a training sample of 156 non-CF subjects and 107 patients with CF, and (2) a validation cohort of 202 patients with single-organ CF-like phenotypes. All subjects had genotyping, sweat test, and nasal potential difference (NPD). Principal components analysis was applied to derive various candidate C-ICMs by combining sweat chloride plus every one or two combination(s) of four NPD parameters (maximal potential difference [MaxPD], change in potential difference in response to perfusion with amiloride [ΔAmil], change after chloride-free and isoproterenol perfusion [ΔCl-free+Iso], and total change in potential difference [ΔAmil+Cl-free+Iso]). The best of the 10 candidate C-ICMs, which combined sweat chloride and two NPD parameters (ΔCl-free+Iso and ΔAmil+Cl-free+Iso), diagnosed CF in the training sample with 100% sensitivity and specificity (CF cutoff > 0). In the validation cohort, C-ICM was normal in all subjects with normal sweat test and normal/borderline NPD, with the exception of one subject. C-ICM was abnormal in all subjects when the sweat test was abnormal and the NPD was abnormal/borderline, and when the sweat test was borderline and the NPD was abnormal. C-ICM was abnormal in 75 and 85.7% of subjects with normal sweat chloride plus abnormal NPD, and those with abnormal sweat test plus normal NPD, respectively. In borderline sweat test cases, 23.5, 90, and 100% of subjects had abnormal C-ICM with normal, borderline, and abnormal NPD, respectively. The concept of combining different measures of cystic fibrosis transmembrane conductance regulator function into a single composite score is feasible. The C-ICM may be useful for diagnostic determination of patients with questionable CF.


The effect of mental stress on catecholamines, their metabolites and plasma renin activity in patients with essential hypertension and in healthy subjects.
1. Ten patients with essential hypertension and ten healthy men were submitted to mental stress consisting of Kraepelin's arithmetic test combined with noise. Concentrations of plasma and urine catecholamines and of their metabolites as well as plasma renin activity before and after the test were studied. 2. In both groups a significant increase of noradrenaline and adrenaline in blood and noradrenaline in urine was observed. The urinary excretion of dopamine fell significantly in both groups after stress. 3. After mental stress a significant increase in urinary excretion of 3-methoxy-4-hydroxyphenylglycol was observed in both groups. The excretion of vanillylmandelic acid decreased significantly only in healthy subjects. 4. The plasma renin activity rose significantly in both groups but the increase was more pronounced in healthy subjects.


Cytomorphology of cervicovaginal melanoma: ThinPrep versus conventional Papanicolaou tests.
Primary cervicovaginal melanoma is a rare malignancy associated with a high risk of recurrence. Prior studies discussing the cytomorphology of cervicovaginal melanoma have been based primarily on review of conventional Papanicolaou (Pap) smears. The aim of this study was to evaluate cervicovaginal melanomas identified in liquid-based Pap tests, in comparison with features seen on conventional Pap smear preparation. Cases of cervicovaginal melanoma identified on Pap tests with concurrent or subsequent histopathologic confirmation were collected from the Baystate Medical Center cytopathology files and personal archives of the authors over a total period of 34 years. All cytopathology (n = 6) and the available histology slides (n = 5) were reviewed. Cases were analyzed regarding clinical, histopathologic and cytomorphological findings. A total of six cases with invasive cervicovaginal melanoma diagnosed on Pap tests were identified. Most patients were postmenopausal with contact bleeding, correlating with surface ulceration (identified in biopsy/excision material in 5/5 cases). Most cases had deeply invasive tumors (5/5: modified Breslow's thickness > 5 mm and Chung's level of invasion IV/V). Pap tests included four ThinPrep and two conventional smears. Overall, ThinPrep Pap tests exhibited a higher ratio of tumor cells to background squamous cells. While all Pap tests were bloodstained, tumor diathesis was prominent only within conventional smears. Melanoma cells were present both as clusters and scattered single cells in each Pap test type. Both the preparations contained epithelioid tumor cells, whereas spindled tumor cells were seen in only two ThinPrep cases. Prominent nucleoli and binucleation of tumor cells were seen in both the preparations. Melanin pigment was identified in only ThinPrep (3/4) cases and nuclear pseudo-inclusions in one conventional Pap smear. Cell blocks were made in three ThinPrep cases and immunocytochemistry (S-100, HMB45, Melan-A) performed on additional vial material (one ThinPrep slide and one cell block) was immunoreactive in melanoma cells. Primary cervicovaginal melanoma, a rare malignancy seen predominantly in postmenopausal women, may be successfully diagnosed in either ThinPrep Pap tests or conventional Pap smears. While ThinPrep Pap tests did not demonstrate morphological advantage over conventional smears, liquid-based cytology specimens did provide additional material for cellblock preparation and immunocytochemical evaluation in a subset of cases.


Comparison of K-ras point mutation distributions in intraductal papillary-mucinous tumors and ductal adenocarcinoma of the pancreas.
Intraductal papillary-mucinous tumors (IPMT) consist of cells with varying histologic degrees of severity and exhibit multiple tumor loci; however, whether or not these lesions exhibit the same genetic changes has not been clarified. To investigate this point, we analyzed K-ras mutations in multiple IPMT lesions from each patient enrolled in our study and compared our findings to those for patients with ductal adenocarcinoma of the pancreas (DC). Twenty IPMT specimens and 7 DC specimens were resected, microdissected and analyzed for the presence of K-ras mutations. The mutated genes were then sequenced using a genetic analyzer. K-ras mutations were observed in 80% of IPMT and 100% of DC patients. More than 2 types of K-ras mutation were observed in the main tumors of 43.8% of IPMT and 0% of DC patients. K-ras mutations in peritumoral and separated lesions were observed in 66.7% and 62.5% of IPMT patients, respectively. At least one identical mutation between the main tumor and the peritumoral or separated lesions was recognized in all of the IPMT patients with those lesions. Different mutations from those in the main tumor were observed in 40% of IPMT patients with separated lesions. The survival curve of IPMT-carcinoma patients with more than 2 types of K-ras mutation in the main tumor was better than that with one type of K-ras mutation. IPMT patients exhibit a remarkably genetic heterogeneity in main tumor and have good prognosis.


Geosphere-biosphere interactions in bio-activity volcanic lakes: evidences from Hule and Rìo Cuarto (Costa Rica).
Hule and Río Cuarto are maar lakes located 11 and 18 km N of Poás volcano along a 27 km long fracture zone, in the Central Volcanic Range of Costa Rica. Both lakes are characterized by a stable thermic and chemical stratification and recently they were affected by fish killing events likely related to the uprising of deep anoxic waters to the surface caused by rollover phenomena. The vertical profiles of temperature, pH, redox potential, chemical and isotopic compositions of water and dissolved gases, as well as prokaryotic diversity estimated by DNA fingerprinting and massive 16S rRNA pyrosequencing along the water column of the two lakes, have highlighted that different bio-geochemical processes occur in these meromictic lakes. Although the two lakes host different bacterial and archaeal phylogenetic groups, water and gas chemistry in both lakes is controlled by the same prokaryotic functions, especially regarding the CO2-CH4 cycle. Addition of hydrothermal CO2 through the bottom of the lakes plays a fundamental priming role in developing a stable water stratification and fuelling anoxic bacterial and archaeal populations. Methanogens and methane oxidizers as well as autotrophic and heterotrophic aerobic bacteria responsible of organic carbon recycling resulted to be stratified with depth and strictly related to the chemical-physical conditions and availability of free oxygen, affecting both the CO2 and CH4 chemical concentrations and their isotopic compositions along the water column. Hule and Río Cuarto lakes were demonstrated to contain a CO2 (CH4, N2)-rich gas reservoir mainly controlled by the interactions occurring between geosphere and biosphere. Thus, we introduced the term of bio-activity volcanic lakes to distinguish these lakes, which have analogues worldwide (e.g. Kivu: D.R.C.-Rwanda; Albano, Monticchio and Averno: Italy; Pavin: France) from volcanic lakes only characterized by geogenic CO2 reservoir such as Nyos and Monoun (Cameroon).


Mice lacking the PACAP type I receptor have impaired photic entrainment and negative masking.
The retinohypothalamic tract (RHT) is a retinofugal neuronal pathway which, in mammals, mediates nonimage-forming vision to various areas in the brain involved in circadian timing, masking behavior, and regulation of the pupillary light reflex. The RHT costores the two neurotransmitters glutamate and pituitary adenylate cyclase activating peptide (PACAP), which in a rather complex interplay are mediators of photic adjustment of the circadian system. To further characterize the role of PACAP/PACAP receptor type 1 (PAC1) receptor signaling in light entrainment of the clock and in negative masking behavior, we extended previous studies in mice lacking the PAC1 receptor (PAC1 KO) by examining their phase response to single light pulses using Aschoff type II regime, their ability to entrain to non-24-h light-dark (LD) cycles and large phase shifts of the LD cycle (jet lag), as well as their negative masking response during different light intensities. A prominent finding in PAC1 KO mice was a significantly decreased phase delay of the endogenous rhythm at early night. In accordance, PAC1 KO mice had a reduced ability to entrain to T cycles longer than 26 h and needed more time to reentrain to large phase delays, which was prominent at low light intensities. The data obtained at late night indicated that PACAP/PAC1 receptor signaling is less important during the phase-advancing part of the phase-response curve. Finally, the PAC1 KO mice showed impaired negative masking behavior at low light intensities. Our findings substantiate a role for PACAP/PAC1 receptor signaling in nonimage-forming vision and indicate that the system is particularly important at lower light intensities.


Benign familial tremor treated with primidone.
Primidone given to a patient for epilepsy produced an unexpected reduction in benign familial tremor. Over the next eight years the drug was therefore tried in a prospective study of 20 other patients with benign familial tremor alone. Of these, six could not tolerate the drug because of vertigo and nausea but 12 obtained a good response, which in some cases was dramatic. Investigations in two patients suggested that the effect was mediated predominantly by derived phenylethylmalonamide, though primidone had some effect, since tremor recurred slightly on withdrawing the drug despite a constant or rising blood phenylethylmalonamide concentration. Primidone is highly effective in benign familial tremor. More patients with the condition are intolerant of the drug than are usually found with epilepsy.


Examining the validity of the columbia impairment scale for assessing level of functioning in youth with autism spectrum disorder.
Youth with autism spectrum disorder (ASD) exhibit impairment in numerous areas of functioning, most notably in the areas related to social interactions, communication, and behavior at school and at home. Understanding the severity of the impairment in each of the domains associated with areas of functioning is imperative when evaluating the efficacy of an intervention, whether it be medical, therapeutic, or both. This study sought to examine the convergent and discriminant validity of the Columbia Impairment Scale (CIS) for youth with ASD, and their parents. A sample of 77 adolescents with ASD and their parents completed the CIS and various other measures that examined mood, anxiety, and behavior. Although there was some evidence of convergent validity for the parent-report CIS, there was inadequate discriminant validity. The child-report version of the CIS yielded generally poor validity indices. There appear to be important limitations when using this measure for youth with ASD.


Methods for qPCR gene expression profiling applied to 1440 lymphoblastoid single cells.
The stochastic nature of generating eukaryotic transcripts challenges conventional methods for obtaining and analyzing single-cell gene expression data. In order to address the inherent noise, detailed methods are described on how to collect data on multiple genes in a large number of single cells using microfluidic arrays. As part of a study exploring the effect of genotype on Wnt pathway activation, data were collected for 96 qPCR assays on 1440 lymphoblastoid cells. The description of methods includes preliminary data processing steps. The methods used in the collection and analysis of single-cell qPCR data are contrasted with those used in conventional qPCR.


Clinical use of cold atmospheric pressure argon plasma in chronic leg ulcers: A pilot study.
In the age of multiresistant microbes and the increasing lack of efficient antibiotics, conventional antiseptics play a critical role in the prevention and therapy of wound infections. Recent studies have demonstrated the antiseptic effects of cold atmospheric pressure plasma (APP). In this pilot, study we investigate the overall suitability of one of the first APP sources for wound treatment focusing on its potential antimicrobial effects. The wound closure rate and the bacterial colonisation of the wounds were investigated. Patients suffering from chronic leg ulcers were treated in a clinical controlled monocentric trial with either APP or octenidine (OCT). In patients who presented with more than one ulceration in different locations, one was treated with APP and the other one with OCT. Each group was treated three times a week over a period of two weeks. The antimicrobial efficacy was evaluated immediately after and following two weeks of treatment. Wounds treated with OCT showed a significantly higher microbial reduction (64%) compared to wounds treated with APP (47%) immediately after the treatment. Over two weeks of antiseptic treatment the bacterial density was reduced within the OCT group (-35%) compared to a slight increase in bacterial density in the APP-treated group (+12%). Clinically, there were no signs of delayed wound healing observed in either group and both treatments were well tolerated. The immediate antimicrobial effects of the APP prototype source were almost comparable to OCT without any signs of cytotoxicity. This pilot study is limited by current configurations of the plasma source, where the narrow plasma beam made it difficult to cover larger wound surface areas and in order to avoid untreated areas of the wound bed, smaller wounds were assigned to the APP-treatment group. This limits the significance of AAP-related effects on the wound healing dynamics, as smaller wounds tend to heal faster than larger wounds. However, clinical wound healing studies on a larger scale now seem justifiable. A more advanced plasma source prototype allowing the treatment of larger wounds will address APP's influence on healing dynamics, synergetic treatment with current antiseptics and effects on multiresistant bacteria.


Optic neuritis, its differential diagnosis and management.
The aim of this review is to summarize the latest information about optic neuritis, its differential diagnosis and management. Optic Neuritis (ON) is defined as inflammation of the optic nerve, which is mostly idiopathic. However it can be associated with variable causes (demyelinating lesions, autoimmune disorders, infectious and inflammatory conditions). Out of these, multiple sclerosis (MS) is the most common cause of demyelinating ON. ON occurs due to inflammatory processes which lead to activation of T-cells that can cross the blood brain barrier and cause hypersensitivity reaction to neuronal structures. For unknown reasons, ON mostly occurs in adult women and people who live in high latitude. The clinical diagnosis of ON consists of the classic triad of visual loss, periocular pain and dyschromatopsia which requires careful ophthalmic, neurologic and systemic examinations to distinguish between typical and atypical ON. ON in neuromyelitis optica (NMO) is initially misdiagnosed as ON in MS or other conditions such as Anterior Ischemic Optic Neuropathy (AION) and Leber's disease. Therefore, differential diagnosis is necessary to make a proper treatment plan. According to Optic Neuritis Treatment Trial (ONTT) the first line of treatment is intravenous methylprednisolone with faster recovery and less chance of recurrence of ON and conversion to MS. However oral prednisolone alone is contraindicated due to increased risk of a second episode. Controlled High-Risk Subjects Avonex(®) Multiple Sclerosis Prevention Study "CHAMPS", Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment "BENEFIT" and Early Treatment of MS study "ETOMS" have reported that treatment with interferon β-1a,b results in reduced risk of MS and MRI characteristics of ON. Contrast sensitivity, color vision and visual field are the parameters which remain impaired mostly even after good recovery of visual acuity.


Robot-Assisted Proprioceptive Training with Added Vibro-Tactile Feedback Enhances Somatosensory and Motor Performance.
This study examined the trainability of the proprioceptive sense and explored the relationship between proprioception and motor learning. With vision blocked, human learners had to perform goal-directed wrist movements relying solely on proprioceptive/haptic cues to reach several haptically specified targets. One group received additional somatosensory movement error feedback in form of vibro-tactile cues applied to the skin of the forearm. We used a haptic robotic device for the wrist and implemented a 3-day training regimen that required learners to make spatially precise goal-directed wrist reaching movements without vision. We assessed whether training improved the acuity of the wrist joint position sense. In addition, we checked if sensory learning generalized to the motor domain and improved spatial precision of wrist tracking movements that were not trained. The main findings of the study are: First, proprioceptive acuity of the wrist joint position sense improved after training for the group that received the combined proprioceptive/haptic and vibro-tactile feedback (VTF). Second, training had no impact on the spatial accuracy of the untrained tracking task. However, learners who had received VTF significantly reduced their reliance on haptic guidance feedback when performing the untrained motor task. That is, concurrent VTF was highly salient movement feedback and obviated the need for haptic feedback. Third, VTF can be also provided by the limb not involved in the task. Learners who received VTF to the contralateral limb equally benefitted. In conclusion, somatosensory training can significantly enhance proprioceptive acuity within days when learning is coupled with vibro-tactile sensory cues that provide feedback about movement errors. The observable sensory improvements in proprioception facilitates motor learning and such learning may generalize to the sensorimotor control of the untrained motor tasks. The implications of these findings for neurorehabilitation are discussed.


Very sensitive fiber Bragg grating accelerometer using transverse forces with an easy over-range protection and low cross axial sensitivity.
The first fiber Bragg grating (FBG) accelerometer using direct transverse forces is demonstrated by fixing the FBG by its two ends and placing a transversely moving inertial object at its middle. It is very sensitive because a lightly stretched FBG is more sensitive to transverse forces than axial forces. Its resonant frequency and static sensitivity are analyzed by the classic spring-mass theory, assuming the axial force changes little. The experiments show that the theory can be modified for cases where the assumption does not hold. The resonant frequency can be modified by a linear relationship experimentally achieved, and the static sensitivity by an alternative method proposed. The principles of the over-range protection and low cross axial sensitivity are achieved by limiting the movement of the FBG and were validated experimentally. The sensitivities 1.333 and 0.634 nm/g were experimentally achieved by 5.29 and 2.83 gram inertial objects at 10 Hz from 0.1 to 0.4 g (g = 9.8 × m/s2), respectively, and their resonant frequencies were around 25 Hz. Their theoretical static sensitivities and resonant frequencies found by the modifications are 1.188 nm/g and 26.81 Hz for the 5.29 gram one and 0.784 nm/g and 29.04 Hz for the 2.83 gram one, respectively.


Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses.
Lysosphingolipids potently and reversibly inhibited protein kinase C activity and binding of phorbol dibutyrate in vitro and in human platelets. As with activation of protein kinase C by phosphatidylserine and sn-1,2-diacylglycerol, inhibition was subject to surface dilution. Accordingly, inhibition in mixed micelle assays was dependent on the molar percentage of lysosphingolipids rather than the bulk concentration. Lysosphingolipids inhibited protein kinase C activity at molar percentages similar to those required for activation by phosphatidylserine and sn-1,2-diacylglycerol. Since lysosphingolipids accumulate in Krabbe's disease, Gaucher's disease, and other sphingolipidoses, the hypothesis that lysosphingolipid inhibition of protein kinase C represents the missing functional link between the accumulation of sphingolipids and the pathogenesis of these disorders appears to unify existing data. The accumulation of lysosphingolipids would cause progressive dysfunction of signal transduction mechanisms vital for neural transmission, differentiation, development, and proliferation and would eventually lead to cell death.


Ecological structure of assemblages of coral reef fishes on isolated patch reefs.
A 9-year study of the structure of assemblages of fish on 20 coral patch reefs, based on 20 non-manipulative censuses, revealed a total of 141 species from 34 families, although 40 species accounted for over 95% of sightings of fish. The average patch reef was 8.5 m2 in surface area, and supported 125 fish of 20 species at a census. All reefs showed at least a two-fold variation among censuses in total numbers of fish present, and 12 showed ten-fold variations. There was also substantial variation in the composition and relative abundances of species present on each patch reef, such that censuses of a single patch reef were on average about 50% different from each other in percent similarity of species composition (Czekanowski's index). Species differed substantially in the degree to which their numbers varied from census to census, and in the degree to which their dispersion among patch reefs was modified from census to census. We characterize the 40 most common species with respect to these attributes. The variations in assemblage structure cannot be attributed to responses of fish to a changing physical structure of patch reefs, nor to the comings and goings of numerous rare species. Our results support and extend earlier reports on this study, which have stressed the lack of persistant structure for assemblages on these patch reefs. While reef fishes clearly have microhabitat preferences which are expressed at settlement, the variations in microhabitat offered by the patch reefs are insufficient to segregate many species of fish by patch reef. Instead, at the scale of single patch reefs, and, to a degree, at the larger scale of the 20 patch reefs, most of the 141 species of fish are distributed without regard to differences in habitat structure among reefs, and patterns of distribution change over time. Implications for general understanding of assemblage dynamics for fish over more extensive patches of reef habitat are considered.


Phase II study of concurrent capecitabine and external beam radiotherapy for pain control of bone metastases of breast cancer origin.
Pain from bone metastases of breast cancer origin is treated with localized radiation. Modulating doses and schedules has shown little efficacy in improving results. Given the synergistic therapeutic effect reported for combined systemic chemotherapy with local radiation in anal, rectal, and head and neck malignancies, we sought to evaluate the tolerability and efficacy of combined capecitabine and radiation for palliation of pain due to bone metastases from breast cancer. Twenty-nine women with painful bone metastases from breast cancer were treated with external beam radiation in 10 fractions of 3 Gy, 5 fractions a week for 2 consecutive weeks. Oral capecitabine 700 mg/m(2) twice daily was administered throughout radiation therapy. Rates of complete response, defined as a score of 0 on a 10-point pain scale and no increase in analgesic consumption, were 14% at 1 week, 38% at 2 weeks, 52% at 4 weeks, 52% at 8 weeks, and 48% at 12 weeks. Corresponding rates of partial response, defined as a reduction of at least 2 points in pain score without an increase in analgesics consumption, were 31%, 38%, 28%, 34% and 38%. The overall response rate (complete and partial) at 12 weeks was 86%. Side effects were of mild intensity (grade I or II) and included nausea (38% of patients), weakness (24%), diarrhea (24%), mucositis (10%), and hand and foot syndrome (7%). External beam radiation with concurrent capecitabine is safe and tolerable for the treatment of pain from bone metastases of breast cancer origin. The overall and complete response rates in our study are unusually high compared to those reported for radiation alone. Further evaluation of this approach, in a randomized study, is warranted. ClinicalTrials.gov NCT01784393NCT01784393.


Acoustic communication in noise: regulation of call characteristics in a New World monkey.
This study on common marmosets Callithrix jacchus is the first to examine noise-dependent mechanisms of vocal plasticity in a New World monkey. Since acoustic communication can be considerably impaired by environmental noise, some animals have evolved adaptations to counteract its masking effects. The studied marmosets increased the sound level of their spontaneous calls in response to increased levels of white noise broadcast to them. Possibly, such noise-dependent adjustment of vocal amplitude serves to maintain a specific signal-to-noise ratio that is favourable for signal production. Concurrently, the adjustment of vocal amplitude can maintain a given active space for communication. In contrast to some bird species, no noise-induced increase in the number of syllables per call series could be found, showing that an increased serial redundancy of vocal signals was not used to communicate under noisy conditions. Finally, we examined a possible noise-dependent prolongation of vocal signals. This approach was guided by the findings of perceptional studies, which suggest an increased detection probability of prolonged signals in noise by temporal summation. Marmosets indeed increased the duration of their call syllables along with increasing background noise levels. This is the first evidence of such mechanism of vocal plasticity in an animal communication system.


Antiadhesive effect of mixed solution of sodium hyaluronate and sodium carboxymethylcellulose after blow-out fracture repair.
Treatment of blow-out fractures is aimed at the prevention of permanent diplopia and cosmetically unacceptable enophthalmos. Porous polyethylene sheets are one of the most common alloplastic implants for blow-out fracture repair. Because adhesion between the porous polyethylene and the orbital soft tissue can result in restrictions of ocular motility, prevention of postoperative adhesion is important in the reconstruction of blow-out fractures. The purpose of this study was to find out the effect of the mixed solution of sodium hyaluronate and sodium carboxymethylcellulose (HACMC) on postoperative adhesion in blow-out fracture repair in an animal model.Twenty-four New Zealand white rabbits were used. An 8-mm defect was made in the maxillary sinuses including the bone and mucosa. A 10-mm porous polyethylene sheet (Medpor; Porex Surgical Inc., Newnan, GA) was inserted in to the defect. The rabbits were divided into a control group and a HACMC group. In the HACMC group, HACMC solution was instilled onto the surface of the implant and then the implant was inserted. The implants were harvested at 1, 2, 4, and 8 weeks after surgery (3 implants each period). Hematoxylin and eosin, Masson trichrome, and CD31 (platelet endothelial cell adhesion molecule-1) stains were performed for evaluation of inflammation, fibrosis, and vascularization.Inflammation appeared less severe in the HACMC group, but the difference between the 2 groups was not statistically significant. The degree of fibrosis was more severe in the control group. There were significant differences in the degree of fibrosis between the 2 groups 4 and 8 weeks after surgery (P = 0.046). The amount of vascularization was similar in both groups.The HACMC solution seemed to be effective for reducing postoperative adhesion in reconstruction of blow-out fractures in a rabbit model. Our results suggest that the application of HACMC solution could be an effective adjunct for the repair of trap-door fractures or revision of blow-out fractures.


Pyramidal neurons of upper cortical layers generated by NEX-positive progenitor cells in the subventricular zone.
The generation of pyramidal neurons in the mammalian neocortex has been attributed to proliferating progenitor cells within the ventricular zone (VZ). Recently, the subventricular zone (SVZ) has been recognized as a possible source of migratory neurons in brain slice preparations, but the relevance of these observations for the developing neocortex in vivo remains to be defined. Here, we demonstrate that a subset of progenitor cells within the SVZ of the mouse neocortex can be molecularly defined by Cre recombinase expression under control of the NEX/Math2 locus, a neuronal basic helix-loop-helix gene that by itself is dispensable for cortical development. NEX-positive progenitors are generated by VZ cells, move into the SVZ, and undergo multiple asymmetrical and symmetrical cell divisions that produce a fraction of the neurons in the upper cortical layers. Our data suggest that NEX-positive progenitors within the SVZ are committed to a glutamatergic neuronal fate and have evolved to expand the number of cortical output neurons that is characteristic for the mammalian forebrain.


Safety of on-scene medical care by EMS nurses in non-transported patients: a prospective, observational study.
After on-scene examination and /or treatment, emergency medical services (EMS) nurses must decide whether the patient requires further assessment or treatment, most frequently in a hospital. The primary objective of this study was to assess the reliability of the current EMS protocol by determining whether the decision not to transport the patient to a care provider was correct or not. Adults receiving on-scene medical care by an EMS rapid responder or full team without transport to the hospital were included in this prospective observational study. The primary outcome measure was secondary consultation within 24 h after an on-scene EMS evaluation without transport for the same or a closely related complaint. The secondary outcome measures were patient satisfaction, type of secondarily consulted health care provider, provisional and definitive diagnosis, and correctness of the EMS members' decision to provide on-scene medical care without transport. Of the 1095 participating patients, 271 (24.7%) patients requested secondary medical attention for the same complaint. This percentage was significantly larger in incidents attended by an ambulance team than by a rapid responder (N = 248 (26.5%) vs. N = 23 (14.4%); p < 0.05). In eleven (1.0%) cases an urgent medical diagnosis requiring admission was missed. A total of 873 (79.7%) patients were satisfied with the decision not to be transported. In 44 (4.0%) cases the EMS nurse's decision was rated incorrect since the patient needed help contradictory to the EMS nurse's recommendation. The data show that EMS nurses can effectively examine patients, but a low threshold of referral for consultation should be considered because one in four patients requested secondary medical attention for the same complaint(s) again. However, due to a low response rate (11.3%) more research is needed to further determine the safety of the current EMS protocol. Not applicable.


Comorbidities, socioeconomic status, drug use, and health care consumption in Danish women with psoriasis: A nationwide cross-sectional study.
Psoriasis is a disease that extends beyond the skin, with profound medical, social, and mental health implications. To our knowledge, no previous studies have specifically investigated the medical and socioeconomic characteristics of women with versus without psoriasis. We investigated whether women with psoriasis differed from women without psoriasis with respect to comorbidities, socioeconomic status, healthcare consumption, and drug use, as well as how these characteristics differed according to psoriasis severity. In this nationwide, register-based, cross-sectional study, data were collected from Danish registries from 1977 to 2017, linked at the individual level, and identified by International Classification of Diseases codes, prescription data, income and educational information, and contact with public health care services. Psoriasis was defined by either a hospital International Classification of Diseases code for psoriasis or calcipotriol prescription data. Psoriasis severity was stratified based on psoriasis treatment. Age-adjusted logistic regression models were used to estimate the odds ratios (ORs) of outcomes compared with those of women without psoriasis. A total of 77,143 women (3%) met the criteria for psoriasis. Psoriasis was significantly associated with all investigated outcomes. Women with psoriasis were less likely to have a high income (OR: 0.89; 95% confidence interval [CI], 0.87-0.91), more likely to visit their general practitioner more often (OR: 3.82; 95% CI, 3.70-3.95), and received pain medication more often (OR: 1.57; 95% CI, 1.52-1.62) compared with women without psoriasis. Psoriasis was significantly associated with all investigated adverse medical and socioeconomic outcomes. Risk of outcomes increased with psoriasis severity. Our study highlights the need for a multidisciplinary collaboration to optimize medical care for women with (especially moderate and severe) psoriasis.


Anterior cingulate neurons represent errors and preparatory attention within the same behavioral sequence.
The anterior cingulate cortex (ACC) has been implicated in both preparatory attention (i.e., selecting behaviorally relevant stimuli) and in detecting errors. We recorded from the rat ACC and medial prefrontal cortex (mPFC), which is functionally homologous to the primate dorsolateral PFC, during an attention task. The three-choice serial reaction time task requires a rat to orient toward and divide attention between three brief (300 ms duration) light stimuli presented in random order across nose poke holes in an operant chamber. In both the ACC and mPFC, we found that neural activity was related to the level of preparatory (precue) attention and subsequent correct or incorrect choice, in that the magnitude of the single units' response to the cue was lower on incorrect trials and was not different than baseline on unattended trials. This preparatory neural activity consisted of both excitatory and inhibitory phasic responses. The number of units responding to the cue was similarly graded, in that fewer units exhibited phasic responses to the cue on incorrect and unattended trials, compared with correct trials. Although preparatory activity was found in both the ACC and mPFC, activity after incorrect nose pokes, which may be related to error detection, were only observed in the ACC. Thus, during the same behavioral sequence, the ACC encodes both error-related events and preparatory attention, whereas the mPFC only participates in preparatory attention. The finding of substantial inhibitory activity during the preparatory period suggests a critical role for inhibition of pyramidal cells in PFC-mediated cognitive functions.


A Detailed View of KIR Haplotype Structures and Gene Families as Provided by a New Motif-Based Multiple Sequence Alignment.
Human chromosome 19q13.4 contains genes encoding killer-cell immunoglobulin-like receptors (KIR). Reported haplotype lengths range from 67 to 269 kb and contain 4 to 18 genes. The region has certain properties such as single nucleotide variation, structural variation, homology, and repetitive elements that make it hard to align accurately beyond single gene alleles. To the best of our knowledge, a multiple sequence alignment of KIR haplotypes has never been published or presented. Such an alignment would be useful to precisely define KIR haplotypes and loci, provide context for assigning alleles (especially fusion alleles) to genes, infer evolutionary history, impute alleles, interpret and predict co-expression, and generate markers. In order to extend the framework of KIR haplotype sequences in the human genome reference, 27 new sequences were generated including 24 haplotypes from 12 individuals of African American ancestry that were selected for genotypic diversity and novelty to the reference, to bring the total to 68 full length genomic KIR haplotype sequences. We leveraged these data and tools from our long-read KIR haplotype assembly algorithm to define and align KIR haplotypes at <5 kb resolution on average. We then used a standard alignment algorithm to refine that alignment down to single base resolution. This processing demonstrated that the high-level alignment recapitulates human-curated annotation of the human haplotypes as well as a chimpanzee haplotype. Further, assignments and alignments of gene alleles were consistent with their human curation in haplotype and allele databases. These results define KIR haplotypes as 14 loci containing 9 genes. The multiple sequence alignments have been applied in two software packages as probes to capture and annotate KIR haplotypes and as markers to genotype KIR from WGS.


Protective effects of camel milk against pathogenicity induced by Escherichia coli and Staphylococcus aureus in Wistar rats.
The aim of the present study was to investigate the protective effects of camel milk on hepatic pathogenicity induced by experimental infection with Escherichia (E. coli) and Staphylococcus aureus (S. aureus) in Wistar rats. The rats were divided into six groups: The control and camel milk groups received water and camel milk, respectively; two groups received camel milk for 2 weeks prior to intraperitoneal injection of either E. coli or S. aureus; and two groups were injected intraperitoneally with E. coli and S. aureus, respectively. All animals were maintained under observation for 7 days prior to biochemical and gene expression analyses. The rats treated with camel milk alone exhibited no changes in expression levels of glutamic‑pyruvate transaminase (GPT) or glutamic‑oxaloacetic transaminase (GOT), compared with the water‑treated group. The E. coli‑ and S. aureus‑injected rats exhibited a significant increase in oxidative stress, and prior treatment with camel milk normalized the observed changes in the expression levels of GPT, GOT and malondialdehyde (MDA). Treatment with camel milk decreased the total bacterial count in liver tissue samples obtained from the rats injected with E. coli and S. aureus. Camel milk administration increased the expression levels of glutathione‑S‑transferase and superoxide dismutase, which were downregulated following E. coli and S. aureus injection. In addition, camel milk downregulated the increased expression of interleukin‑6 and apoptosis‑associated genes. Of note, administration of camel milk alone increased the expression levels of the B cell lymphoma 2‑associated X protein and survivin anti‑apoptotic genes, and supplementation prior to the injection of E. coli and S. aureus induced further upregulation, In conclusion, camel milk exerted protective effects against E. coli and S. aureus pathogenicity, by modulating the extent of lipid peroxidation, together with the antioxidant defense system, immune cytokines, apoptosis and the expression of anti-apoptotic genes in the liver of Wistar rats.


Greenhouse gas emissions from waste management--assessment of quantification methods.
Of the many sources of urban greenhouse gas (GHG) emissions, solid waste is the only one for which management decisions are undertaken primarily by municipal governments themselves and is hence often the largest component of cities' corporate inventories. It is essential that decision-makers select an appropriate quantification methodology and have an appreciation of methodological strengths and shortcomings. This work compares four different waste emissions quantification methods, including Intergovernmental Panel on Climate Change (IPCC) 1996 guidelines, IPCC 2006 guidelines, U.S. Environmental Protection Agency (EPA) Waste Reduction Model (WARM), and the Federation of Canadian Municipalities-Partners for Climate Protection (FCM-PCP) quantification tool. Waste disposal data for the greater Toronto area (GTA) in 2005 are used for all methodologies; treatment options (including landfill, incineration, compost, and anaerobic digestion) are examined where available in methodologies. Landfill was shown to be the greatest source of GHG emissions, contributing more than three-quarters of total emissions associated with waste management. Results from the different landfill gas (LFG) quantification approaches ranged from an emissions source of 557 kt carbon dioxide equivalents (CO2e) (FCM-PCP) to a carbon sink of -53 kt CO2e (EPA WARM). Similar values were obtained between IPCC approaches. The IPCC 2006 method was found to be more appropriate for inventorying applications because it uses a waste-in-place (WIP) approach, rather than a methane commitment (MC) approach, despite perceived onerous data requirements for WIP. MC approaches were found to be useful from a planning standpoint; however, uncertainty associated with their projections of future parameter values limits their applicability for GHG inventorying. MC and WIP methods provided similar results in this case study; however, this is case specific because of similarity in assumptions of present and future landfill parameters and quantities of annual waste deposited in recent years being relatively consistent.


The association between self-reported and clinically determined hypomanic symptoms and the onset of major mood disorders.
Hypomanic symptoms may be a useful predictor of mood disorder among young people at high risk for bipolar disorder. To determine whether hypomanic symptoms differentiate offspring of parents with bipolar disorder (high risk) and offspring of well parents (control) and predict the development of mood episodes. High-risk and control offspring were prospectively assessed using semi-structured clinical interviews annually and completed the Hypomania Checklist-32 Revised (HCL-32). Clinically significant sub-threshold hypomanic symptoms (CSHS) were coded. HCL-32 total and active or elated scores were higher in control compared with high-risk offspring, whereas 14% of high-risk and 0% of control offspring had CSHS. High-risk offspring with CSHS had a fivefold increased risk of developing recurrent major depression (P=0.0002). The median onset of CSHS in high-risk offspring was 16.4 (6-31) years and was before the onset of major mood episodes. CSHS are precursors to major mood episodes in high-risk offspring and could identify individuals at ultra-high risk for developing bipolar disorder. None. © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.


Delta-like 1 and lateral inhibition during hair cell formation in the chicken inner ear: evidence against cis-inhibition.
The formation of the salt-and-pepper mosaic of hair cells and supporting cells in the sensory epithelia of the inner ear is regulated by Notch signalling and lateral inhibition, but the dynamics of this process and precise mode of action of delta-like 1 (Dll1) in this context are unclear. Here, we transfected the chicken inner ear with a fluorescent reporter that includes elements of the mammalian Hes5 promoter to monitor Notch activity in the developing sensory patches. The Hes5 reporter was active in proliferating cells and supporting cells, and Dll1 expression was highest in prospective hair cells with low levels of Notch activity, which occasionally contacted more differentiated hair cells. To investigate Dll1 functions we used constructs in which Dll1 expression was either constitutive, regulated by the Hes5 promoter, or induced by doxycycline. In support of the standard lateral inhibition model, both continuous and Hes5-regulated expression of Dll1 promoted hair cell differentiation cell-autonomously (in cis) and inhibited hair cell formation in trans. However, some hair cells formed despite contacting Dll1-overexpressing cells, suggesting that some progenitor cells are insensitive to lateral inhibition. This is not due to the cis-inhibition of Notch activity by Dll1 itself, as induction of Dll1 did not cell-autonomously reduce the activity of the Hes5 reporter in progenitor and supporting cells. Altogether, our results show that Dll1 functions primarily in trans to regulate hair cell production but also that additional mechanisms operate downstream of lateral inhibition to eliminate patterning errors in the sensory epithelia of the inner ear.


Discovery of adamantyl heterocyclic ketones as potent 11β-hydroxysteroid dehydrogenase type 1 inhibitors.
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11β-HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11β-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11β-HSD1 and are selective with no activity against 11β-HSD2 and 17β-HSD1. Selected potent 11β-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes.


A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain.
Phosphoprotein phosphatase 2A (PP2A) is one of the four major protein serine/threonine phosphatases found in all eukaryotic cells. We have shown that the 36-kDa catalytic subunit of PP2A is carboxyl methylated in eukaryotic cells, and we have previously identified and purified a novel methyltransferase (MTase) that is responsible for this modification. Here, we describe a novel protein carboxyl methyl-esterase (MEase) from bovine brain that demethylates PP2A. The enzyme has been purified to homogeneity as a monomeric 46-kDa soluble protein. The MEase is highly specific for PP2A. It does not catalyze the demethylation of other protein or peptide methylesters. Moreover, MEase activity is dramatically inhibited by nanomolar concentrations of okadaic acid, a specific inhibitor of PP2A. From these results, we conclude that PP2A methylation is controlled by two specific enzymes, a MTase and a MEase. Since PP2A methylation is highly conserved in eukaryotes ranging from human to yeast, it is likely that this system plays an important role in phosphatase regulation.


The Childhood Obesity Data Initiative: A Case Study in Implementing Clinical-Community Infrastructure Enhancements to Support Health Services Research and Public Health.
We describe a participatory framework that enhanced and implemented innovative changes to an existing distributed health data network (DHDN) infrastructure to support linkage across sectors and systems. Our processes and lessons learned provide a potential framework for other multidisciplinary infrastructure development projects that engage in a participatory decision-making process. The Childhood Obesity Data Initiative (CODI) provides a potential framework for local and national stakeholders with public health, clinical, health services research, community intervention, and information technology expertise to collaboratively develop a DHDN infrastructure that enhances data capacity for patient-centered outcomes research and public health surveillance. CODI utilizes a participatory approach to guide decision making among clinical and community partners. CODI's multidisciplinary group of public health and clinical scientists and information technology experts collectively defined key components of CODI's infrastructure and selected and enhanced existing tools and data models. We conducted a pilot implementation with 3 health care systems and 2 community partners in the greater Denver Metro Area during 2018-2020. We developed an evaluation plan based primarily on the Good Evaluation Practice in Health Informatics guideline. An independent third party implemented the evaluation plan for the CODI development phase by conducting interviews to identify lessons learned from the participatory decision-making processes. We demonstrate the feasibility of rapid innovation based upon an iterative and collaborative process and existing infrastructure. Collaborative engagement of stakeholders early and iteratively was critical to ensure a common understanding of the research and project objectives, current state of technological capacity, intended use, and the desired future state of CODI architecture. Integration of community partners' data with clinical data may require the use of a trusted third party's infrastructure. Lessons learned from our process may help others develop or improve similar DHDNs.


Alkanindiges illinoisensis gen. nov., sp. nov., an obligately hydrocarbonoclastic, aerobic squalane-degrading bacterium isolated from oilfield soils.
An alkane-degrading bacterium, designated GTI MVAB Hex1(T), was isolated from chronically crude oil-contaminated soil from an oilfield in southern Illinois. The isolate grew very weakly or not at all in minimal or rich media without hydrocarbons. Straight-chain aliphatic hydrocarbons, such as hexadecane and heptadecane, greatly stimulated growth; shorter-chain (</=C(15)) hydrocarbons did not (with decane as the sole exception). Growth was also greatly enhanced by the branched aliphatic hydrocarbons pristane and squalane. The latter of these was most intriguing, as catabolism of squalane has hitherto been reported only for Mycobacterium species. Although unable to utilize mono- or polycyclic aromatic hydrocarbons as sole carbon sources, the isolate did show slight fluorene-mineralizing capability in Luria-Bertani medium, which was partially repressed by hexadecane. In contrast, hexadecane supplementation greatly increased mineralization of (14)C-dodecane, which was not a growth substrate. Further testing emphasized the isolate's extremely narrow substrate range, as only Tween 40 and Tween 80 supported significant growth. Microscopic examination (by scanning and transmission electron microscopy) revealed a slightly polymorphic coccoidal to bacillar morphology, with hydrocarbon-grown cells tending to be more elongated. When grown with hexadecane, GTI MVAB Hex1(T) accumulated a large number of electron-transparent intracytoplasmic inclusion bodies. These were also prevalent during growth in the presence of squalane. Smaller inclusion bodies were observed occasionally with pristane supplementation; they were, however, absent during growth on crude oil. On the basis of 16S rRNA gene sequence data and range of growth substrates, classification of this isolate as the type strain of Alkanindiges illinoisensis gen. nov., sp. nov. is proposed, which is most closely related (approx. 94 % sequence similarity) to Acinetobacter junii.


Presaccadic motion integration drives a predictive postsaccadic following response.
Saccadic eye movements sample the visual world and ensure high acuity across the visual field. To compensate for delays in processing, saccades to moving targets require predictions: The eyes must intercept the target's future position to then pursue its direction of motion. Although prediction is crucial to voluntary pursuit, it is unclear whether it is an obligatory feature of saccade planning. Saccade planning involves an involuntary enhanced processing of the target, called presaccadic attention. Does this presaccadic attention recruit smooth eye movements automatically? To test this, we had human participants perform a saccade to one of four apertures, which were static, but each contained a random dot field with motion tangential to the required saccade. In this task, saccades were deviated along the direction of target motion, and the eyes exhibited a following response upon saccade landing. This postsaccadic following response (PFR) increased with spatial uncertainty of the target position and persisted even when we removed the motion stimulus in midflight of the saccade, confirming that it relied on presaccadic information. Motion from 50-100 ms prior to the saccade had the strongest influence on PFR, consistent with the time course of perceptual enhancements reported in presaccadic attention. Finally, the PFR magnitude related linearly to the logarithm of stimulus velocity and generally had low gain, similar to involuntary ocular following movements commonly observed after sudden motion onsets. These results suggest that presaccadic attention selects motion features of targets predictively, presumably to ensure successful immediate tracking of saccade targets in motion.


The prevalence of Samter's triad in patients undergoing functional endoscopic sinus surgery.
We conducted a retrospective study to determine the prevalence of Samter's triad (nasal polyps, asthma, and aspirin sensitivity) in 208 consecutively presenting patients who had undergone functional endoscopic sinus surgery (FESS) for chronic rhinosinusitis from September 2001 through August 2003. Overall, Samter's triad was found in 10 patients (4.8%); subgroup analyses showed that the prevalence of Samter's triad was 5.9% in adults, 9.4% in patients with nasal polyps alone, 16.9% in patients with asthma alone, and 25.6% among patients with both polyps and asthma. On average, patients with Samter's triad had undergone approximately 10 times as many previous FESS procedures as had the patients without Samter's triad (mean: 5.2 vs. 0.53; p < 0.001). In addition to Samter's triad, four other factors were independently and significantly associated with a higher number of previous FESS procedures: nasal polyps alone, asthma alone, both polyps and asthma, and cystic fibrosis alone. Finally, at 6 months following their most recent surgery, patients with Samter's triad had significantly higher rates of symptom recurrence (nasal obstruction, facial pain, postnasal drip, and anosmia) and a recurrence of nasal polyps.


Longitudinal prevalence of potentially inappropriate medicines and potential prescribing omissions in a cohort of community-dwelling older people.
This study aims to compare the prevalence of potentially inappropriate medicines (PIMs) and potential prescribing omissions (PPOs) using several screening tools in an Irish community-dwelling older cohort, to assess if the prevalence changes over time and to determine factors associated with any change. This is a prospective cohort study of participants aged ≥65 years in The Irish Longitudinal Study on Ageing (TILDA) with linked pharmacy claims data (n = 2051). PIM and PPO prevalence was measured in the year preceding participants' TILDA baseline interviews and in the year preceding their follow-up interviews using the Screening Tool for Older Persons' Prescriptions (STOPP), Beers criteria (2012), Assessing Care of Vulnerable Elders (ACOVE) indicators and the Screening Tool to Alert doctors to Right Treatment (START). Generalised estimating equations were used to determine factors associated with change in prevalence over time. Depending on the screening tool used, between 19.8% (ACOVE indicators) and 52.7% (STOPP) of participants received a PIM at baseline, and PPO prevalence ranged from 38.2% (START) to 44.8% (ACOVE indicators), while 36.7% of participants had both a PIM and PPO. Common criteria were aspirin for primary prevention (19.6%) and omission of calcium/vitamin D in osteoporosis (14.7%). Prevalence of PIMs and PPOs increased at follow-up (PIMs range 22-56.1%, PPOs range 40.5-49.3%), and this was associated with patient age, female sex, and numbers of medicines and chronic conditions. Sub-optimal prescribing is common in older patients. Ongoing prescribing review to optimise care is important, particularly as patients get older, receive more medicines or develop more illnesses.


Automated grading system of retinal arterio-venous crossing patterns: A deep learning approach replicating ophthalmologist's diagnostic process of arteriolosclerosis.
The morphological feature of retinal arterio-venous crossing patterns is a valuable source of cardiovascular risk stratification as it directly captures vascular health. Although Scheie's classification, which was proposed in 1953, has been used to grade the severity of arteriolosclerosis as diagnostic criteria, it is not widely used in clinical settings as mastering this grading is challenging as it requires vast experience. In this paper, we propose a deep learning approach to replicate a diagnostic process of ophthalmologists while providing a checkpoint to secure explainability to understand the grading process. The proposed pipeline is three-fold to replicate a diagnostic process of ophthalmologists. First, we adopt segmentation and classification models to automatically obtain vessels in a retinal image with the corresponding artery/vein labels and find candidate arterio-venous crossing points. Second, we use a classification model to validate the true crossing point. At last, the grade of severity for the vessel crossings is classified. To better address the problem of label ambiguity and imbalanced label distribution, we propose a new model, named multi-diagnosis team network (MDTNet), in which the sub-models with different structures or different loss functions provide different decisions. MDTNet unifies these diverse theories to give the final decision with high accuracy. Our automated grading pipeline was able to validate crossing points with precision and recall of 96.3% and 96.3%, respectively. Among correctly detected crossing points, the kappa value for the agreement between the grading by a retina specialist and the estimated score was 0.85, with an accuracy of 0.92. The numerical results demonstrate that our method can achieve a good performance in both arterio-venous crossing validation and severity grading tasks following the diagnostic process of ophthalmologists. By the proposed models, we could build a pipeline reproducing ophthalmologists' diagnostic process without requiring subjective feature extractions. The code is available (https://github.com/conscienceli/MDTNet).


Association between insomnia and social network site use in Indonesian adolescents.
Sleep deprivation can cause serious physical and mental problems. Although sleep deprivation among adolescents is not a new phenomenon, this problem has recently gained more attention due to the frequent use of smartphones. This study aimed to explain the correlations among family support, academic stress, social network site (SNS) use, and insomnia in adolescents. This cross-sectional study included 180 adolescents aged 16 to 17 years, with simple random sampling. This study used a questionnaire that included the frequency and duration of social media use, reasons for using social media, family support, academic stress, and insomnia. Data were analyzed using multiple logistic regression with a degree of significance at P < 0.05. This study showed that insomnia was associated with duration of SNS use (P = 0.011), reasons of SNS usage ( P = 0.004), and academic stress ( P = 0.013). The frequency of SNS use ( P = 0.645), types of SNS ( P = 0.965), and family support ( P = 0.150) were not associated with insomnia in adolescents. The reasons of SNS usage, duration of SNS usage, and academic stress are major factors associated with insomnia in adolescents. These components should be embedded in multicomponent educational intervention addressed to both adolescents and parents to reduce insomnia.


Nitric oxide inhibits the synthesis of type-II collagen without altering Col2A1 mRNA abundance: prolyl hydroxylase as a possible target.
The addition of human recombinant interleukin-1beta (IL-1beta) to cultures of lapine articular chondrocytes provoked the synthesis of large amounts of NO and reduced the production of type-II collagen. NG-Monomethyl-l-arginine (L-NMA), an inhibitor of NO synthase, strongly suppressed the production of NO and partially relieved the inhibition of collagen synthesis in response to IL-1beta. The NO donor S-nitrosoacetylpenicillamine (SNAP), on the other hand, inhibited collagen production. IL-1 lowered the abundance of Col2A1 mRNA in an NO-independent manner. Collectively, these data indicate that IL-1 suppresses collagen synthesis at two levels: a pretranslational level which is NO-independent, and a translational or post-translational level which is NO-mediated. These effects are presumably specific as L-NMA and SNAP had no effect on total protein synthesis or on the distribution of newly synthesized proteins between the cellular and extracellular compartments. Prolyl hydroxylase is an important enzyme in the post-translational processing of collagen, and its regulation and cofactor requirements suggest possible sensitivity to NO. Extracts of cells treated with IL-1 or SNAP had lower prolyl hydroxylase activity, and L-NMA was partially able to reverse the effects of IL-1. These data suggest that prolyl hydroxylase might indeed be a target for NO. Because underhydroxylated collagen monomers fail to anneal into stable triple helices, they are degraded intracellularly. Inhibition of prolyl hydroxylase by NO might thus account for the suppressive effect of this radical on collagen synthesis.


Effect of Self-monitoring of Blood Pressure on Diagnosis of Hypertension During Higher-Risk Pregnancy: The BUMP 1 Randomized Clinical Trial.
Inadequate management of elevated blood pressure (BP) is a significant contributing factor to maternal deaths. Self-monitoring of BP in the general population has been shown to improve the diagnosis and management of hypertension; however, little is known about its use in pregnancy. To determine whether self-monitoring of BP in higher-risk pregnancies leads to earlier detection of pregnancy hypertension. Unblinded, randomized clinical trial that included 2441 pregnant individuals at higher risk of preeclampsia and recruited at a mean of 20 weeks' gestation from 15 hospital maternity units in England between November 2018 and October 2019. Final follow-up was completed in April 2020. Participating individuals were randomized to either BP self-monitoring with telemonitoring (n = 1223) plus usual care or usual antenatal care alone (n = 1218) without access to telemonitored BP. The primary outcome was time to first recorded hypertension measured by a health care professional. Among 2441 participants who were randomized (mean [SD] age, 33 [5.6] years; mean gestation, 20 [1.6] weeks), 2346 (96%) completed the trial. The time from randomization to clinic recording of hypertension was not significantly different between individuals in the self-monitoring group (mean [SD], 104.3 [32.6] days) vs in the usual care group (mean [SD], 106.2 [32.0] days) (mean difference, -1.6 days [95% CI, -8.1 to 4.9]; P = .64). Eighteen serious adverse events were reported during the trial with none judged as related to the intervention (12 [1%] in the self-monitoring group vs 6 [0.5%] in the usual care group). Among pregnant individuals at higher risk of preeclampsia, blood pressure self-monitoring with telemonitoring, compared with usual care, did not lead to significantly earlier clinic-based detection of hypertension. ClinicalTrials.gov Identifier: NCT03334149.


Sexual dimorphism revealed in the structure of the mouse brain using three-dimensional magnetic resonance imaging.
A large variety of sexual dimorphisms have been described in the brains of many vertebrate species, including humans. Naturally occurring sexual dimorphism has been implicated in the risk, progression and recovery from numerous neurological disorders, including head injury, multiple sclerosis and stroke. Genetically altered mice are a key tool in the study of structure-function relationships in the mammalian central nervous system and serve as models for human neuropsychiatric and neurological disorders. However, there are a limited number of quantitative three-dimensional analyses of the adult mouse brain structures. In order to address limitations in our knowledge of anatomical differences, a comprehensive study was undertaken using full 3D magnetic resonance imaging (MRI) to examine sexual dimorphisms in the C57BL/6J whole mouse brain. An expected difference in overall brain size between the sexes was found, where male brains were 2.5% larger in volume than female brains. Beyond the overall brain size differences in the sexes, the following significantly different regions were found: males were larger in the thalamus, primary motor cortex and posterior hippocampus, while females were larger in posterior hypothalamic area, entorhinal cortex and anterior hippocampus. Using high-definition 3D MRI on a normal inbred mouse strain, we have mapped in detail many sex-associated statistically significant differences in brain structures.


Primary care preparedness for the SARS-CoV-2 pandemic: a survey of NHS GPs.
Primary care manages a significant proportion of healthcare in the United Kingdom and should be a key part of the SARS-CoV-2 pandemic response. To assess preparedness for the SARS-CoV-2 pandemic by understanding GPs' perception of their ability to manage current and future service demand, set-up of triage processes, and training in Covid-19 infection prevention and control procedures. Cross-sectional survey of practicing GPs in the United Kingdom, with 2 rounds of data collection early in the pandemic. Online survey, scripted and hosted by medeConnect Healthcare, comprising 6 closed prompts on 7-point Likert scales, and an optional free-text component. Quantitative data were analysed using descriptive statistics. Free-text data were analysed thematically. One thousand two GPs completed each round; 51 GPs completed free-text responses in March, and 64 in April. Quantitative data showed greatest confidence in triage of Covid-19 patients, and GPs were more confident managing current than future Covid-19 demand. GPs' responses were more optimistic and aligned in April than March. Free-text data highlighted that GPs were concerned about lack of appropriate personal protective equipment and personal risk of Covid-19 infection in March, and unmet needs of non-Covid-19 patients in April. In both rounds, GPs expressed feeling overlooked by government and public health bodies. Guidance to support general practice clinicians to manage future waves of Covid-19 or other health emergencies must be tailored to general practice from the outset, to support clinicians to manage competing health demands, and mitigate impacts on primary care providers' wellbeing.


Postganglionic muscarinic inhibitory receptors in pulmonary parasympathetic nerves in the guinea-pig.
The location of neuronal inhibitory muscarinic receptors in pulmonary parasympathetic nerves was investigated in vivo and in vitro. The effects of an agonist for neuronal muscarinic receptors (pilocarpine) and an antagonist (gallamine) were tested on contractions of airway smooth muscle induced by pre- and postganglionic cholinergic nerve stimulation. In anaesthetized guinea-pigs, gallamine potentiated constriction of the tracheal tube and smaller airways induced by preganglionic stimulation. Gallamine also potentiated postganglionic stimulation induced by transmural stimulation of the tracheal tube and by 1-1-dimethyl-4-phenylpiperazinium iodide in the rest of the lung. Bronchoconstriction and contraction of the tracheal tube induced by intravenous acetylcholine were not potentiated by gallamine, indicating that postjunctional muscarinic receptors in airway smooth muscle were not involved in the potentiation. The muscarinic agonist, pilocarpine, had the opposite effect to gallamine and inhibited contractions of the tracheal tube induced by both types of nerve stimulation. In vitro, the inhibitory effect of pilocarpine was demonstrated in the tracheal tube preparation stimulated both pre- and postganglionically. The effect of pilocarpine was antagonized by gallamine. Because gallamine and pilocarpine affected the responses to postganglionic stimulation, the inhibitory muscarinic receptors must be located on the postganglionic neurones of the parasympathetic nerves innervating the trachea and the smaller airways. However, these experiments cannot exclude the possibility that muscarinic receptors may also be located on the soma of the ganglion cells.


The chemically elegant proton pump inhibitors.
Medicinal chemistry instruction at Creighton University is designed to provide an in-depth scientifically grounded and clinically relevant learning experience for pharmacy students. Each topic covered in the 2-semester required course sequence is selected based on the general utility of the compounds in question and/or the therapeutic importance of the drugs in treating life-threatening diseases. All lessons provided to campus- and Web-based students by the author are in the form of a descriptive and conversational narrative and course requirements are in place to assure that students read the lesson prior to the class period in which it is discussed. Learning tools and aids are provided to help students more readily discern the most critical aspects of each lesson, to practice required critical thinking and structure analysis skills, and to self-assess competency in meeting specific learning objectives. This manuscript illustrates this approach by sharing a lesson on the chemistry and clinically relevant structure-activity relationships of proton pump inhibitors.


Adequate wound care and use of bed nets as protective factors against Buruli Ulcer: results from a case control study in Cameroon.
Buruli ulcer is an infectious disease involving the skin, caused by Mycobacterium ulcerans. Its exact transmission mechanism remains unknown. Several arguments indicate a possible role for insects in its transmission. A previous case-control study in the Nyong valley region in central Cameroon showed an unexpected association between bed net use and protection against Buruli ulcer. We investigated whether this association persisted in a newly discovered endemic Buruli ulcer focus in Bankim, northwestern Cameroon. We conducted a case-control study on 77 Buruli ulcer cases and 153 age-, gender- and village-matched controls. Participants were interviewed about their activities and habits. Multivariate conditional logistic regression analysis identified systematic use of a bed net (Odds-Ratio (OR) = 0.4, 95% Confidence Interval [95%CI] = [0.2-0.9], p-value (p) = 0.04), cleansing wounds with soap (OR [95%CI] = 0.1 [0.03-0.3], p<0.0001) and growing cassava (OR [95%CI] = 0.3 [0.2-0.7], p = 0.005) as independent protective factors. Independent risk factors were bathing in the Mbam River (OR [95%CI] = 6.9 [1.4-35], p = 0.02) and reporting scratch lesions after insect bites (OR [95%CI] = 2.7 [1.4-5.4], p = 0.004). The proportion of cases that could be prevented by systematic bed net use was 32%, and by adequate wound care was 34%. Our study confirms that two previously identified factors, adequate wound care and bed net use, significantly decreased the risk of Buruli ulcer. These associations withstand generalization to different geographic, climatic and epidemiologic settings. Involvement of insects in the household environment, and the relationship between wound hygiene and M. ulcerans infection should now be investigated.


The relationship between burnout, PTSD symptoms and injuries in firefighters.
Firefighters participate in activities with intense physical and psychological stress. To examine the correlation between work-related injuries (WRIs), burnout and post-traumatic stress disorder (PTSD) symptoms in firefighters. The method used for the recording of the elements was the collection of self-report anonymous questionnaires, the completion of which was optional. The questionnaires used were: (i) a WRIs questionnaire, (ii) the Maslach Burnout Inventory (MBI) and (iii) the Impact of Event Scale-Revised-Greek version. Descriptive statistics along with univariate and multivariate logistic regression analyses were applied. The study population consisted of 3289 firefighters. There was a significant association between WRIs, burnout syndrome, PTSD symptoms and age, work experience and physical condition. Relationships were found between PTSD symptoms, the MBI-emotional exhaustion dimension and WRIs and between MBI-depersonalization dimension and PTSD symptoms. The most traumatic event was the 'dealing with death or rescue of a child' and the top stress factor was 'depression about the responsibility for quality of victims' life'. The occupational obligations may be responsible for the psychological and musculoskeletal problems experienced by firefighters. Early recognition and response to psychosomatic issues in firefighters is of high importance.


Thymidine phosphorylase induces carcinoma cell oxidative stress and promotes secretion of angiogenic factors.
Thymidine phosphorylase (TP) (E.C. 184.108.40.206), also known as platelet-derived endothelial cell growth factor, is a potent angiogenic factor. The expression of TP correlates with poor prognosis in a range of tumor types. 2-Deoxy-D-ribose-1-phosphate, a product of thymidine catabolism by TP, is a strongly reducing sugar that generates oxygen radical species during the early stages of protein glycation. We show that thymidine induces oxidative stress in TP-overexpressing carcinoma cells, promoting secretion of the stress-induced angiogenic factors vascular endothelial growth factor and interleukin-8, and inducing matrix metalloproteinase-1. Our findings outline a putative mechanism for TP-induced angiogenesis and identify novel targets for intervention.


Licofelone Enhances the Efficacy of Paclitaxel in Ovarian Cancer by Reversing Drug Resistance and Tumor Stem-like Properties.
Drug development for first-line treatment of epithelial ovarian cancer (EOC) has been stagnant for almost three decades. Traditional cell culture methods for primary drug screening do not always accurately reflect clinical disease. To overcome this barrier, we grew a panel of EOC cell lines in three-dimensional (3D) cell cultures to form multicellular tumor spheroids (MCTS). We characterized these MCTS for molecular and cellular features of EOC and performed a comparative screen with cells grown using two-dimensional (2D) cell culture to identify previously unappreciated anticancer drugs. MCTS exhibited greater resistance to chemotherapeutic agents, showed signs of senescence and hypoxia, and expressed a number of stem cell-associated transcripts including ALDH1A and CD133, also known as PROM1 Using a library of clinically repurposed drugs, we identified candidates with preferential activity in MCTS over 2D cultured cells. One of the lead compounds, the dual COX/LOX inhibitor licofelone, reversed the stem-like properties of ovarian MCTS. Licofelone also synergized with paclitaxel in ovarian MCTS models and in a patient-derived tumor xenograft model. Importantly, the combination of licofelone with paclitaxel prolonged the median survival of mice (>141 days) relative to paclitaxel (115 days), licofelone (37 days), or vehicle (30 days). Increased efficacy was confirmed by Mantel-Haenszel HR compared with vehicle (HR = 0.037) and paclitaxel (HR = 0.017). These results identify for the first time an unappreciated, anti-inflammatory drug that can reverse chemotherapeutic resistance in ovarian cancer, highlighting the need to clinically evaluate licofelone in combination with first-line chemotherapy in primary and chemotherapy-refractory EOC.Significance: This study highlights the use of an in vitro spheroid 3D drug screening model to identify new therapeutic approaches to reverse chemotherapy resistance in ovarian cancer. Cancer Res; 78(15); 4370-85. ©2018 AACR.


Predicting response to physiotherapy treatment for musculoskeletal shoulder pain: a systematic review.
People suffering from musculoskeletal shoulder pain are frequently referred to physiotherapy. Physiotherapy generally involves a multimodal approach to management that may include; exercise, manual therapy and techniques to reduce pain. At present it is not possible to predict which patients will respond positively to physiotherapy treatment. The purpose of this systematic review was to identify which prognostic factors are associated with the outcome of physiotherapy in the management of musculoskeletal shoulder pain. A comprehensive search was undertaken of Ovid Medline, EMBASE, CINAHL and AMED (from inception to January 2013). Prospective studies of participants with shoulder pain receiving physiotherapy which investigated the association between baseline prognostic factors and change in pain and function over time were included. Study selection, data extraction and appraisal of study quality were undertaken by two independent assessors. Quality criteria were selected from previously published guidelines to form a checklist of 24 items. The study protocol was prospectively registered onto the International Prospective Register of Systematic Reviews. A total of 5023 titles were retrieved and screened for eligibility, 154 articles were assessed as full text and 16 met the inclusion criteria: 11 cohort studies, 3 randomised controlled trials and 2 controlled trials. Results were presented for the 9 studies meeting 13 or more of the 24 quality criteria. Clinical and statistical heterogeneity resulted in qualitative synthesis rather than meta-analysis. Three studies demonstrated that high functional disability at baseline was associated with poor functional outcome (p ≤ 0.05). Four studies demonstrated a significant association (p ≤ 0.05) between longer duration of shoulder pain and poorer outcome. Three studies, demonstrated a significant association (p ≤ 0.05) between increasing age and poorer function; three studies demonstrated no association (p > 0.05). Associations between prognostic factors and outcome were often inconsistent between studies. This may be due to clinical heterogeneity or type II errors. Only two baseline prognostic factors demonstrated a consistent association with outcome in two or more studies; duration of shoulder pain and baseline function. Prior to developing a predictive model for the outcome of physiotherapy treatment for shoulder pain, a large adequately powered prospective cohort study is required in which a broad range of prognostic factors are incorporated.


Probabilistic differential diagnosis of Middle East respiratory syndrome (MERS) using the time from immigration to illness onset among imported cases.
Middle East respiratory syndrome (MERS) has spread worldwide since 2012. As the clinical symptoms of MERS tend to be non-specific, the incubation period has been shown to complement differential diagnosis, especially to rule out influenza. However, because an infection event is seldom directly observable, the present study aims to construct a diagnostic model that predicts the probability of MERS diagnosis given the time from immigration to illness onset among imported cases which are suspected of MERS. Addressing censoring by considering the transmission dynamics in an exporting country, we demonstrate that the illness onset within 2 days from immigration is suggestive of influenza. Two exceptions to suspect MERS even for those with illness onset within 2 days since immigration are (i) when we observe substantial community transmissions of MERS and (ii) when the cases are at high risk of MERS (e.g. cases with close contact in hospital or household). It is vital to collect the information of the incubation period upon emergence of a novel infectious disease, and moreover, in our model, the fundamental transmission dynamics including the initial growth rate has to be explored to differentiate the disease diagnoses with non-specific symptoms.


Therapies for musculoskeletal disease: can we treat two birds with one stone?
Musculoskeletal diseases are highly prevalent with staggering annual health care costs across the globe. The combined wasting of muscle (sarcopenia) and bone (osteoporosis)-both in normal aging and pathologic states-can lead to vastly compounded risk for fracture in patients. Until now, our therapeutic approach to the prevention of such fractures has focused solely on bone, but our increasing understanding of the interconnected biology of muscle and bone has begun to shift our treatment paradigm for musculoskeletal disease. Targeting pathways that centrally regulate both bone and muscle (eg, GH/IGF-1, sex steroids, etc.) and newly emerging pathways that might facilitate communication between these 2 tissues (eg, activin/myostatin) might allow a greater therapeutic benefit and/or previously unanticipated means by which to treat these frail patients and prevent fracture. In this review, we will discuss a number of therapies currently under development that aim to treat musculoskeletal disease in precisely such a holistic fashion.


Cyclic AMP concentrations in human peripheral blood lymphocytes. Changes in association with cell purification.
In studies over a several year period of cAMP in human peripheral blood lymphocytes, a wide range of concentrations has been from low values (1 to 5 pmole/10(7) cells) to high values (80 to 160). Evaluation of this variation indicated that between cell separation and completion of the experiment, there eas a progressive decrease in lymphocyte cAMP as determined by RIA or immunocytochemistry. After a 2 hr incubation at 37 degrees C, a new steady state was reached at 5% to 30% of the initial concentration. This phenomenon was unique to lymphocytes and not preventable by manipulation of the incubation conditions. The cause of the cAMP reduction was shown to be decreasing AC activity. These data suggested the possibility that AC was activated during cell isolation. However, the phenomenon was present in cells not exposed to dextran or Ficoll-Hypaque, and simulation of conditions employed during purification did not result in increased cAMP. Consequently, high-lymphocyte cAMP concentrations may be the normal levels in vivo.


Pre-departure training and the social accountability of International Medical Electives.
Due to widespread awareness of global inequities in health and development, participation and interest in International Medical Electives has grown. However, it has been suggested that the benefits of these electives for students and communities may not outweigh the harms. Pre-departure training (PDT) has been proposed as a route through which participants can adequately prepare for their elective experience. Through a review of the current literature, this article explores the ethics of international medical electives using a social accountability framework and assesses the success of PDT in mitigating harms for students and communities. We find that the literature on PDT is limited. What is clear from completed studies is that the focus of PDT has often been centered on the clinical experience, while theories of development and health inequity remain minor topics. We argue that a greater benefit for students and communities could be gained from framing health inequity from a critical perspective, and integrating mandatory global health education into medical school curricula. We suggest that attention to only PDT is not enough. In a socially accountable program, community partnerships must be bilateral and respect communities as primary stakeholders in the training of students and in program evaluation. Unfortunately, research to-date has focused on the student experience; further studies of the community perspective would help to elicit how PDT and partnership models can be strengthened, improving the experiences of both students and communities. Finally, individual medical schools and organizations that offer global health elective experiences must ensure that they take responsibility for monitoring PDT.


Protein N-terminal methionine excision.
N-terminal methionine excision (NME) is the major proteolytic pathway responsible for the diversity of N-terminal amino acids in proteins. Dedicated NME components have been identified in all organisms, in all compartments in which protein synthesis occurs: cytoplasm, plastids and mitochondria. Recent studies have revealed that NME is regulated at various levels and plays an important role in controlling protein turnover. NME is essential in Eubacteria and lower eukaryotes and is the target of many natural and synthetic inhibitors. Such inhibitors have considerable potential for use in the treatment of various human diseases, from cancer to bacterial and parasitic infections.


Should health care providers be forced to apologise after things go wrong?
The issue of apologising to patients harmed by adverse events has been a subject of interest and debate within medicine, politics, and the law since the early 1980s. Although apology serves several important social roles, including recognising the victims of harm, providing an opportunity for redress, and repairing relationships, compelled apologies ring hollow and ultimately undermine these goals. Apologies that stem from external authorities' edicts rather than an offender's own self-criticism and moral reflection are inauthentic and contribute to a "moral flabbiness" that stunts the moral development of both individual providers and the medical profession. Following a discussion of a recent case from New Zealand in which a midwife was required to apologise not only to the parents but also to the baby, it is argued that rather than requiring health care providers to apologise, authorities should instead train, foster, and support the capacity of providers to apologise voluntarily.


Climatic predictors of the intra- and inter-annual distributions of plague cases in New Mexico based on 29 years of animal-based surveillance data.
Within the United States, the majority of human plague cases are reported from New Mexico. We describe climatic factors involved in intra- and inter-annual plague dynamics using animal-based surveillance data from that state. Unlike the clear seasonal pattern observed at lower elevations, cases occur randomly throughout the year at higher elevations. Increasing elevation corresponded with delayed mean time in case presentation. Using local meteorological data (previous year mean annual precipitation, total degrees over 27 degrees C 3 years before and maximum winter temperatures 4 years before) we built a time-series model predicting annual case load that explained 75% of the variance in pet cases between years. Moreover, we found a significant correlation with observed annual human cases and predicted pet cases. Because covariates were time-lagged by at least 1 year, intensity of case loads can be predicted in advance of a plague season. Understanding associations between environmental and meteorological factors can be useful for anticipating future disease trends.