Why um helps auditory word recognition: the temporal delay hypothesis.
Several studies suggest that speech understanding can sometimes benefit from the presence of filled pauses (uh, um, and the like), and that words following such filled pauses are recognised more quickly. Three experiments examined whether this is because filled pauses serve to delay the onset of upcoming words and these delays facilitate auditory word recognition, or whether the fillers themselves serve to signal upcoming delays in a way which informs listeners' reactions. Participants viewed pairs of images on a computer screen, and followed recorded instructions to press buttons corresponding to either an easy (unmanipulated, with a high-frequency name) or a difficult (visually blurred, low-frequency) image. In all three experiments, participants were faster to respond to easy images. In 50% of trials in each experiment, the name of the image was directly preceded by a delay; in the remaining trials an equivalent delay was included earlier in the instruction. Participants were quicker to respond when a name was directly preceded by a delay, regardless of whether this delay was filled with a spoken um, was silent, or contained an artificial tone. This effect did not interact with the effect of image difficulty, nor did it change over the course of each experiment. Taken together, our consistent finding that delays of any kind help word recognition indicates that natural delays such as fillers need not be seen as 'signals' to explain the benefits they have to listeners' ability to recognise and respond to the words which follow them.


Clinical application of an acellular biologic scaffold for surgical repair of a large, traumatic quadriceps femoris muscle defect.
Many battlefield injuries involve penetrating soft tissue trauma often accompanied by skeletal muscle defects, known as volumetric muscle loss. This article presents the first known case of a surgical technique involving an innovative tissue engineering approach for the repair of a large volumetric muscle loss. A 19-year-old Marine presented with large volumentric muscle loss of the right thigh as a result of an explosion. The patient reported muscle weakness with right knee extension, secondary to volumentric muscle loss, primarily involving the vastus medialis muscle. This persisted 3 years postinjury, despite extensive physical therapy. With all existing management options exhausted, restoration of a portion of the lost vastus medialis muscle was attempted by surgical implantation of a multi-layered scaffold composed of extracellular matrix derived from porcine intestinal submucossa. The patient had no complications, was discharged home on postoperative day 5, and resumed physical therapy after 4 weeks. Four months postoperatively, the patient demonstrated marked gains in isokinetic performance. Computer tomography indicated new tissue at the implant site. This approach offers a treatment option to a heretofore untreatable injury and will allow us to improve future surgical treatments for volumetric muscle loss.


Dynamics and feedback loops in the transforming growth factor β signaling pathway.
Transforming growth factor β (TGF-β) ligands activate a signaling cascade with multiple cell context dependent outcomes. Disruption or disturbance leads to variant clinical disorders. To develop strategies for disease intervention, delineation of the pathway in further detail is required. Current theoretical models of this pathway describe production and degradation of signal mediating proteins and signal transduction from the cell surface into the nucleus, whereas feedback loops have not exhaustively been included. In this study we present a mathematical model to determine the relevance of feedback regulators (Arkadia, Smad7, Smurf1, Smurf2, SnoN and Ski) on TGF-β target gene expression and the potential to initiate stable oscillations within a realistic parameter space. We employed massive sampling of the parameters space to pinpoint crucial players for potential oscillations as well as transcriptional product levels. We identified Smad7 and Smurf2 with the highest impact on the dynamics. Based on these findings, we conducted preliminary time course experiments.


An unusual case of refractory wheeze.
A 37-year-old man presented with a history of episodic wheeze and breathlessness of 3 years' duration refractory to treatment. Physical examination revealed diffuse expiratory polyphonic rhonchi while the remainder of the examination including the cardiac examination was reported as normal. Pulmonary function testing revealed mild obstruction with bronchodilator reversibility. The patient was discharged on a 6-month course of antitubercular treatment (ATT) as bronchial brush cytology (obtained via bronchoscopy) was positive for acid-fast bacilli. The patient presented after completing 6 months of ATT with persistent symptoms, a loud S1 and a mid-diastolic murmur at the apex. High-resolution CT of the chest showed bilateral dependent ground glass opacities. An echocardiogram revealed a left atrial myxoma, and normal RV size and pressures. The patient underwent successful surgical removal of the same, and made a complete recovery. Refractory wheeze is a very unusual presentation of a left atrial myxoma.


Plastic Surgery in the Time of COVID-19.
The novel coronavirus disease 2019 (COVID-19) has swept the world in the last several months, causing massive disruption to existing social, economic, and health care systems. As with all medical fields, plastic and reconstructive surgery has been profoundly impacted across the entire spectrum of practice from academic medical centers to solo private practice. The decision to preserve vital life-saving equipment and cancel elective procedures to protect patients and medical staff has been extremely challenging on multiple levels. Frequent and inconsistent messaging disseminated by many voices on the national stage often conflicts and serves only to exacerbate an already difficult decision-making process. A survey of relevant COVID-19 literature is presented, and bioethical principles are utilized to generate guidelines for plastic surgeons in patient care through this pandemic. A cohesive framework based upon core bioethical values is presented here to assist plastic surgeons in navigating this rapidly evolving global pandemic. Plastic surgeons around the world have been affected by COVID-19 and will adapt to continue serving their patients. The lessons learned in this present pandemic will undoubtedly prove useful in future challenges to come.


Local synteny and codon usage contribute to asymmetric sequence divergence of Saccharomyces cerevisiae gene duplicates.
Duplicated genes frequently experience asymmetric rates of sequence evolution. Relaxed selective constraints and positive selection have both been invoked to explain the observation that one paralog within a gene-duplicate pair exhibits an accelerated rate of sequence evolution. In the majority of studies where asymmetric divergence has been established, there is no indication as to which gene copy, ancestral or derived, is evolving more rapidly. In this study we investigated the effect of local synteny (gene-neighborhood conservation) and codon usage on the sequence evolution of gene duplicates in the S. cerevisiae genome. We further distinguish the gene duplicates into those that originated from a whole-genome duplication (WGD) event (ohnologs) versus small-scale duplications (SSD) to determine if there exist any differences in their patterns of sequence evolution. For SSD pairs, the derived copy evolves faster than the ancestral copy. However, there is no relationship between rate asymmetry and synteny conservation (ancestral-like versus derived-like) in ohnologs. mRNA abundance and optimal codon usage as measured by the CAI is lower in the derived SSD copies relative to ancestral paralogs. Moreover, in the case of ohnologs, the faster-evolving copy has lower CAI and lowered expression. Together, these results suggest that relaxation of selection for codon usage and gene expression contribute to rate asymmetry in the evolution of duplicated genes and that in SSD pairs, the relaxation of selection stems from the loss of ancestral regulatory information in the derived copy.


Incidence and Determinants of Intraocular Lens Implantation in Type 2 Diabetes: The Fremantle Diabetes Study Phase II.
To compare the incidence of intraocular lens (IOL) implantation for cataracts between people with and without type 2 diabetes and to determine associated risk factors in those with type 2 diabetes. Participants with type 2 diabetes (n = 1,499) from the community-based observational Fremantle Diabetes Study Phase II (FDS2) were age, sex, and zip code matched 1:4 with residents without diabetes. IOL implantation status was ascertained between entry (2008-2011) and the end of 2016 using validated data linkage. Age-specific incidence rates and incidence rate ratios (IRRs) for cataract surgery were calculated. Predictors of IOL implantation in FDS2 participants were assessed using proportional hazards and competing risk regression modeling. The crude IRR (95% CI) for cataract surgery in FDS2 participants (mean ± SD age 62.8 ± 10.8 years at entry) versus the matched group without diabetes was 1.50 (1.32-1.71), with the highest relative risk in those aged 45-54 years at the time of surgery (7.12 [2.05-27.66]). Competing risk analysis showed that age at entry, diabetes duration, serum HDL cholesterol, serum triglycerides, a severe hypoglycemic episode in the past year, and Asian and southern European ethnicity increased the risk of cataract surgery in participants with type 2 diabetes (P ≤ 0.025). People with type 2 diabetes, especially those in younger age-groups, are at a significantly increased risk of cataract surgery than matched people without diabetes. Multifaceted prevention strategies should be incorporated as part of routine care. As well as limiting ultraviolet light exposure, these might include lipid-modifying treatment and strategies to avoid severe hypoglycemia.


Soil zinc, serum zinc, and the potential for agronomic biofortification to reduce human zinc deficiency in Ethiopia.
Human zinc deficiency is a global public health problem. Many African soils are zinc deficient (ZnD), indicating fertilizers could increase crop yields and grain Zn levels, thereby increasing Zn in the food supply and alleviating human Zn deficiency. To analyze associations among soil Zn, human Zn deficiency, and child nutritional status, we combined the Ethiopian soil Zn map and the Ethiopian National Micronutrient Survey (ENMS). ENMS provides representative, georeferenced data on child nutritional status using anthropometry of children under five years old (CU5) and on human Zn deficiency among CU5 and women of reproductive age (WRA) using the recommended biomarker, serum Zn. ZnD soils mostly occur in lower altitudes, which are less populated and outside the main crop-producing areas. Serum Zn deficiencies were high, and correlated to soil Zn for children, but not for WRA. About 4 million Ethiopian CU5 are ZnD, and, of these, about 1.5 million live on low-Zn soils (< 2.5 mg/kg), while 0.3 million live on ZnD soils (< 1.5 mg/kg). Therefore, if Zn fertilizers are only applied on ZnD soils, their impact on child Zn deficiency may be limited. Greater impact is possible if Zn fertilizers are applied to soils with sufficient Zn for plant growth and if this results in increased grain Zn. Optimal soil Zn levels for plant and human nutrition may be different, and context-specific optimal levels for the latter must be determined to develop nutrition-sensitive fertilizer policies and recommendations.


A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis.
Recent clinical studies reveal that selective agonists of group II metabotropic glutamate (mGlu) receptors have robust efficacy in treating positive and negative symptoms in patients with schizophrenia. Group II mGlu receptor agonists also modulate the in vivo activity of psychotomimetic drugs and reduce the ability of psychotomimetic hallucinogens to increase glutamatergic transmission. Because increased excitation of the medial prefrontal cortex (mPFC) has been implicated in pathophysiology of schizophrenia, the ability of group II mGlu receptor agonists to reduce hallucinogenic drug action in this region is believed to be directly related to their antipsychotic efficacy. A novel class of ligands, termed positive allosteric modulators, has recently been identified, displaying exceptional mGlu2 receptor selectivity. These compounds do not activate mGlu2 receptors directly but potentiate the ability of glutamate and other agonists to activate this receptor. We now report that the mGlu2 receptor-selective positive allosteric modulator biphenyl-indanone A (BINA) modulates excitatory neurotransmission in the mPFC and attenuates the in vivo actions of the hallucinogenic 5-HT(2A/2C) receptor agonist (-)2,5-dimethoxy-4-bromoamphetamine [(-)DOB]. BINA attenuates serotonin-induced increases in spontaneous excitatory postsynaptic currents in the mPFC, mimicking the effect of the mGlu2/3 receptor agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV). In addition, BINA reduced (-)DOB-induced head twitch behavior and Fos expression in mPFC, effects reversed by pretreatment with the mGlu2/3 receptor antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl) -3 - (xanth-9-yl-)propionic acid (LY341495). These data confirm the relevance of excitatory signaling in the mPFC to the behavioral actions of hallucinogens and further support the targeting of mGlu2 receptors as a novel strategy for treating glutamatergic dysfunction in schizophrenia.


Down-regulation of HLA-A and HLA-Bw6, but not HLA-Bw4, allospecificities in leukemic cells: an escape mechanism from CTL and NK attack?
Human leukocyte antigen (HLA) class I antigen defects may have a negative impact on the growing application of T-cell-based immunotherapeutic strategies for treatment of leukemia. Therefore in the present study, taking advantage of a large panel of HLA class I allele-specific human monoclonal antibodies, we have compared HLA class I antigen expression on leukemic cells with that on autologous and allogeneic normal cells. Down-regulation of HLA-A and/or -B allospecificities was present in the majority of the patients studied. However, down-regulation did not affect all HLA class I alleles uniformly, but was almost exclusively restricted to HLA-A allospecificities and to HLA-B allospecificities which belong to the HLA-Bw6 group. The latter allospecificities, at variance from those that belong to the HLA-Bw4 group, do not modulate the interactions of leukemic cells with natural killer (NK) cells. Therefore, our results suggest that the selective down-regulation of HLA-A and HLA-Bw6 allospecificities associated with HLA-Bw4 preservation provides leukemic cells with an escape mechanism not only from cytotoxic T lymphocytes (CTLs), but also from NK cells. As a result T-cell-based immunotherapeutic strategies for leukemia should utilize HLA-Bw4 alloantigens as restricting elements since a selective HLA-Bw4 allele loss would provide leukemic cells with an escape mechanism from CTLs, but would increase their susceptibility to NK cell-mediated lysis.


Mutations in the nuclear localization sequence of the Aristaless related homeobox; sequestration of mutant ARX with IPO13 disrupts normal subcellular distribution of the transcription factor and retards cell division.
Aristaless related homeobox (ARX) is a paired-type homeobox gene. ARX function is frequently affected by naturally occurring mutations. Nonsense mutations, polyalanine tract expansions and missense mutations in ARX cause a range of intellectual disability and epilepsy phenotypes with or without additional features including hand dystonia, lissencephaly, autism or dysarthria. Severe malformation phenotypes, such as X-linked lissencephaly with ambiguous genitalia (XLAG), are frequently observed in individuals with protein truncating or missense mutations clustered in the highly conserved paired-type homeodomain. We have identified two novel point mutations in the R379 residue of the ARX homeodomain; c.1135C>A, p.R379S in a patient with infantile spasms and intellectual disability and c.1136G>T, p.R379L in a patient with XLAG. We investigated these and other missense mutations (R332P, R332H, R332C, T333N: associated with XLAG and Proud syndrome) predicted to affect the nuclear localisation sequences (NLS) flanking either end of the ARX homeodomain. The NLS regions are required for correct nuclear import facilitated by Importin 13 (IPO13). We demonstrate that missense mutations in either the N- or C-terminal NLS regions of the homeodomain cause significant disruption to nuclear localisation of the ARX protein in vitro. Surprisingly, none of these mutations abolished the binding of ARX to IPO13. This was confirmed by co-immunoprecipitation and immmuno fluorescence studies. Instead, tagged and endogenous IPO13 remained bound to the mutant ARX proteins, even in the RanGTP rich nuclear environment. We also identify the microtubule protein TUBA1A as a novel interacting protein for ARX and show cells expressing mutant ARX protein accumulate in mitosis, indicating normal cell division may be disrupted. We show that the most likely, common pathogenic mechanism of the missense mutations in NLS regions of the ARX homeodomain is inadequate accumulation and distribution of the ARX transcription factor within the nucleus due to sequestration of ARX with IPO13.


Deletion of the SNARE vti1b in mice results in the loss of a single SNARE partner, syntaxin 8.
SNARE proteins participate in recognition and fusion of membranes. A SNARE complex consisting of vti1b, syntaxin 8, syntaxin 7, and endobrevin/VAMP-8 which is required for fusion of late endosomes in vitro has been identified recently. Here, we generated mice deficient in vti1b to study the function of this protein in vivo. vti1b-deficient mice had reduced amounts of syntaxin 8 due to degradation of the syntaxin 8 protein, while the amounts of syntaxin 7 and endobrevin did not change. These data indicate that vti1b is specifically required for the stability of a single SNARE partner. vti1b-deficient mice were viable and fertile. Most vti1b-deficient mice were indistinguishable from wild-type mice and did not display defects in transport to the lysosome. However, 20% of the vti1b-deficient mice were smaller. Lysosomal degradation of an endocytosed protein was slightly delayed in hepatocytes derived from these mice. Multivesicular bodies and autophagic vacuoles accumulated in hepatocytes of some smaller vti1b-deficient mice. This suggests that other SNAREs can compensate for the reduction in syntaxin 8 and for the loss of vti1b in most mice even though vti1b shows only 30% amino acid identity with its closest relative.


Robotic systems in orthopaedic surgery.
Robots have been used in surgery since the late 1980s. Orthopaedic surgery began to incorporate robotic technology in 1992, with the introduction of ROBODOC, for the planning and performance of total hip replacement. The use of robotic systems has subsequently increased, with promising short-term radiological outcomes when compared with traditional orthopaedic procedures. Robotic systems can be classified into two categories: autonomous and haptic (or surgeon-guided). Passive surgery systems, which represent a third type of technology, have also been adopted recently by orthopaedic surgeons. While autonomous systems have fallen out of favour, tactile systems with technological improvements have become widely used. Specifically, the use of tactile and passive robotic systems in unicompartmental knee replacement (UKR) has addressed some of the historical mechanisms of failure of non-robotic UKR. These systems assist with increasing the accuracy of the alignment of the components and produce more consistent ligament balance. Short-term improvements in clinical and radiological outcomes have increased the popularity of robot-assisted UKR. Robot-assisted orthopaedic surgery has the potential for improving surgical outcomes. We discuss the different types of robotic systems available for use in orthopaedics and consider the indication, contraindications and limitations of these technologies.


ASCIA guidelines for prevention of anaphylaxis in schools, pre-schools and childcare: 2015 update.
The aim of these guidelines is to assist staff in school and childcare settings to plan and implement appropriate risk minimisation strategies, taking into consideration the needs of the allergic child, the likely effectiveness of measures and the practicality of implementation. Although these guidelines include risk minimisation strategies for allergic reactions to insect stings or bites, latex and medication, the major focus relates to food allergy. This is due to the higher relative prevalence of food allergy in childhood (compared with other allergic triggers) and the higher likelihood of accidental exposure in these settings. Care of the allergic child in the school, pre-school or childcare settings requires accurate information obtained from parents and carers, staff training in the recognition and management of acute allergic reactions, planning for unexpected reactions (including in those not previously identified as being at risk), age appropriate education of children with severe allergies and their peers, and implementation of practical strategies to reduce the risk of accidental exposure to known allergic triggers. Strategy development also needs to take into account local or regional established legislative or procedural guidelines and the possibility that the first episode of anaphylaxis may occur outside the home. Food bans are not recommended as the primary risk minimisation strategy due to difficulties in implementation and lack of proven effectiveness.


Precise detection of rearrangement breakpoints in mammalian chromosomes.
Genomes undergo large structural changes that alter their organisation. The chromosomal regions affected by these rearrangements are called breakpoints, while those which have not been rearranged are called synteny blocks. We developed a method to precisely delimit rearrangement breakpoints on a genome by comparison with the genome of a related species. Contrary to current methods which search for synteny blocks and simply return what remains in the genome as breakpoints, we propose to go further and to investigate the breakpoints themselves in order to refine them. Given some reliable and non overlapping synteny blocks, the core of the method consists in refining the regions that are not contained in them. By aligning each breakpoint sequence against its specific orthologous sequences in the other species, we can look for weak similarities inside the breakpoint, thus extending the synteny blocks and narrowing the breakpoints. The identification of the narrowed breakpoints relies on a segmentation algorithm and is statistically assessed. Since this method requires as input synteny blocks with some properties which, though they appear natural, are not verified by current methods for detecting such blocks, we further give a formal definition and provide an algorithm to compute them. The whole method is applied to delimit breakpoints on the human genome when compared to the mouse and dog genomes. Among the 355 human-mouse and 240 human-dog breakpoints, 168 and 146 respectively span less than 50 Kb. We compared the resulting breakpoints with some publicly available ones and show that we achieve a better resolution. Furthermore, we suggest that breakpoints are rarely reduced to a point, and instead consist in often large regions that can be distinguished from the sequences around in terms of segmental duplications, similarity with related species, and transposable elements. Our method leads to smaller breakpoints than already published ones and allows for a better description of their internal structure. In the majority of cases, our refined regions of breakpoint exhibit specific biological properties (no similarity, presence of segmental duplications and of transposable elements). We hope that this new result may provide some insight into the mechanism and evolutionary properties of chromosomal rearrangements.


The emerging world of synthetic genetics.
For over 20 years, laboratories around the world have been applying the principles of Darwinian evolution to isolate DNA and RNA molecules with specific ligand-binding or catalytic activities. This area of synthetic biology, commonly referred to as in vitro genetics, is made possible by the availability of natural polymerases that can replicate genetic information in the laboratory. Moving beyond natural nucleic acids requires organic chemistry to synthesize unnatural analogues and polymerase engineering to create enzymes that recognize artificial substrates. Progress in both of these areas has led to the emerging field of synthetic genetics, which explores the structural and functional properties of synthetic genetic polymers by in vitro evolution. This review examines recent advances in the Darwinian evolution of artificial genetic polymers and their potential downstream applications in exobiology, molecular medicine, and synthetic biology.


Age patterns of severe paediatric malaria and their relationship to Plasmodium falciparum transmission intensity.
The understanding of the epidemiology of severe malaria in African children remains incomplete across the spectrum of Plasmodium falciparum transmission intensities through which communities might expect to transition, as intervention coverage expands. Paediatric admission data were assembled from 13 hospitals serving 17 communities between 1990 and 2007. Estimates of Plasmodium falciparum transmission intensity in these communities were assembled to be spatially and temporally congruent to the clinical admission data. The analysis focused on the relationships between community derived parasite prevalence and the age and clinical presentation of paediatric malaria in children aged 0-9 years admitted to hospital. As transmission intensity declined a greater proportion of malaria admissions were in older children. There was a strong linear relationship between increasing transmission intensity and the proportion of paediatric malaria admissions that were infants (R2 = 0.73, p < 0.001). Cerebral malaria was reported among 4% and severe malaria anaemia among 17% of all malaria admissions. At higher transmission intensity cerebral malaria was a less common presentation compared to lower transmission sites. There was no obvious relationship between the proportions of children with severe malaria anaemia and transmission intensity. As the intensity of malaria transmission declines in Africa through the scaling up of insecticide-treated nets and other vector control measures a focus of disease prevention among very young children becomes less appropriate. The understanding of the relationship between parasite exposure and patterns of disease risk should be used to adapt malaria control strategies in different epidemiological settings.


Positive fluorescent selection permits precise, rapid, and in-depth overexpression analysis in plant protoplasts.
Transient genetic modification of plant protoplasts is a straightforward and rapid technique for the study of numerous aspects of plant biology. Recent studies in metazoan systems have utilized cell-based assays to interrogate signal transduction pathways using high-throughput methods. Plant biologists could benefit from new tools that expand the use of cell culture for large-scale analysis of gene function. We have developed a system that employs fluorescent positive selection in combination with flow cytometric analysis and fluorescence-activated cell sorting to isolate responses in the transformed protoplasts exclusively. The system overcomes the drawback that transfected protoplast suspensions are often a heterogeneous mix of cells that have and have not been successfully transformed. This Gateway-compatible system enables high-throughput screening of genetic circuitry using overexpression. The incorporation of a red fluorescent protein selection marker enables combined utilization with widely available green fluorescent protein (GFP) tools. For instance, such a dual labeling approach allows cytometric analysis of GFP reporter gene activation expressly in the transformed cells or fluorescence-activated cell sorting-mediated isolation and downstream examination of overexpression effects in a specific GFP-marked cell population. Here, as an example, novel uses of this system are applied to the study of auxin signaling, exploiting the red fluorescent protein/GFP dual labeling capability. In response to manipulation of the auxin response network through overexpression of dominant negative auxin signaling components, we quantify effects on auxin-responsive DR5::GFP reporter gene activation as well as profile genome-wide transcriptional changes specifically in cells expressing a root epidermal marker.


Floral volatiles, pollinator sharing and diversification in the fig-wasp mutualism: insights from Ficus natalensis, and its two wasp pollinators (South Africa).
Combining biogeographic, ecological, morphological, molecular and chemical data, we document departure from strict specialization in the fig-pollinating wasp mutualism. We show that the pollinating wasps Elisabethiella stuckenbergi and Elisabethiella socotrensis form a species complex of five lineages in East and Southern Africa. Up to two morphologically distinct lineages were found to co-occur locally in the southern African region. Wasps belonging to a single lineage were frequently the main regional pollinators of several Ficus species. In South Africa, two sister lineages, E. stuckenbergi and E. socotrensis, pollinate Ficus natalensis but only E. stuckenbergi also regularly pollinates Ficus burkei. The two wasp species co-occur in individual trees of F. natalensis throughout KwaZulu-Natal. Floral volatile blends emitted by F. natalensis in KwaZulu-Natal were similar to those emitted by F. burkei and different from those produced by other African Ficus species. The fig odour similarity suggests evolutionary convergence to attract particular wasp species. The observed pattern may result from selection for pollinator sharing among Ficus species. Such a process, with one wasp species regionally pollinating several hosts, but several wasp species pollinating a given Ficus species across its geographical range could play an important role in the evolutionary dynamics of the Ficus-pollinating wasp association.


Perioperative outcomes after adrenalectomy for malignant neoplasm in laparoscopic era: a multicenter retrospective study.
This study aims to review perioperative outcomes of adrenalectomy for malignant neoplasm performed by open or laparoscopic technique and comparing them with benign diseases. This study is a multicenter, retrospective analysis utilizing a large administrative database. The University Health System Consortium is an alliance of over 100 academic medical centers and 250 affiliate hospitals. The University Health System Consortium database was accessed using International Classification of Diseases codes. A total of 6157 patients underwent adrenalectomy between January 2008 and June 2011. Of these, 5101 patients underwent open adrenalectomy (OA) and 1056 underwent adrenalectomy by laparoscopic technique (LA). Comparison between LA and OA showed lower morbidity (4.8% vs. 7.2%, P=0.0007), hospital length of stay (d) (3.23±5.66 vs. 4.35±6.59, P<0.0001), ICU admission rate (18.19% vs. 23.75%, P<0.0001), and cost ($) (9250±14306 vs. 11634±16547, P<0.0001) for LA, with no statistical difference in observed mortality or 30-day readmission rate. We then compared open and laparoscopic procedures performed for benign and malignant diagnoses. Overall, LA had better outcomes than OA. When comparisons were made between LA and OA for benign adrenal diseases, all outcomes were significantly better in the laparoscopic group. There were, however, no statistical differences when LA was compared with OA for malignant diagnoses.


Increasing extraocular muscle strength with insulin-like growth factor II.
Botulinum toxin type A and, more recently, the immunotoxin ricin-mAb35 have been effective as means of pharmacologically weakening the extraocular muscle. However, currently there are no drug treatments to strengthen an underacting extraocular muscle. In limb muscle, treatment with insulin-like growth factor causes myofiber hypertrophy. In this study, the short-term effects of insulin-like growth factor II (IGF-II) on extraocular muscle morphometry and force generation were examined. One superior rectus muscle in normal adult rabbits received a single injection of 10 micro g IGF-II, and the contralateral muscle received an injection of saline only. One week after injection, muscle morphology and muscle force were compared between the IGF-treated and control muscles. In the treated muscle, there was no significant change in the mean cross-sectional area of myofibers compared with the control. However, there was an increase in the heterogeneity of myofiber cross-sectional area, with increases in both small and very large myofibers. Mean single-twitch force generation was 0.48 +/- 0.12 mN/cm(3) compared with 0.27 +/- 0.04 mN/cm(3) (P = 0.0473) in control samples. Mean tetanic force generation was increased significantly at all stimulation frequencies. Treatment had no effect on muscle fatigability. Extraocular muscle is very responsive to direct injection of IGF-II. Although no difference was seen in mean myofiber cross-sectional area, overall there was sufficient alteration in myofiber heterogeneity to result in increased force generation. If a sustained treatment effect can be achieved with IGF-II and, potentially, other growth factors, the pharmacological treatment of strabismus could be advanced by simultaneous injection of agonist-antagonist pairs with agents that weaken and strengthen the treated extraocular muscle.


Localized frustration and binding-induced conformational change in recognition of 5S RNA by TFIIIA zinc finger.
Protein TFIIIA is composed of nine tandemly arranged Cys2His2 zinc fingers. It can bind either to the 5S RNA gene as a transcription factor or to the 5S RNA transcript as a chaperone. Although structural and biochemical data provided valuable information on the recognition between the TFIIIIA and the 5S DNA/RNA, the involved conformational motions and energetic factors contributing to the binding affinity and specificity remain unclear. In this work, we conducted MD simulations and MM/GBSA calculations to investigate the binding-induced conformational changes in the recognition of the 5S RNA by the central three zinc fingers of TFIIIA and the energetic factors that influence the binding affinity and specificity at an atomistic level. Our results revealed drastic interdomain conformational changes between these three zinc fingers, involving the exposure/burial of several crucial DNA/RNA binding residues, which can be related to the competition between DNA and RNA for the binding of TFIIIA. We also showed that the specific recognition between finger 4/finger 6 and the 5S RNA introduces frustrations to the nonspecific interactions between finger 5 and the 5S RNA, which may be important to achieve optimal binding affinity and specificity.


Intravenous access in the prehospital settings: What can be learned from point-of-injury experience.
Intravenous (IV) access has an essential role in the care provided for trauma patients, allowing for transfusion of blood products, fluids, and drugs. Decisions should be made regarding the necessity of IV access while considering cost-benefit of the procedure in terms of delayed evacuation times. A retrospective review of all trauma patients in whom at least one attempt at IV access was performed were reviewed. Data were abstracted from the Israeli Defense Force Trauma Registry. Of 7,476 patients, 1,082 patients who had at least one documented attempt at IV access between January 1997 and April 2013 were included in this study. Overall cumulative success rate at IV access was 82%. Success rates for IV access were 86%, 68%, 63%, 50%, 20% for the first, second, third, fourth, and fifth attempts, respectively. The first and second attempts accounted for 96% of the successful procedures. Mortality in patients for whom IV access was successful was 13%; mortality in patients for whom IV access was not successful was 35%. The success rate of IV access declined with each subsequent attempt. There was minimal improvement of overall success rate seen after the second attempt. Our findings suggest that the inability to obtain peripheral venous access is associated with severe injuries. These finding support a policy of limiting the number of venous access attempts to two attempts, followed by a reevaluation of need for parenteral access. Improved training of combat medics and paramedics might marginally increase the success rates of IV access. Point-of-injury data, used for ongoing learning and research, form the ground for improving combat casualty care and thus help saving lives. Therapeutic study, level IV.


Approximated and User Steerable tSNE for Progressive Visual Analytics.
Progressive Visual Analytics aims at improving the interactivity in existing analytics techniques by means of visualization as well as interaction with intermediate results. One key method for data analysis is dimensionality reduction, for example, to produce 2D embeddings that can be visualized and analyzed efficiently. t-Distributed Stochastic Neighbor Embedding (tSNE) is a well-suited technique for the visualization of high-dimensional data. tSNE can create meaningful intermediate results but suffers from a slow initialization that constrains its application in Progressive Visual Analytics. We introduce a controllable tSNE approximation (A-tSNE), which trades off speed and accuracy, to enable interactive data exploration. We offer real-time visualization techniques, including a density-based solution and a Magic Lens to inspect the degree of approximation. With this feedback, the user can decide on local refinements and steer the approximation level during the analysis. We demonstrate our technique with several datasets, in a real-world research scenario and for the real-time analysis of high-dimensional streams to illustrate its effectiveness for interactive data analysis.


Reversible redox switching of magnetic order and electrical conductivity in a 2D manganese benzoquinoid framework.
Materials with switchable magnetic and electrical properties may enable future spintronic technologies, and thus hold the potential to revolutionize how information is processed and stored. While reversible switching of magnetic order or electrical conductivity has been independently realized in materials, the ability to simultaneously switch both properties in a single material presents a formidable challenge. Here, we report the 2D manganese benzoquinoid framework (Me4N)2[MnII2(L2-)3] (H2L = 2,5-dichloro-3,6-dihydroxo-1,4-benzoquinone), as synthesized via post-synthetic counterion exchange. This material is paramagnetic above 1.8 K and exhibits an ambient-temperature electrical conductivity of σ 295 K = 1.14(3) × 10-13 S cm-1 (E a = 0.74(3) eV). Upon soaking in a solution of sodium naphthalenide and 1,2-dihydroacenaphthylene, this compound undergoes a single-crystal-to-single-crystal (SC-SC) reduction to give Na3(Me4N)2[Mn2L3]. Structural and spectroscopic analyses confirm this reduction to be ligand-based, and as such the anionic framework is formulated as [MnII2(L3-˙)3]5-. Magnetic measurements confirm that this reduced material is a permanent magnet below T c = 41 K and exhibits a conductivity value of σ 295 K = 2.27(1) × 10-8 S cm-1 (E a = 0.489(8) eV), representing a remarkable 200 000-fold increase over the parent material. Finally, soaking the reduced compound in a solution of [Cp2Fe]+ affords Na(Me4N)[MnII2(L2-)3] via a SC-SC process, with magnetic and electrical properties similar to those observed for the original oxidized material. Taken together, these results highlight the ability of metal benzoquinoid frameworks to undergo reversible, simultaneous redox switching of magnetic order and electrical conductivity.


Correlation of apparent diffusion coefficient and fractional anisotropy values in the developing infant brain.
The purpose of our study was to correlate decrease in apparent diffusion coefficient (ADC) and increase in fractional anisotropy (FA) in various white matter (WM) regions using diffusion tenor imaging (DTI) within the first year of life. We performed DTI on 53 infants and measured FA and ADC within 10 WM regions important in brain development. For each region, we calculated the slope of ADC as a function of FA, the correlation coefficient (r) and correlation of determination (r(2)). We performed a group analysis of r values and r(2)values for six WM regions primarily composed of crossing fibers and four regions primarily having parallel fibers. Upon finding that a strong correlation of FA with age existed, we adjusted for age and calculated partial correlation coefficients. Slopes of FA versus ADC ranged from -1.00711 to -1.67592 (p < 0.05); r values ranged from -0.81 to -0.50 and r(2) values from 0.25 to 0.66. The four greatest r(2) values were within WM regions having large numbers of crossing fibers and the three lowest r(2) values were in regions having predominantly parallel fibers. After adjusting for age, slopes ranged from -1.08095 to 0.09612 (p < 0.05 in five cases); partial correlation coefficients ranged from -0.49 to 0.03 and r(2) values from 0.31 to 0.79. The highest partial correlation coefficients were then relatively equally distributed between the two types of WM regions. In various regions, FA and ADC evolved with differing degrees of correlation. We found a strong influence of age on the relationship between FA and ADC.


Social and structural factors associated with substance use within the support network of adults living in precarious housing in a socially marginalized neighborhood of Vancouver, Canada.
The structure of a social network as well as peer behaviours are thought to affect personal substance use. Where substance use may create health risks, understanding the contribution of social networks to substance use may be valuable for the design and implementation of harm reduction or other interventions. We examined the social support network of people living in precarious housing in a socially marginalized neighborhood of Vancouver, and analysed associations between social network structure, personal substance use, and supporters' substance use. An ongoing, longitudinal study recruited 246 participants from four single room occupancy hotels, with 201 providing social network information aligned with a 6-month observation period. Use of tobacco, alcohol, cannabis, cocaine (crack and powder), methamphetamine, and heroin was recorded at monthly visits. Ego- and graph-level measures were calculated; the dispersion and prevalence of substances in the network was described. Logistic mixed effects models were used to estimate the association between ego substance use and peer substance use. Permutation analysis was done to test for randomness of substance use dispersion on the social network. The network topology corresponded to residence (Hotel) with two clusters differing in demographic characteristics (Cluster 1 -Hotel A: 94% of members, Cluster 2 -Hotel B: 95% of members). Dispersion of substance use across the network demonstrated differences according to network topology and specific substance. Methamphetamine use (overall 12%) was almost entirely limited to Cluster 1, and absent from Cluster 2. Different patterns were observed for other substances. Overall, ego substance use did not differ over the six-month period of observation. Ego heroin, cannabis, or crack cocaine use was associated with alter use of the same substances. Ego methamphetamine, powder cocaine, or alcohol use was not associated with alter use, with the exception for methamphetamine in a densely using part of the network. For alters using multiple substances, cannabis use was associated with lower ego heroin use, and lower ego crack cocaine use. Permutation analysis also provided evidence that dispersion of substance use, and the association between ego and alter use was not random for all substances. In a socially marginalized neighborhood, social network topology was strongly influenced by residence, and in turn was associated with type(s) of substance use. Associations between personal use and supporter's use of a substance differed across substances. These complex associations may merit consideration in the design of interventions to reduce risk and harms associated with substance use in people living in precarious housing.


Computational modelling methods for assessing the risks from lead in drinking water.
Computational modelling methods have been used to predict the risks from lead in drinking water across a simulated supply zone, for a range of plumbosolvency conditions and a range of extents of occurrence of houses having a lead pipe, on the basis of five risk benchmarking methods. For the worst case modelled (very high plumbosolvency and 90% houses with a lead pipe) the percentage of houses at risk in the simulated zone ranged from 34.1 to 73.3%. In contrast, for a simulated phosphate-treated zone and 10% houses with a lead pipe, the percentage of houses at risk in the simulated zone ranged from 0 to 0.4%. Methods are proposed for using computational modelling for different levels of risk assessment, for both water supply zones and individual houses. These risk assessment methods will inform policy, help to set improvement priorities and facilitate a better understanding of corrective options.


Cuticle structure of the scarab beetle Cetonia aurata analyzed by regression analysis of Mueller-matrix ellipsometric data.
Since one hundred years it is known that some scarab beetles reflect elliptically and near-circular polarized light as demonstrated by Michelson for the beetle Chrysina resplendens. The handedness of the polarization is in a majority of cases left-handed but also right-handed polarization has been found. In addition, brilliant colors with metallic shine are observed. The polarization and color effects are generated in the beetle exoskeleton, the so-called cuticle. The objective of this work is to demonstrate that structural parameters and materials optical functions of these photonic structures can be extracted by advanced modeling of spectral multi-angle Mueller-matrix data recorded from beetle cuticles. A dual-rotating compensator ellipsometer is used to record normalized Mueller-matrix data in the spectral range 400 - 800 nm at angles of incidence in the range 25-75°. Analysis of data measured on the scarab beetle Cetonia aurata are presented in detail. The model used in the analysis mimics a chiral nanostructure and is based on a twisted layered structure. Given the complexity of the nanostructure, an excellent fit between experimental and model data is achieved. The obtained model parameters are the spectral variation of the refractive indices of the cuticle layers and structural parameters of the chiral structure.


Evaluating the efficacy in improving facial photodamage with a mixture of topical antioxidants.
This study evaluates the efficacy and tolerability of an investigational study cream composed of 3 ingredients (green and white teas, mangosteen, and pomegranate extract), Vitaphenol Skin Cream (La Jolla Spa MD, La Jolla CA), as compared to a placebo cream in rejuvenating facial skin. Twenty healthy females between the ages of 35 and 65 with demonstrable facial wrinkling, achieving a Rao-Goldman wrinkle scale score of 2 or above, applied either Vitaphenol Skin Cream or placebo cream to a randomized half of their face twice daily for 60 days and returned for follow-up after 2 weeks. Twice as many subjects indicated an enhancement of skin texture (eg, reduction in pore size, roughness, and touch) with the usage of Vitaphenol versus placebo. In all, 41% of the study subjects preferred the half of their face that had been receiving Vitaphenol, while only 0.06% of the subjects favored the placebo side. PRIMOS images from periorbital skin treated with Vitaphenol demonstrated an average improvement in skin smoothness of 1 mm3, whereas skin treated with placebo showed an average decrease in smoothness or an increase in skin roughness of 0.9 mm3. The addition of 3 antioxidants, green and white teas, mangosteen, and pomegranate, have an additive effect to enhance the improvement of age-related changes in the skin.


Telephone and in-person cognitive behavioral therapy for major depression after traumatic brain injury: a randomized controlled trial.
Major depressive disorder (MDD) is prevalent after traumatic brain injury (TBI); however, there is a lack of evidence regarding effective treatment approaches. We conducted a choice-stratified randomized controlled trial in 100 adults with MDD within 10 years of complicated mild to severe TBI to test the effectiveness of brief cognitive behavioral therapy administered over the telephone (CBT-T) (n = 40) or in-person (CBT-IP) (n = 18), compared with usual care (UC) (n = 42). Participants were recruited from clinical and community settings throughout the United States. The main outcomes were change in depression severity on the clinician-rated 17 item Hamilton Depression Rating Scale (HAMD-17) and the patient-reported Symptom Checklist-20 (SCL-20) over 16 weeks. There was no significant difference between the combined CBT and UC groups over 16 weeks on the HAMD-17 (treatment effect = 1.2, 95% CI: -1.5-4.0; p = 0.37) and a nonsignificant trend favoring CBT on the SCL-20 (treatment effect = 0.28, 95% CI: -0.03-0.59; p = 0.074). In follow-up comparisons, the CBT-T group had significantly more improvement on the SCL-20 than the UC group (treatment effect = 0.36, 95% CI: 0.01-0.70; p = 0.043) and completers of eight or more CBT sessions had significantly improved SCL-20 scores compared with the UC group (treatment effect = 0.43, 95% CI: 0.10-0.76; p = 0.011). CBT participants reported significantly more symptom improvement (p = 0.010) and greater satisfaction with depression care (p < 0.001), than did the UC group. In-person and telephone-administered CBT are acceptable and feasible in persons with TBI. Although further research is warranted, telephone CBT holds particular promise for enhancing access and adherence to effective depression treatment.


Cathepsin g Degrades Both Glycosylated and Unglycosylated Regions of Lubricin, a Synovial Mucin.
Lubricin (PRG4) is a mucin type protein that plays an important role in maintaining normal joint function by providing lubrication and chondroprotection. Improper lubricin modification and degradation has been observed in idiopathic osteoarthritis (OA), while the detailed mechanism still remains unknown. We hypothesized that the protease cathepsin G (CG) may participate in degrading lubricin in synovial fluid (SF). The presence of endogenous CG in SF was confirmed in 16 patients with knee OA. Recombinant human lubricin (rhPRG4) and native lubricin purified from the SF of patients were incubated with exogenous CG and lubricin degradation was monitored using western blot, staining by Coomassie or Periodic Acid-Schiff base in gels, and with proteomics. Full length lubricin (∼300 kDa), was efficiently digested with CG generating a 25-kDa protein fragment, originating from the densely glycosylated mucin domain (∼250 kDa). The 25-kDa fragment was present in the SF from OA patients, and the amount was increased after incubation with CG. A CG digest of rhPRG4 revealed 135 peptides and 72 glycopeptides, and confirmed that the protease could cleave in all domains of lubricin, including the mucin domain. Our results suggest that synovial CG may take part in the degradation of lubricin, which could affect the pathological decrease of the lubrication in degenerative joint disease.


Transplantation tolerance-where do we stand?
Our understanding of tolerance mechanisms has progressed to the point that tolerance-induction protocols are being tested in humans for organ transplantation. However, a range of scientific, ethical, logistic and commercial issues have arisen, and must be resolved before tolerance induction for human allograft patients can become a reality.


RNA-Sequencing for profiling goat milk transcriptome in colostrum and mature milk.
In this work we aimed at sequencing and assembling the goat milk transcriptome corresponding at colostrum and 120 days of lactation. To reconstruct transcripts we used both the genome as reference, and a de novo assembly approach. Additionally, we aimed at identifying the differentially expressed genes (DEGs) between the two lactation stages and at analyzing the expression of genes involved in oligosaccharides metabolism. A total of 44,635 different transcripts, organized in 33,757 tentative genes, were obtained using the goat genome as reference. A significant sequence similarity match was found for 40,353 transcripts (90%) against the NCBI NT and for 35,701 (80%) against the NR databases. 68% and 69% of the de novo assembled transcripts, in colostrum and 120 days of lactation samples respectively, have a significant match with the merged transcriptome obtained using Cufflinks/Cuffmerge. CSN2, PAEP, CSN1S2, CSN3, LALBA, TPT1, FTH1, M-SAA3, SPP1, GLYCAM1, EEF1A1, CTSD, FASN, RPS29, CSN1S1, KRT19 and CHEK1 were found between the top fifteen highly expressed genes. 418 loci were differentially expressed between lactation stages, among which 207 and 122 were significantly up- and down-regulated in colostrum, respectively. Functional annotation and pathway enrichment analysis showed that in goat colostrum somatic cells predominate biological processes involved in glycolysis, carbohydrate metabolism, defense response, cytokine activity, regulation of cell proliferation and cell death, vasculature development, while in mature milk, biological process associated with positive regulation of lymphocyte activation and anatomical structure morphogenesis are enriched. The analysis of 144 different oligosaccharide metabolism-related genes showed that most of these (64%) were more expressed in colostrum than in mature milk, with eight expressed at very high levels (SLCA3, GMSD, NME2, SLC2A1, B4GALT1, B3GNT2, NANS, HEXB). To our knowledge, this is the first study comparing goat transcriptome of two lactation stages: colostrum and 120 days. Our findings suggest putative differences of expression between stages and can be envisioned as a base for further research in the topic. Moreover because a higher expression of genes involved in immune defense response, carbohydrate metabolism and related to oligosaccharide metabolism was identified in colostrum we here corroborate the potential of goat milk as a natural source of lactose-derived oligosaccharides and for the development of functional foods.


Intravenous ketamine for adult procedural sedation in the emergency department: a prospective cohort study.
To evaluate the use of intravenous ketamine for procedural sedation in adults attending the emergency department. A prospective study was performed over a 2-year period in 92 patients who received intravenous ketamine for procedural sedation in the emergency department of St Thomas' Hospital. All patients received 0.5-1.0 mg/kg ketamine intravenously for the procedure. Pulse rate, blood pressure oxygen saturations and incidence of adverse events (clonic movements, hypersalivation, laryngospasm, recovery agitation and vomiting) were recorded for all patients. Adequate sedation was obtained in 91 of the 92 patients (98.9%) and successful completion of the procedure was achieved in 91 patients (98.9%). Adverse events occurred in 20 patients (21.7%). Four patients (7%) developed clonic movements, none of which required treatment. Twelve patients (13.0%) developed recovery agitation. In five cases the agitation was transient and required no treatment; the other seven patients were treated with intravenous midazolam. One of the patients who experienced recovery agitation also developed vomiting. Two other patients vomited, and one patient had vomiting and hypersalivation. One further patient developed hypersalivation. There were no reported episodes of laryngospasm. Ketamine is an effective agent for procedural sedation in the emergency department. There were no serious adverse events associated with its use, but there is a significant incidence of recovery agitation which may require treatment with a benzodiazepine.


Automatic detection and classification of hypodense hepatic lesions on contrast-enhanced venous-phase CT.
The objective of this work was to develop and validate algorithms for detection and classification of hypodense hepatic lesions, specifically cysts, hemangiomas, and metastases from CT scans in the portal venous phase of enhancement. Fifty-six CT sections from 51 patients were used as representative of common hypodense liver lesions, including 22 simple cysts, 11 hemangiomas, 22 metastases, and 1 image containing both a cyst and a hemangioma. The detection algorithm uses intensity-based histogram methods to find central lesions, followed by liver contour refinement to identify peripheral lesions. The classification algorithm operates on the focal lesions identified during detection, and includes shape-based segmentation, edge pixel weighting, and lesion texture filtering. Support vector machines are then used to perform a pair-wise lesion classification. For the detection algorithm, 80% lesion sensitivity was achieved at approximately 0.3 false positives (FP) per slice for central lesions, and 0.5 FP per slice for peripheral lesions, giving a total of 0.8 FP per section. For 90% sensitivity, the total number of FP rises to about 2.2 per section. The pair-wise classification yielded good discrimination between cysts and metastases (at 95% sensitivity for detection of metastases, only about 5% of cysts are incorrectly classified as metastases), perfect discrimination between hemangiomas and cysts, and was least accurate in discriminating between hemangiomas and metastases (at 90% sensitivity for detection of hemangiomas, about 28% of metastases were incorrectly classified as hemangiomas). Initial implementations of our algorithms are promising for automating liver lesion detection and classification.


T cell subsets in the immune rejection of murine heterotopic corneal allografts.
Using a previously described murine heterotopic corneal allograft model, we examined the roles of delayed-type hypersensitivity (DTH) and cytotoxic T lymphocytes (CTL) in corneal allograft rejection. We have previously shown that normal C57BL/6 mice consistently reject heterotopic corneal allografts within 14 days of grafting. These hosts develop antigen-specific CTL responses but no evidence of DTH reactivity. The absence of DTH suggested that this T cell subset was unnecessary for corneal allograft rejection. The present studies using T cell-deficient mice selectively reconstituted with specific T cell subsets confirmed this suspicion. T cell-deficient (i.e., adult thymectomized, lethally irradiated, bone marrow-reconstituted = ATXBM) C57BL/6 mice were selectively reconstituted with the following categories of syngeneic lymph node cells (LNC): BALB/c skin-immune LNC treated with anti-Lyt 1 antibody + complement; BALB/c skin- or cornea-immune LNC treated with anti-Lyt 2 antibody + complement; or BALB/c cornea- or skin-immune LNC not treated with antibody. ATXBM mice reconstituted with syngeneic Lyt 1-depleted, BALB/c skin-immunized LNC failed to develop DTH, yet rapidly rejected BALB/c corneal allografts. Similarly, ATXBM mice reconstituted with Lyt 1-depleted cornea-immune LNC did not demonstrate DTH responses but were able to reject 100% of the corneal allografts in an accelerated fashion. By contrast, corneal allograft rejection was significantly delayed in ATXBM mice reconstituted with cornea-immune LNC partially depleted of Lyt 2+ T cells. Collectively, the results indicate that: heterotopic corneal allografts can be rejected in the absence of DTH; heterotopic corneal allografts fail to induce allospecific DTH; and partial depletion of Lyt 2+ CTL leads to a prolongation of heterotopic corneal allograft survival. Thus, the primary T cell-dependent immune effector elements responsible for heterotopic corneal allograft rejection appears to reside in the cytolytic T lymphocyte population.


Replication of O6-methylguanine-containing DNA by repair and replicative DNA polymerases.
The biological consequences of O6-methylguanine (m6G) in DNA are well recognized. When template m6G is encountered by DNA polymerases, replication is hindered and trans-lesion replication results in the preferential incorporation of dTMP opposite template m6G. Thus, unrepaired m6G in DNA is both cytotoxic and mutagenic. Yet, cell lines tolerant to m6G in DNA have been isolated, which indicates that some cellular DNA polymerases may replicate m6G-containing DNA with reasonable efficiency. Previous reports suggested that mammalian pol beta could not replicate m6G-containing DNA, but we find that pol beta can catalyze trans-lesion replication; however, the lesion must reside in the optimal context for pol beta activity, single- or short nucleotide gapped substrates. Primed single-stranded DNA templates, with or without template m6G, were poor substrates for pol beta as reported in earlier studies. In contrast, trans-lesion replication by bacteriophage T4 DNA polymerase was observed for primed single-stranded DNA templates. Replication of m6G-containing DNA by T4 DNA polymerase required the gp45 accessory protein that clamps the polymerase to the DNA template. The rate-limiting step in replicating m6G-containing DNAs by both DNA polymerases tested was incorporation of dTMP across from the lesion.


The use of poly(lactic-co-glycolic acid) microspheres as injectable cell carriers for cartilage regeneration in rabbit knees.
The use of injectable scaffolding materials for in vivo tissue regeneration has raised great interest because it allows cell implantation through minimally invasive surgical procedures. Previously, we showed that poly(lactic-co-glycolic acid) (PLGA) microspheres can be used as an injectable scaffold to engineer cartilage in the subcutaneous space of athymic mice. The purpose of this study was to determine whether PLGA microspheres can be used as an injectable scaffold to regenerate hyaline cartilage in the osteochondral defects of rabbit knees. A full-thickness wound to the patellar groove of the articular cartilage was made in the knees of rabbits. Rabbit chondrocytes were mixed with PLGA microspheres and injected immediately into these osteochondral wounds. Both chondrocyte transplantations without PLGA microspheres and culture medium injections without chondrocytes served as controls. Sixteen weeks after implantation, chondrocytes implanted using the PLGA microspheres formed white cartilaginous tissues. Histological scores indicating the extent of the cartilaginous tissue repair and the absence of degenerative changes were significantly higher in the experimental group than in the control groups (P < 0.05). Histological analysis by a hematoxylin and eosin stain of the group transplanted with microspheres showed thicker and better-formed cartilage compared to the control groups. Alcian blue staining and Masson's trichrome staining indicated a higher content of the major extracellular matrices of cartilage, sulfated glycosaminoglycans and collagen in the group transplanted with microspheres than in the control groups. In addition, immunohistochemical analysis showed a higher content of collagen type II, the major collagen type in cartilage, in the microsphere transplanted group compared to the control groups. In the group transplanted without microspheres, the wounds were repaired with fibro-cartilaginous tissues. This study demonstrates the feasibility of using PLGA microspheres as an injectable scaffold for cartilage regeneration in a rabbit model of osteochondral wound repair.


Spectral control of an alexandrite laser for an airborne water-vapor differential absorption lidar system.
A narrow-linewidth pulsed alexandrite laser has been greatly modified for improved spectral stability in an aircraft environment, and its operation has been evaluated in the laboratory for making water-vapor differential absorption lidar measurements. An alignment technique is described to achieve the optimum free spectral range ratio for the two étalons inserted in the alexandrite laser cavity, and the sensitivity of this ratio is analyzed. This technique drastically decreases the occurrence of mode hopping, which is commonly observed in a tunable, two-intracavity-étalon laser system. High spectral purity (> 99.85%) at 730 nm is demonstrated by the use of a water-vapor absorption line as a notch filter. The effective cross sections of 760-nm oxygen and 730-nm water-vapor absorption lines are measured at different pressures by usingthis laser, which has a finite linewidth of 0.02 cm(-1) (FWHM). It is found that for water-vapor absorption linewidths greater than 0.04 cm(-1) (HWHM), or for altitudes below 10 km, the laser line can be considered monochromatic because the measured effective absorption cross section is within 1% of the calculated monochromatic cross section. An analysis of the environmental sensitivity of the two intracavity étalons is presented, and a closed-loop computer control for active stabilization of the two intracavity étalons in the alexandrite laser is described. Using a water-vapor absorption line as a wavelength reference, we measure a long-term frequency drift (≈ 1.5 h) of less than 0.7 pm in the laboratory.


DUOX2-mediated production of reactive oxygen species induces epithelial mesenchymal transition in 5-fluorouracil resistant human colon cancer cells.
The therapeutic benefits offered by 5-fluorouracil (5-FU) are limited because of the acquisition of drug resistance, the main cause of treatment failure and metastasis. The ability of the cancer cells to undergo epithelial-mesenchymal transition (EMT) contributes significantly to cancer metastatic potential and chemo-resistance. However, the underlying molecular mechanisms of 5-FU-resistance have remained elusive. Here, we show that reactive oxygen species (ROS), produced by dual oxidase 2 (DUOX2), promote 5-FU-induced EMT. First, we showed that 5-FU-resistant SNUC5 colon cancer cells (SNUC5/FUR cells) undergo EMT by analyzing the expression of EMT markers such as N-cadherin, vimentin and E-cadherin. In addition, we found that the resistant cells expressed higher levels of Snail, Slug, Twist and Zeb1, which are all critical EMT regulators and had enhanced migratory and invasive capabilities. Furthermore, SNUC5/FUR cells had increased level of DUOX2, resulting in increased ROS level. This effect was due to the enhanced binding of the ten eleven translocation 1 (TET1) demethylase to the DUOX2 promoter in the SNUC5/FUR cells. Importantly, silencing of TET1 reversed the effects of 5-FU on the cells. Finally, the antioxidant N-acetylcysteine attenuated the effects of 5-FU on EMT and metastasis. Our study demonstrates the existence of a TET1/DUOX2/ROS/EMT axis that could play a role in colon cancer chemo-resistance and the aggressiveness of this cancer.


Simultaneous submicrometric 3D imaging of the micro-vascular network and the neuronal system in a mouse spinal cord.
Faults in vascular (VN) and neuronal networks of spinal cord are responsible for serious neurodegenerative pathologies. Because of inadequate investigation tools, the lacking knowledge of the complete fine structure of VN and neuronal system represents a crucial problem. Conventional 2D imaging yields incomplete spatial coverage leading to possible data misinterpretation, whereas standard 3D computed tomography imaging achieves insufficient resolution and contrast. We show that X-ray high-resolution phase-contrast tomography allows the simultaneous visualization of three-dimensional VN and neuronal systems of ex-vivo mouse spinal cord at scales spanning from millimeters to hundreds of nanometers, with nor contrast agent nor sectioning and neither destructive sample-preparation. We image both the 3D distribution of micro-capillary network and the micrometric nerve fibers, axon-bundles and neuron soma. Our approach is very suitable for pre-clinical investigation of neurodegenerative pathologies and spinal-cord-injuries, in particular to resolve the entangled relationship between VN and neuronal system.


A Machine Learning Platform to Optimize the Translation of Personalized Network Models to the Clinic.
Dynamic network models predict clinical prognosis and inform therapeutic intervention by elucidating disease-driven aberrations at the systems level. However, the personalization of model predictions requires the profiling of multiple model inputs, which hampers clinical translation. We applied APOPTO-CELL, a prognostic model of apoptosis signaling, to showcase the establishment of computational platforms that require a reduced set of inputs. We designed two distinct and complementary pipelines: a probabilistic approach to exploit a consistent subpanel of inputs across the whole cohort (Ensemble) and a machine learning approach to identify a reduced protein set tailored for individual patients (Tree). Development was performed on a virtual cohort of 3,200,000 patients, with inputs estimated from clinically relevant protein profiles. Validation was carried out in an in-house stage III colorectal cancer cohort, with inputs profiled in surgical resections by reverse phase protein array (n = 120) and/or immunohistochemistry (n = 117). Ensemble and Tree reproduced APOPTO-CELL predictions in the virtual patient cohort with 92% and 99% accuracy while decreasing the number of inputs to a consistent subset of three proteins (40% reduction) or a personalized subset of 2.7 proteins on average (46% reduction), respectively. Ensemble and Tree retained prognostic utility in the in-house colorectal cancer cohort. The association between the Ensemble accuracy and prognostic value (Spearman ρ = 0.43; P = .02) provided a rationale to optimize the input composition for specific clinical settings. Comparison between profiling by reverse phase protein array (gold standard) and immunohistochemistry (clinical routine) revealed that the latter is a suitable technology to quantify model inputs. This study provides a generalizable framework to optimize the development of network-based prognostic assays and, ultimately, to facilitate their integration in the routine clinical workflow.


Patient-related barriers to cancer pain management in Taiwan.
The reluctance of patients with cancer to report pain and to use analgesics hinders the management of their pain. In the United States, this reluctance is related to the patient's misconceptions regarding addiction and tolerance to analgesics and the desire to be a "good patient" who does not complain. Reports in the literature suggest that patients in Taiwan may have these same concerns and misconceptions. This study was designed to explore (a) the concerns of patients in Taiwan about reporting pain and using analgesics and (b) the relationship between these concerns and the adequacy of analgesics used by the patients. Sixty-three patients with cancer completed the Barriers Questionnaire-Taiwan (BTQ) form, a self-report instrument that measures the extent to which patients have eight specific concerns about reporting pain and using analgesics. The responses indicated that patients who were less educated were more likely to have concerns and that patients in general were most worried about tolerance. Patients who were inadequately medicated, as determined by an index of "adequate pain management" constructed for the study, had significantly higher levels of concerns. Open communication between health professionals and patients and educational programs about pain and about the concerns measured in this study could help overcome these concerns and misconceptions and improve pain management.


Core binding factor β of osteoblasts maintains cortical bone mass via stabilization of Runx2 in mice.
Core binding factor beta (Cbfβ), the partner protein of Runx family transcription factors, enhances Runx function by increasing the binding of Runx to DNA. Null mutations of Cbfb result in embryonic death, which can be rescued by restoring fetal hematopoiesis but only until birth, where bone formation is still nearly absent. Here, we address a direct role of Cbfβ in skeletal homeostasis by generating osteoblast-specific Cbfβ-deficient mice (Cbfb(Δob/Δob) ) from Cbfb-floxed mice crossed with mice expressing Cre from the Col1a1 promoter. Cbfb(Δob/Δob) mice showed normal growth and development but exhibited reduced bone mass, particularly of cortical bone. The reduction of bone mass in Cbfb(Δob/Δob) mice is similar to the phenotype of mice with haploinsufficiency of Runx2. Although the number of osteoblasts remained unchanged, the number of active osteoblasts decreased in Cbfb(Δob/Δob) mice and resulted in lower mineral apposition rate. Immunohistochemical and quantitative real-time PCR analyses showed that the expression of osteogenic markers, including Runx2, osterix, osteocalcin, and osteopontin, was significantly repressed in Cbfb(Δob/Δob) mice compared with wild-type mice. Cbfβ deficiency also reduced Runx2 protein levels in osteoblasts. The mechanism was revealed by forced expression of Cbfβ, which increased Runx2 protein levels in vitro by inhibiting polyubiquitination-mediated proteosomal degradation. Collectively, these findings indicate that Cbfβ stabilizes Runx2 in osteoblasts by forming a complex and thus facilitates the proper maintenance of bone mass, particularly cortical bone.


Photo recall reaction following the use of vancomycin.
Drug-induced erythema in the distribution of prior sunburn is called photo recall. Although more commonly induced by chemotherapeutics, it has also been associated with antibiotics such as ampicillin, cephalosporin, and gentamicin. Vancomycin has not been previously reported as a causal agent. This case report describes photo recall in a fifty-three year old woman undergoing treatment with vancomycin for a MRSA infection of the spine. Her eruption followed a photo-distributed pattern on the chest, shoulders, neck and face sparing areas previously protected by her bathing suit. Of note, she reported a similar eruption following vancomycin two years prior.


Native roles of Baeyer-Villiger monooxygenases in the microbial metabolism of natural compounds.
Covering: up to end of June 2018 Baeyer-Villiger monooxygenases (BVMOs) are flavin-dependent enzymes that catalyse the oxidation of ketones and cyclic ketones to esters and lactones, respectively, by using molecular oxygen and NAD(P)H. BVMOs also catalyse sulfoxidations and N-oxidations. BVMOs are widely studied as attractive biocatalysts, but also catalyse key reactions in metabolic pathways of the organisms from which they are sourced. BVMOs are involved in the primary metabolism of atypical carbon sources, thereby conferring an evolutionary advantage to the host organism. In addition, BVMOs catalyse a plethora of diverse Baeyer-Villiger and heteroatom oxidations in the construction of complex secondary metabolites. These natural products often have attractive biological properties, such as anti-bacterial, anti-cancer and anti-proliferative activity, and can have clinical applications. In contrast, BVMOs are also involved in the synthesis of microbial toxins. This review will discuss the inherent roles of type I, type II and type O BVMOs in the metabolism of microorganisms.


Neuroimaging of central breathlessness mechanisms.
Breathlessness debilitates millions of people with cardiorespiratory conditions and cancer. Symptoms correlate poorly with the objective measures of disease (e.g. spirometry). Altered brain processing of respiratory sensations may contribute to this disparity. This article summarizes how functional neuroimaging works, focussing on functional MRI (FMRI) and magnetoencephalography, how neuroimaging has shed light on the central mechanisms of breathlessness and thus how it may help target new therapies. Current understanding of central neural activity in breathlessness comes mainly from a small number of studies in healthy volunteers using models of induced acute breathlessness. Parallels with neuroimaging findings in pain and fear or anxiety have been used to interpret the neuroimaging studies of breathlessness to form hypotheses. Despite the lack of recent neuroimaging studies in breathlessness, there have been methodological advances in overcoming confounders with respiratory FMRI. In addition, developing interest in the distinction of emotional from the sensory aspects of breathlessness and the use of opioids for breathlessness has driven mechanistic understandings. Neuroimaging of breathlessness remains in its infancy. However, advances in the understanding of central perception, combined with novel neuroimaging techniques, means that we are poised to increase our understanding of the brain processes of breathlessness and their modulation.


Variations in inpatient mortality among hospitals in different system types, 1995 to 2000.
Relatively few studies focused on the impact of system formation and hospital merger on quality, and these studies reported typically little or no quality effect. To study associations among 5 main types of health systems--centralized, centralized physician/insurance, moderately centralized, decentralized, and independent--and inpatient mortality from acute myocardial infarction (AMI), congestive heart failure, stroke, and pneumonia. Panel data (1995-2000) were assembled from 11 states and multiple sources: Agency for Healthcare Research and Quality State Inpatient Database, American Hospital Association Annual Surveys, Area Resource File, HMO InterStudy, and the Centers for Medicare and Medicaid Services. We applied a panel study design with fixed effects models using information on variation within hospitals. We found that centralized health systems are associated with lower AMI, congestive heart failure, and pneumonia mortality. Independent hospital systems had better AMI quality outcomes than centralized physician/insurance and moderately centralized health systems. We found no difference in inpatient mortality among system types for the stroke outcome. Thus, for certain types of clinical service lines and patients, hospital system type matters. Research that focuses only on system membership may mask the impact of system type on the quality of care.


Terminal repeats impact collagen triple-helix stability through hydrogen bonding.
Nearly 30% of human proteins have tandem repeating sequences. Structural understanding of the terminal repeats is well-established for many repeat proteins with the common α-helix and β-sheet foldings. By contrast, the sequence-structure interplay of the terminal repeats of the collagen triple-helix remains to be fully explored. As the most abundant human repeat protein and the most prevalent structural component of the extracellular matrix, collagen features a hallmark triple-helix formed by three supercoiled polypeptide chains of long repeating sequences of the Gly-X-Y triplets. Here, with CD characterization of 28 collagen-mimetic peptides (CMPs) featuring various terminal motifs, as well as DSC measurements, crystal structure analysis, and computational simulations, we show that CMPs only differing in terminal repeat may have distinct end structures and stabilities. We reveal that the cross-chain hydrogen bonding mediated by the terminal repeat is key to maintaining the triple-helix's end structure, and that disruption of it with a single amide to carboxylate substitution can lead to destabilization as drastic as 19 °C. We further demonstrate that the terminal repeat also impacts how strong the CMP strands form hybrid triple-helices with unfolded natural collagen chains in tissue. Our findings provide a spatial profile of hydrogen bonding within the CMP triple-helix, marking a critical guideline for future crystallographic or NMR studies of collagen, and algorithms for predicting triple-helix stability, as well as peptide-based collagen assemblies and materials. This study will also inspire new understanding of the sequence-structure relationship of many other complex structural proteins with repeating sequences.


Development of patient education for older adults receiving chemotherapy.
The diagnosis of cancer is a significant and often overwhelming event. Older adults may have age-related physical and cognitive changes in addition to the stresses of cancer diagnosis and treatment. The combination can present significant barriers to learning readiness in older adults who choose chemotherapy. Older adults receiving chemotherapy need to learn self-care for risks such as neutropenia; however, patient teaching materials typically are not developed with consideration for this group of learners. This article reviews the current literature on effective chemotherapy patient education, the physical and cognitive changes related to aging learners, and strategies appropriate for teaching older adults. As described in this article, best practices were synthesized from the literature, and educational materials for teaching basic chemotherapy safety practices to older adults were developed. The materials then were pilot tested with a select group of older adults receiving chemotherapy, and their feedback was incorporated into recommendations for future research and practice.


Career preferences of graduate and non-graduate entrants to medical schools in the UK.
Recent UK policy has been to increase substantially the number of graduate entrants to medical schools. Our aim was to study whether graduate and non-graduate entrants have different long-term career preferences. We conducted postal questionnaire surveys of medical qualifiers from all UK medical schools in 1999, 2000 and 2002, surveyed 1 year after qualification, and qualifiers of 1999 and 2000, surveyed 3 years after qualification. By Year 3 after qualification, general practice was the choice of 33% of men graduate entrants and 21% of men non-graduates ( = 12.5, P < 0.001) and of 43% of women graduates and 38% of women non-graduates ( = 1.6, P = 0.2). Surgery was a much less popular choice for men graduate entrants than for men non-graduates; but similar percentages of women graduate and non-graduate entrants chose surgery. A lower percentage of graduate entrants than of non-graduates favoured paediatrics. Other differences between graduates and non-graduates were generally small. General practice was the preferred career for a much lower percentage of those who took an intercalated degree while at medical school, than of those who did not. Increasing graduate entry to medical school is likely to increase the percentage of doctors who want to become general practitioners, but only modestly so. It may also lead to a decline in the percentages choosing surgery and paediatrics. Otherwise, at least on the current criteria used for selecting students, increasing graduate entry will probably not make much difference to the percentage of newly qualified doctors seeking careers in different branches of practice.


Development of prophylactic vaccines against HIV-1.
The focus of most current HIV-1 vaccine development is on antibody-based approaches. This is because certain antibody responses correlated with protection from HIV-1 acquisition in the RV144 phase III trial, and because a series of potent and broad spectrum neutralizing antibodies have been isolated from infected individuals. Taken together, these two findings suggest ways forward to develop a neutralizing antibody-based vaccine. However, understanding of the correlates of protection from disease in HIV-1 and other infections strongly suggests that we should not ignore CTL-based research. Here we review recent progress in the field and highlight the challenges implicit in HIV-1 vaccine design and some potential solutions.


N-cadherin gene expression in prostate carcinoma is modulated by integrin-dependent nuclear translocation of Twist1.
The gain of N-cadherin expression in carcinomas has been shown to be important in the regulation of cell migration, invasion, and survival. Here, we show that N-cadherin mRNA expression in PC-3 prostate carcinoma cells is dependent on beta(1) integrin-mediated cell adhesion to fibronectin and the basic helix-loop-helix transcription factor Twist1. Depletion of Twist1 mRNA by small interfering RNA resulted in decreased expression of both Twist1 and N-cadherin and the inhibition of cell migration. Whereas Twist1 gene expression was independent of beta(1) integrin-mediated adhesion, Twist1 protein failed to accumulate in the nuclei of cells cultured in anchorage-independent conditions. The increased nuclear accumulation of Twist1 following cell attachment was suppressed by treatment with an inhibitor of Rho kinase or a beta(1) integrin neutralizing antibody. The effect of Twist1 on induction of N-cadherin mRNA required an E-box cis-element located within the first intron (+2,627) of the N-cadherin gene. These data raise the possibility that integrin-mediated adhesion to interstitial matrix proteins during metastasis differentially regulates the nuclear/cytoplasmic translocation and DNA binding of Twist1, activating N-cadherin transcription.


Penetration mechanics of a beetle intromittent organ with bending stiffness gradient and a soft tip.
Hyper-elongated structures and their penetration are widespread among insects, for example, intromittent organs, ovipositors, and piercing-sucking mouthparts. The penetration of thin structures with high aspect ratio without buckling and rupturing is mechanically very challenging. However, this problem is economically solved in nature, and the solutions might be helpful for, for example, in the development of harmless catheters. We focus on the penetration process of a hyper-elongated structure of a cassidine beetle intromittent organ, termed a flagellum. We applied a three-point bending test for the flagellum to measure its bending stiffness along the entire flagellum. We demonstrated the bending stiffness gradient, in which the basal half is relatively stiff and the apical half is softer, whose good performance during copulation had been previously numerically demonstrated. The stiffness gradient is the result of the flagellum shape, which is cylindrical and tapered toward the tip. Moreover, the curved tip comprises a harder outer curve and a softer inner curve. Considering the findings of preceding studies, the flagellum works in the following way: (i) the bending stiffness gradient supports the flagellum, easily fitting to a shape of a highly coiled spermathecal duct, (ii) the stiffness property of the very tip may make the tip tougher, and (iii) the curled tip and homogeneously cylindrical shape of the organ help the very tip to fit the shape of the spermathecal duct of the female. Our study shows that the apparently simple flagellum penetration is achieved with numerous elaborate mechanical adaptations.


Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993.
The predictive value of molecular minimal residual disease (MRD) monitoring using polymerase chain reaction amplification of clone-specific immunoglobulin or T-cell Receptor rearrangements was analysed in 161 patients with non T-lineage Philadelphia-negative acute lymphoblastic leukaemia (ALL) participating in the UK arm of the international ALL trial UKALL XII/Eastern Cooperative Oncology Group (ECOG) 2993. MRD positivity (> or =10(-4)) in patients treated with chemotherapy alone was associated with significantly shorter relapse-free survival (RFS) at several time-points during the first year of therapy. MRD status best discriminated outcome after phase 2 induction, when the relative risk of relapse was 8.95 (2.85-28.09)-fold higher in MRD-positive (> or =10(-4)) patients and the 5-year RFS 15% [95% confidence interval (CI) 0-40%] compared to 71% (56-85%) in MRD-negative (<10(-4)) patients (P = 0.0002) When MRD was detected prior to autologous stem cell transplantation (SCT), a significantly higher rate of treatment failure was observed [5-year RFS 25% (CI 0-55%) vs. 77% (95% CI 54-100%) in MRD-negative/<10(-4), P = 0.01] whereas in recipients of allogeneic-SCT in first complete remission, MRD positivity pre-transplant did not adversely affect outcome. These data provide a rationale for introducing MRD-based risk stratification in future studies for the delineation of those at significant risk of treatment failure in whom intensification of therapy should be evaluated.


Using body size to understand the structural design of animals: quadrupedal locomotion.
Many parameters of gait and performance, including stride frequency, stride length, maximum speed, and rate of O2 uptake are experimentally found to be power-law functions of body weight in running quadrupeds. All of these parameters are reasonably easy to measure except maximum speed, where the question arises whether one means top sprinting speed or top speed for sustained running. Moreover, differences in training and motivation make comparisons of top speed difficult. The problem is circumvented by comparing animals running at the transition between trotting and galloping, a physiologically similar speed. Theoretical models are proposed which preserve either geometric similarity, elastic similarity, or static stress similarity between animals of large and small body weights. The model postulating elastic similarity provides the best correlation with published data on body and bone proportions, body surface area, resting metabolic rate, and basal heart and lung frequencies. It also makes the most successful prediction of stride frequency, stride length, limb excursion angles, and the metabolic power required for running at the trot-gallop transition in quadrupeds ranging in size from mice to horses.


Postoperative complications in the seriously mentally ill: a systematic review of the literature.
To determine the knowledge base on clinical outcomes of surgery among persons diagnosed with serious mental illness. Despite a burgeoning literature during the last 20 years regarding perioperative risk management, little is known about intraoperative and postoperative complications among patients with schizophrenia and other serious mental illnesses. A systematic literature search of Medline (1966-August 2007) and review of studies was conducted. Eligible studies were of any design with at least 10 patients diagnosed with serious mental illness, reporting perioperative medical, surgical, or psychiatric complications. The search identified 1367 potentially relevant publications; only 12 met eligibility criteria. Of 10 studies of patients with schizophrenia, 9 had fewer than 100 patients, whereas one large retrospective study reported higher rates of postoperative complications among 466 schizophrenia patients compared with 338,257 controls. These studies suggest that patients with schizophrenia, compared with those without mental illness, may have higher pain thresholds, higher rates of death and postoperative complications, and differential outcomes (eg, confusion, ileus) by anesthetic technique. Two studies evaluated outcomes in patients with major depressive disorder and found higher rates of postoperative delirium and postoperative confusion. Both schizophrenia and depression patients experienced more postoperative confusion or delirium when psychiatric medications were discontinued preoperatively. We identified no studies of perioperative outcomes in patients with bipolar or posttraumatic stress disorder. There are few studies of perioperative outcomes in patients with serious mental illness. Future research should assess surgical risks among patients with serious psychiatric conditions using rigorous methods and well-defined clinical outcomes.


Molecular pathways: deregulation of histone h3 lysine 27 methylation in cancer-different paths, same destination.
Methylation of lysine 27 on histone H3 (H3K27me), a modification associated with gene repression, plays a critical role in regulating the expression of genes that determine the balance between cell differentiation and proliferation. Alteration of the level of this histone modification has emerged as a recurrent theme in many types of cancer, demonstrating that either excess or lack of H3K27 methylation can have oncogenic effects. Cancer genome sequencing has revealed the genetic basis of H3K27me deregulation, including mutations of the components of the H3K27 methyltransferase complex PRC2 and accessory proteins, and deletions and inactivating mutations of the H3K27 demethylase UTX in a wide variety of neoplasms. More recently, mutations of lysine 27 on histone H3 itself were shown to prevent H3K27me in pediatric glioblastomas. Aberrant expression or mutations in proteins that recognize H3K27me3 also occur in cancer and may result in misinterpretation of this mark. In addition, due to the cross-talk between different epigenetic modifications, alterations of chromatin modifiers controlling H3K36me, or even mutations of this residue, can ultimately regulate H3K27me levels and distribution across the genome. The significance of mutations altering H3K27me is underscored by the fact that many tumors harboring such lesions often have a poor clinical outcome. New therapeutic approaches targeting aberrant H3K27 methylation include small molecules that block the action of mutant EZH2 in germinal center-derived lymphoma. Understanding the biologic consequences and gene expression pathways affected by aberrant H3K27 methylation may also lead to other new therapeutic strategies.


A graphic three-step test.
A graphic technique is used to analyze cyclovertical muscle palsies. This technique is similar to that presented in the Ophthalmology Basic and Clinical Science Course, but has the following advantages: only one diagram is required to apply the method, and knowledge of the actions of the cyclovertical muscles, when analyzing the Bielschowsky head tilt test, is not required.


Single-cell O2 exchange imaging shows that cytoplasmic diffusion is a dominant barrier to efficient gas transport in red blood cells.
Disorders of oxygen transport are commonly attributed to inadequate carrying capacity (anemia) but may also relate to inefficient gas exchange by red blood cells (RBCs), a process that is poorly characterized yet assumed to be rapid. Without direct measurements of gas exchange at the single-cell level, the barriers to O2 transport and their relationship with hematological disorders remain ill defined. We developed a method to track the flow of O2 in individual RBCs by combining ultrarapid solution switching (to manipulate gas tension) with single-cell O2 saturation fluorescence microscopy. O2 unloading from RBCs was considerably slower than previously estimated in acellular hemoglobin solutions, indicating the presence of diffusional barriers in intact cells. Rate-limiting diffusion across cytoplasm was demonstrated by osmotically induced changes to hemoglobin concentration (i.e., diffusive tortuosity) and cell size (i.e., diffusion pathlength) and by comparing wild-type cells with hemoglobin H (HbH) thalassemia (shorter pathlength and reduced tortuosity) and hereditary spherocytosis (HS; expanded pathlength). Analysis of the distribution of O2 unloading rates in HS RBCs identified a subpopulation of spherocytes with greatly impaired gas exchange. Tortuosity imposed by hemoglobin was verified by demonstrating restricted diffusivity of CO2, an acidic gas, from the dissipative spread of photolytically uncaged H+ ions across cytoplasm. Our findings indicate that cytoplasmic diffusion, determined by pathlength and tortuosity, is a major barrier to efficient gas handling by RBCs. Consequently, changes in RBC shape and hemoglobin concentration, which are common manifestations of hematological disorders, can have hitherto unrecognized and clinically significant implications on gas exchange.


New insights into the dichotomous role of innate cytokines in gut homeostasis and inflammation.
In addition to their well-known role in acute injury and chronic inflammation, "innate" cytokines play an important role in health and the maintenance of normal immune homeostasis. This group includes the prototypic cytokines IL-1 and TNFα, as well as several other members belonging to the IL-1 and TNF family, such as IL-18, IL-33, IL-36-38, and TL1A. The dichotomous role of these cytokines has been best characterized in the intestine where innate cytokines may play both a protective and a pro-inflammatory role, depending upon the immmunological status of the host or the type and phase of the inflammatory process. This new information has produced novel pathogenetic hypotheses that have important translational implications both in regard to the prevention and treatment of chronic intestinal inflammation, including Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease. This review will discuss and summarize current data regarding the role of IL-1, TNFα, and their family members in regulating gut mucosal homeostasis and chronic intestinal inflammation.