Keratinocyte-Specific SOX2 Overexpression Suppressed Pressure Ulcer Formation after Cutaneous Ischemia-Reperfusion Injury via Enhancement of Amphiregulin Production.
Ischemia-reperfusion (I/R) injury is a key player in the pathogeneses of pressure ulcer formation. Our previous work demonstrated that inducing the transcription factor SOX2 promotes cutaneous wound healing through EGFR signaling pathway enhancement. However, its protective effect on cutaneous I/R injury was not well-characterized. We aimed to assess the role of SOX2 in cutaneous I/R injury and the tissue-protective effect of SOX2 induction in keratinocytes (KCs) in cutaneous I/R injury. SOX2 was transiently expressed in KCs after cutaneous I/R injury. Ulcer formation was significantly suppressed in KC-specific SOX2-overexpressing mice. SOX2 in skin KCs significantly suppressed the infiltrating inflammatory cells, apoptotic cells, vascular damage, and hypoxic areas in cutaneous I/R injury. Oxidative stress-induced mRNA levels of inflammatory cytokine expression were suppressed, and antioxidant stress factors and amphiregulin were elevated by SOX2 induction in skin KCs. Recombinant amphiregulin administration suppressed pressure ulcer development after cutaneous I/R injury in mice and suppressed oxidative stress-induced ROS production and apoptosis in vitro. These findings support that SOX2 in KCs might regulate cutaneous I/R injury through amphiregulin production, resulting in oxidative stress suppression. Recombinant amphiregulin can be a potential therapeutic agent for cutaneous I/R injury.


Effects of Mindfulness for Performance Programme on Actual Performance in Ecological Sport Context: Two Studies in Basketball and Table Tennis.
Mindfulness For Performance is a programme that has been developed over 15 years. It aims to help athletes maintain effective attentional focus regardless of the disruptive sensations and thoughts induced by the performance situation. It is inspired by Mindfulness Based Stress Reduction and Acceptance Commitment Therapy programmes and has been adapted to the specificities of sport. It is composed of three steps: (a) psychoeducation and identification of the focus of attention, (b) mindfulness and acceptance training, and (c) integrating skills acquired into training and competition. This article reports the effects of MFP in two studies in national basketball players and in young table tennis players. The first study showed that mindfulness skills and free-throw accuracy during basketball games increased more in the experimental group than in the control group. Table tennis results revealed that participants who showed the highest percentage of adherence to the programme benefited more from MFP training in terms of performance outcome (i.e., accumulated points collected from published results compared with the baseline phase) than participants who showed weaker percentages of adherence to the programme. Both studies provided some evidence on the effects of MFP on specific performance indicators (i.e., free-throw accuracy in basketball and ranking points in table tennis), but this needs to be confirmed by further research measuring other relevant performance indicators. The impact and conditions of adherence also deserve more consideration.


Renal vasodilation with ureteral occlusion and prostaglandins: attenuation by histamine H1 antagonists.
We evaluated the effects of histamine receptor antagonists on the renal vasodilatory responses to ureteral occlusion (UO), to the intrarenal infusion of prostaglandins E2, I2, A2, D2 and E1, and to bradykinin. We also determined the effects of meclofenamic acid, a cyclooxygenase inhibitor, on histamine-induced renal vasodilation and the effects of 2-methylhistamine (2-MeH), and H1 agonist, on glomerular filtration rate (GFR) and renal blood flow (RBF). Experiments were performed on adult mongrel dogs anesthetized with pentobarbital sodium. RBF was measured with an electromagnetic flow probe. Neither UO-induced nor prostaglandin- (PG) induced renal vasodilation was affected by infusion of the histamine H2 receptor antagonist cimetidine into the renal artery at 10(-5) M/min. On the other hand, renal artery infusion of the H1 receptor antagonist chlorpheniramine (CP) at 10(-5) M/min blocked UO-induced renal vasodilation [RBF increased 34 +/- 4% (SE) prior to but only 2 +/- 2% during infusion of CP) and markedly attenuated PGI2-, PGA2-, and PGE2-induced increases in RBF (CP inhibited 64 +/- 9% of the PGE2-induced renal vasodilation). CP had less effect on the renal vasodilation associated with infusion of PGD2 or PGE1 and had no effect on the vasodilation induced by bradykinin. Infusion of exogenous histamine (1 micrograms X kg-1 X min-1) into the renal artery prior to ureteral occlusion resulted in a typical H1 + H2-mediated vasodilatory response (RBF increased 53 +/- 7%).(ABSTRACT TRUNCATED AT 250 WORDS)


Early Parenting Moderates the Association between Parental Depression and Neural Reactivity to Rewards and Losses in Offspring.
Children of parents with depression exhibit neural abnormalities in reward processing. Examining contributions of parenting could provide insight into the development of these abnormalities and to the etiology of depression. We evaluated whether early parenting moderates the effects of parental depression on a neural measure of reward and loss processing in mid-late childhood. Parenting was assessed when children were preschoolers. At age nine, children completed an event-related potential assessment and the feedback negativity (FN) was measured following rewards and losses (N=344). Maternal authoritative parenting moderated the effect of maternal depression; among offspring of mothers with histories of depression, low authoritative parenting predicted a blunted FN. Observed maternal positive parenting interacted with paternal depression in a comparable manner, indicating that maternal parenting may buffer the effects of paternal depression. Early parenting may be important in shaping the neural systems involved in reward processing among children at high risk for depression.


Discrimination of 1990s original automotive paint systems: a collaborative study of black nonmetallic base coat/clear coat finishes using infrared spectroscopy.
The 1990s saw the introduction of significantly new types of paint binder chemistries into the automotive finish coat market. Considering the pronounced changes in the binders that can now be found in automotive paints and their potential use in a wide variety of finishes worldwide, the Paint Subgroup of the Scientific Working Group for Materials (SWGMAT) initiated a validation study to investigate the ability of commonly accepted methods of forensic paint examination to differentiate between these newer types of paints. Nine automotive paint systems typical of original equipment applications were acquired from General Motors Corporation in 1992. They consisted of steel panels coated with typical electrocoat primers and/or primer surfacers followed by a black nonmetallic base coat and clear coat. The primary purpose of this study was to evaluate the discrimination power of common forensic techniques when applied to the newer generation original automotive finishes. The second purpose was to evaluate interlaboratory reproducibility of automotive paint spectra collected on a variety of Fourier transform infrared (FT-IR) spectrometers and accessories normally used for forensic paint examinations. The results demonstrate that infrared spectroscopy is an effective tool for discriminating between the major automotive paint manufacturers' formulation types which are currently used in original finishes. Furthermore, and equally important, the results illustrate that the mid-infrared spectra of these finishes are generally quite reproducible even when comparing data from different laboratories, commercial FT-IR instruments, and accessories in a "real world," mostly uncontrolled, environment.


[Perforation of surgical gloves during cesarean section].
We carried out a prospective study with the object of knowing the frequency of surgical gloves perforation during cesarean section, the member of the surgical team with a major affection and the double gloves importance. We analysed 258 C. section practiced in the Tocosurgery's Service at "Nuevo Hospital Civil de Guadalajara" from September 1993 to January 1994. We used 1052 glove's pairs and we detected 118 perforated pairs (11.2%). The gloves were perforated in one time 60.1%, in two times 26.2%, in three times 6.8%, in four times 1.7% and five times 5.2%. On the other hand, in the he perforated gloves, 74% were simple gloves, while in 26% were double gloves, but only the external glove was perforated. The member of the surgical team with major affectation was the Surgeon with 83%, next the assistant in 13.5% and for last the instrumentist in 3.5%. The left hand was more affected that the right hand. The glove perforations more frequently was done for needle and after for instruments. We concluded that the use of double gloves is correct for a major protection, besides that the C. section must be carefully practiced.


Study of mitochondrial swelling, membrane fluidity and ROS production induced by nano-TiO2 and prevented by Fe incorporation.
The potential impact of TiO2 and Fe incorporated TiO2 nanoparticles at the organelle level has been reported. The toxicity of the samples on mitochondria isolated from chicken liver tissue has been examined through mitochondrial swelling, membrane fluidity, ROS generation capacity, and activity of complex II. The toxic effect of TiO2 was prevented by incorporating Fe into the TiO2 matrix at different concentrations. The activity of the succinate dehydrogenase enzyme complex was affected and permeabilization of the mitochondrial inner membrane to H+ and K+ and its alteration in membrane fluidity at 100 μg mL-1 of nano-TiO2 dosage were investigated, which showed significant changes in the anisotropy of DPH-labeled mitochondria. Fe incorporation into the TiO2 matrix makes it more biocompatible by changing its structure and morphology.


Aversive phototaxic suppression: evaluation of a short-term memory assay in Drosophila melanogaster.
Drosophila melanogaster is increasingly being used to model human conditions that are associated with cognitive deficits including fragile-X syndrome, Alzheimer's disease, Parkinson's disease, sleep loss, etc. With few exceptions, cognitive abilities that are known to be modified in these conditions in humans have not been evaluated in fly models. One reason is the absence of a simple, inexpensive and reliable behavioral assay that can be used by laboratories that are not expert in learning and memory. Aversive phototaxic suppression (APS) is a simple assay in which flies learn to avoid light that is paired with an aversive stimulus (quinine/humidity). However, questions remain about whether the change in the fly's behavior reflects learning an association between light and quinine/humidity or whether the change in behavior is because of nonassociative effects of habituation and/or sensitization. We evaluated potential effects of sensitization and habituation on behavior in the T-maze and conducted a series of yoked control experiments to further exclude nonassociative effects and determine whether this task evaluates operant learning. Together these experiments indicate that a fly must associate the light with quinine/humidity to successfully complete the task. Next, we show that five classic memory mutants are deficient in this assay. Finally, we evaluate performance in a fly model of neurodegenerative disorders associated with the accumulation of Tau. These data indicate that APS is a simple and effective assay that can be used to evaluate fly models of human conditions associated with cognitive deficits.


Guidewire Endpoint Detection Based on Pixel Adjacent Relation in Robot-assisted Cardiovascular Interventions.
Visualization of endovascular tools like guidewire and catheter is essential for procedural success of endovascular interventions. This requires tracking the tool pixels and motion during catheterization; however, detecting the endpoints of the endovascular tools is challenging due to their small size, thin appearance, and flexibility. As this still limit the performances of existing methods used for endovascular tool segmentation, predicting correct object location could provide ways forward. In this paper, we proposed a neighborhood-based method for detecting guidewire endpoints in X-ray angiograms. Typically, it consists of pixel-level segmentation and a post-segmentation step that is based on adjacency relationships of pixels in a given neighborhood. The latter includes skeletonization to predict endpoint pixels of guidewire. The method is evaluated with proprietary guidewire dataset obtained during in-vivo study in six rabbits, and it shows a high segmentation performance characterized with precision of 87.87% and recall of 90.53%, and low detection error with a mean pixel error of 2.26±0.14 pixels. We compared our method with four state-of-the-art detection methods and found it to exhibit the best detection performance. This neighborhood-based detection method can be generalized for other surgical tool detection and in related computer vision tasks.Clinical Relevance- The proposed method can be provided with better tool tracking and visualization systems during robot-assisted intravascular interventional surgery.


Transient arrest in proteasomal degradation during inhibition of translation in the unfolded protein response.
The UPR (unfolded protein response) activates transcription of genes involved in proteasomal degradation. However, we found that in its early stages the UPR leads to a transient inhibition of proteasomal disposal of cytosolic substrates (p53 and p27kip1) and of those targeted to ER (endoplasmic reticulum)-associated degradation (uncleaved precursor of asialoglycoprotein receptor H2a). Degradation resumed soon after the protein synthesis arrest that occurs in early UPR subsided. Consistent with this, protein synthesis inhibitors blocked ubiquitin/proteasomal degradation. Ubiquitination was inhibited during the translation block, suggesting short-lived E3 ubiquitin ligases as candidate depleted proteins. This was indeed the case for p53 whose E3 ligase, Mdm2 (murine double minute 2), when overexpressed, restored the degradation, whereas a mutant Mdm2 in its acidic domain restored the ubiquitination but did not completely restore the degradation. Inhibition of proteasomal degradation early in UPR may prevent depletion of essential short-lived factors during the translation arrest. Stabilization of p27 through this mechanism may explain the cell cycle arrest in G1 when translation is blocked by inhibitors or by the UPR.


Relation Between Chest CT Findings and Clinical Conditions of Coronavirus Disease (COVID-19) Pneumonia: A Multicenter Study.
OBJECTIVE. The increasing number of cases of confirmed coronavirus disease (COVID-19) in China is striking. The purpose of this study was to investigate the relation between chest CT findings and the clinical conditions of COVID-19 pneumonia. MATERIALS AND METHODS. Data on 101 cases of COVID-19 pneumonia were retrospectively collected from four institutions in Hunan, China. Basic clinical characteristics and detailed imaging features were evaluated and compared between two groups on the basis of clinical status: nonemergency (mild or common disease) and emergency (severe or fatal disease). RESULTS. Patients 21-50 years old accounted for most (70.2%) of the cohort, and five (5.0%) patients had disease associated with a family outbreak. Most patients (78.2%) had fever as the onset symptom. Most patients with COVID-19 pneumonia had typical imaging features, such as ground-glass opacities (GGO) (87 [86.1%]) or mixed GGO and consolidation (65 [64.4%]), vascular enlargement in the lesion (72 [71.3%]), and traction bronchiectasis (53 [52.5%]). Lesions present on CT images were more likely to have a peripheral distribution (88 [87.1%]) and bilateral involvement (83 [82.2%]) and be lower lung predominant (55 [54.5%]) and multifocal (55 [54.5%]). Patients in the emergency group were older than those in the non-emergency group. Architectural distortion, traction bronchiectasis, and CT involvement score aided in evaluation of the severity and extent of the disease. CONCLUSION. Patients with confirmed COVID-19 pneumonia have typical imaging features that can be helpful in early screening of highly suspected cases and in evaluation of the severity and extent of disease. Most patients with COVID-19 pneumonia have GGO or mixed GGO and consolidation and vascular enlargement in the lesion. Lesions are more likely to have peripheral distribution and bilateral involvement and be lower lung predominant and multifocal. CT involvement score can help in evaluation of the severity and extent of the disease.


Modelling life course blood pressure trajectories using Bayesian adaptive splines.
No single study has collected data over individuals' entire lifespans. To understand changes over the entire life course, it is necessary to combine data from various studies that cover the whole life course. Such combination may be methodologically challenging due to potential differences in study protocols, information available and instruments used to measure the outcome of interest. Motivated by our interest in modelling blood pressure changes over the life course, we propose the use of Bayesian adaptive splines within a hierarchical setting to combine data from several UK-based longitudinal studies where blood pressure measures were taken in different stages of life. Our method allowed us to obtain a realistic estimate of the mean life course trajectory, quantify the variability both within and between studies, and examine overall and study specific effects of relevant risk factors on life course blood pressure changes.


Intraocular penetration of rosoxacin in rabbits.
Rosoxacin, a new synthetic antimicrobial agent, has a wide spectrum of activity that may prove beneficial in the treatment of ocular infections. To determine the penetration of rosoxacin into ocular tissues and serum of the rabbit after topical, subconjunctival, and intravenous (IV) administration, rosoxacin levels were measured using a microbiological assay after enzymatic digestion of the ocular tissues. Quantities of rosoxacin that should prove to be of therapeutic value were detectable in the anterior segment of the eye after topical or subconjunctival administration. Subconjunctival administration also resulted in high levels in the retina and choroid area and in the optic nerve. Low levels were detected in the retina and choroid 15 minutes following IV injection; however, no detectable levels were found in the ocular tissues after this period.


Gunshot wounds of the abdomen. A review of 277 cases.
During a five-year period from July 1968 throuhgh June 1973, 277 abdominal gunshot wounds (GSWs) occurred, the overall fatality of which was 10%. Abdominal exploration was done in all patients. No intra-abdominal injury was found in 40 patients (14%) and no death occurred in this group. There were 28 fatalities (12%) in 237 patients (86%) who had intra-abdominal injuries. Morbidity and mortality were related not only to the number of organs injured, but also to specific organs injured. The leading cause of early death was hypovolemia due to major vessel injuries. Septicemia was the most common cause of death if the patient survived the first 24 hours of hospitalization. Penetrating abdominal stab wounds and gunshot wounds must be considered separately, and mandatory routine abdominal exploration for all penetrating gunshot wounds is advised. In stab wounds to the abdomen, conservative management may be preferable.


Challenges to mapping the health risk of hepatitis A virus infection.
World maps are among the most effective ways to convey public health messages such as recommended vaccinations, but creating a useful and valid map requires careful deliberation. The changing epidemiology of hepatitis A virus (HAV) in many world regions heightens the need for up-to-date risk maps. HAV infection is usually asymptomatic in children, so low-income areas with high incidence rates usually have a low burden of disease. In higher-income areas, many adults remain susceptible to the virus and, if infected, often experience severe disease. Several challenges associated with presenting hepatitis A risk using maps were identified, including the need to decide whether prior infection or continued susceptibility more aptly indicates risk, whether to display incidence or prevalence, how to distinguish between different levels of risk, how to display changes in risk over time, how to present complex information to target audiences, and how to handle missing or obsolete data. For future maps to be comparable across place and time, we propose the use of the age at midpoint of population susceptibility as a standard indicator for the level of hepatitis A endemicity within a world region. We also call for the creation of an accessible active database for population-based age-specific HAV seroprevalence and incidence studies. Health risk maps for other conditions with rapidly changing epidemiology would benefit from similar strategies.


Arthritogenicity of Borrelia burgdorferi and Borrelia garinii: comparison of infection in mice.
Arthritogenicity, as determined by joint swelling and synovial histology, was compared between or within two Borrelia genospecies that cause Lyme arthritis in humans. The spirochete burden in bladder tissue (a site of spirochete persistence) was documented by quantitative polymerase chain reaction, and immune responses were analyzed. In C3H/HeJ mice, three B. burgdorferi isolates and two of the three B. garinii isolates induced severe arthritis and swelling. Previous designation as invasive or noninvasive B. garinii, or RNA spacer type of B. burgdorferi did not determine arthritis severity induced by isolates. Compared with the other five isolates, the B. garinii PBi isolate induced significantly less arthritis, a lower humoral immune response, and persisted at a much lower level in bladder tissue. However, B. garinii PBi isolates induced similar Borrelia antigen-specific inflammatory T cell responses from the local draining lymph node. Thus, diverse B. burgdorferi and B. garinii isolates were highly arthritogenic in immune competent mice.


Practical approaches to the surgical management of achalasia.
Achalasia is a primary motor disorder of the esophagus characterized by an abnormal hypertensive, nonrelaxing lower esophageal sphincter (LES) and nonfunctioning, aperistaltic esophageal body resulting in significant regurgitation and dysphagia. The primary goal of treatment is palliation of symptoms. At present, all treatment techniques are directed at relieving the functional obstruction at the level of the LES by disruption or paralysis of the esophageal muscle constituting the LES. Destruction of the LES function also places the patient at risk for pathologic gastroesophageal reflux disease. Therefore, the treatment of patients with achalasia must strike a balance between the relief of dysphagia and potential creation of pathologic gastroesophageal reflux. The advent of laparoscopic esophageal myotomy for the treatment of achalasia over the past decade has resulted in most patients with the disease being referred to surgeons for definitive treatment. At the time of consultation the patient may present with a myriad of symptoms, investigative results, and previous treatments. Based on our experience of over 300 patients treated with surgery at our institution between 1990 and 2007, this review will address the practical problems encountered in the surgical management of achalasia.


Biodegradable elastomers for biomedical applications and regenerative medicine.
Synthetic biodegradable polymers are of great value for the preparation of implants that are required to reside only temporarily in the body. The use of biodegradable polymers obviates the need for a second surgery to remove the implant, which is the case when a nondegradable implant is used. After implantation in the body, biomedical devices may be subjected to degradation and erosion. Understanding the mechanisms of these processes is essential for the development of biomedical devices or implants with a specific function, for example, scaffolds for tissue-engineering applications. For the engineering and regeneration of soft tissues (e.g., blood vessels, cardiac muscle and peripheral nerves), biodegradable polymers are needed that are flexible and elastic. The scaffolds prepared from these polymers should have tuneable degradation properties and should perform well under long-term cyclic deformation conditions. The required polymers, which are either physically or chemically crosslinked biodegradable elastomers, are reviewed in this article.


DNA cleavage by the Cu(II) complex of the DNA-intercalating 9-bis(pyridin-2-ylmethyl)aminobenzo[b]quinolizinium.
The synthesis and the investigation of the Cu(II)-binding, the DNA-binding, and the DNA-damaging properties of a conjugate between the benzo[b]quinolizinium ion and the bis(pyridin-2-ylmethyl)amino receptor are presented. Photometric and fluorimetric titrations as well as CD spectroscopic analysis reveal that the 9-bis(pyridin-2-ylmethyl)aminobenzo[b]quinolizinium ligand intercalates into DNA (K(b) = 1.9 x 10(4) M(-1)) and exhibits a high selectivity towards complexation of Cu(2+) in water (K(b) = 4.3 x 10(4) M(-1)). This combination of functionalities allows to localize Cu(2+) in close proximity of DNA, where these metal ions induce efficient DNA damage, as shown by the single-strand cleavage of supercoiled plasmid DNA. Notably, the DNA cleavage does not require additional reagents nor light.


Chemoprotection by organosulfur inducers of phase 2 enzymes: dithiolethiones and dithiins.
One of the major mechanisms of protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by carcinogens is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases, UDP-glucuronosyl transferases, and quinone reductases. Animal studies indicate that induction of phase 2 enzymes is a sufficient condition for obtaining chemoprevention and can be achieved by administering any of a diverse array of naturally-occurring and synthetic chemopreventive agents. Alliaceous and cruciferous plants are rich in organosulfur compounds with inducer activity. Indeed, monitoring of enzyme induction has led to the recognition or isolation of novel, potent chemopreventive agents such as 1,2-dithiole-3-thiones, dithiins and the isothiocyanate sulforaphane. For example, oltipraz, a substituted 1,2-dithiole-3-thione originally developed as an antischistosomal agent, possesses chemopreventive activity against different classes of carcinogens targeting multiple organs. Mechanistic studies in rodent models for chemoprevention of aflatoxin B1 (AFB1)-induced hepatocarcinogenesis by oltipraz indicates that increased expression of phase 2 genes is of central importance, although inhibition of phase 1 activation of aflatoxin B1 can also contribute to protection. Exposure of rodents to 1,2-dithiole-3-thiones triggers nuclear accumulation of the transcription factor Nrf2 and its enhanced binding to the Antioxidant Response Element, leading to transcriptional activation of a score of genes involved in carcinogen detoxification and attenuation of oxidative stress. Nrf2-deficient mice fail to induce many of these genes in response to oltipraz and the impact of this genotype on the chemopreventive efficacy of dithiolethiones is currently under investigation. To test the hypothesis that enzyme induction is a useful strategy for chemoprevention in humans, three key elements are necessary: a candidate agent, an at-risk population and modulatable intermediate endpoints. Towards this end, a placebo-controlled, double blind clinical trial of oltipraz was conducted in residents of Qidong, P.R. China who are exposed to dietary aflatoxins and who are at high risk for the development of liver cancer. Oltipraz significantly enhanced excretion of a phase 2 product, aflatoxin-mercapturic acid, a derivative of the aflatoxin-glutathione conjugate, in the urine of study participants administered 125 mg oltipraz by mouth daily. Administration of 500 mg oltipraz once a week led to a significant reduction in the excretion of the primary oxidative metabolite of AFB1, aflatoxin M1, when measured shortly after drug administration. While this study highlighted the general feasibility of inducing phase 2 enzymes in humans, a longer term intervention is addressing whether protective alterations in aflatoxin metabolism can be sustained for extended periods of time in this high-risk population. Food-based approaches to chemoprotection, targeted both to the general population and high-risk individuals, offer many practical advantages compared to the use of pharmaceutical agents. Thus, identification and utilization of naturally-occurring organosulfur chemoprotectors including dithiins should be a high priority.


The Promise of Neoadjuvant Immunotherapy and Surgery for Cancer Treatment.
Cancer immunotherapies utilizing immune checkpoint inhibitors (ICI) have demonstrated durable efficacy in a proportion of patients with advanced/metastatic cancers. More recently, the use of ICIs for the adjuvant treatment of patients with surgically resectable melanoma has also demonstrated efficacy by improving relapse-free survival and in the case of ipilimumab (anti-CTLA-4) also improving overall survival. Although promising, the effective scheduling of surgery and immunotherapy and its duration is not well elucidated. Recent preclinical studies suggest that surgery followed by adjuvant therapy might be suboptimal as compared with an approach in which immunotherapy is applied before surgery (neoadjuvant immunotherapy). Encouraging findings from early-phase clinical trials in melanoma, non-small cell lung carcinoma, and glioblastoma support the idea that neoadjuvant immunotherapy might have improved clinical efficacy over an adjuvant application. In this review, we discuss the existing rationale for the use of neoadjuvant immunotherapy, its apparent strengths and weaknesses, and implications for the design of future clinical trials.


Effect of sensory training of the posterior thigh on trunk control and upper extremity functions in stroke patients.
Some studies show that sensorial rehabilitation is effective on functionality. The aim of this study is to investigate the effect of sensory training of the posterior thigh on the functionality of upper extremity and trunk control in stroke patients. Thirteen subjects (53.23 ± 6.82 years) were included in the intervention group and 13 subjects (58.69 ± 5.94 years) in the control group. The control and intervention groups were treated for ten sessions. The control group was treated only with neurodevelopmental treatment, and the intervention group was treated with sensorial training on the posterior thigh in addition to the neurodevelopmental treatment. Subjects were evaluated three times, pre- and post-treatment and 10 days after finishing the treatment. Trunk control was assessed by the Trunk Impairment Scale, reaching function by the Functional Reach Test, balance by the Berg Balance Test, upper extremity symptom and disability severity by the Disabilities of the Arm, Shoulder, Hand and Minnesota, independence level in daily living activities by the Barthel Index, and sensory function of the posterior thigh by sensorial tests. In the post-treatment assessment, it was found that the intervention group was better than the control group in the parameter of functional reach while sitting (p < 0.005). In the third assessment, reaching while sitting and independence level were better in the intervention group than the control group (p < 0.005). There was no difference in sensorial assessment between the groups. Sensory training of the posterior thigh should be included in the rehabilitation programme of stroke patients.


Overexpression of Chromatin Assembly Factor-1/p60 helps to predict the prognosis of melanoma patients.
Cutaneous melanoma (CM) is the most lethal form of skin malignancy, which registers a constant increase in incidence worldwide. The identification of molecular alteration(s) involved in its biological aggressiveness represents a major challenge for researchers, considering that existing therapies are ineffective to treat metastasizing cases. The epigenetic control of chromatin dynamics during DNA synthesis, replication, and repair is fundamental for the orderly progression of cell proliferation. The Chromatin Assembly Factor 1 (CAF-1) complex acts as a major regulator of this process; its intermediate (p60) subunit has been recently proposed as a novel proliferation and prognostic marker for several tumors. We aimed to establish if the evaluation of the expression of CAF-1/p60 in primary CM may help define the prevision of outcome of patients. Immunohistochemistry with anti-CAF-1/p60 was performed on paraffin-embedded tissue sections of 130 cases of primary CM retrieved from the archive files of the Department of Biomorphological and Functional Sciences, Section of Pathology, University "Federico II" of Naples, Italy. Results were compared with histopathological and follow-up data of patients. CAF-1/p60 was expressed in all CM. A significant statistical association between the overexpression of the protein and the occurrence of skin, node and/or distant metastases (P < 0.05) emerged, independently from histopathological prognostic factors. CAF-1/p60 looks promising as a new prognostic marker for CM and sheds new light on the molecular events associated with photocancerogenesis and melanoma biology.The screening for CAF-1/p60 might contribute to the molecular sub-classification of CM, with improved translational outcomes.


Understanding ageing well in Australian rural and regional settings: Applying an age-friendly lens.
This study investigates how rural community-dwelling older adults' views on what is important in maintaining health and wellbeing align with the eight age-friendly domains proposed by the World Health Organisation, and which domains are most salient. Data were gathered through open-ended response postcards distributed using a whole-of-community approach. The Rural City of Wangaratta, a rural local government area located in north-east Victoria. 262 postcards were returned by rural older adults, carers and family members. Thematic analysis of open-ended responses to the following question: what is important to you as you grow older (or your loved one), in terms of keeping healthy and well? Even though all eight age-friendly domains were identified as important for health and wellbeing, community and health services was the most frequently discussed domain, followed by transportation and access to outdoor spaces and buildings. However, individual-level factors, inclusive of personal activities, attitudes and capacities, were also identified as important to rural older adults. Findings support the use of the World Health Organization's age-friendly city framework in assessing what is important to rural older adults' health and wellbeing, with the community and health services domain most salient. However, individual-level activities, attitudes and capacities must also be considered.


Interfering with Gal-1-mediated angiogenesis contributes to the pathogenesis of preeclampsia.
Preeclampsia (PE) is a pregnancy-specific disorder characterized by sudden onset of hypertension and proteinuria in the second half of pregnancy (>20 wk). PE is strongly associated with abnormal placentation and an excessive maternal inflammatory response. Galectin-1 (Gal-1), a member of a family of carbohydrate-binding proteins, has been shown to modulate several processes associated with placentation and to promote maternal tolerance toward fetal antigens. Here, we show that Gal-1 exhibits proangiogenic functions during early stages of pregnancy, promoting decidual vascular expansion through VEGF receptor 2 signaling. Blocking Gal-1-mediated angiogenesis or lectin, galactoside-binding, soluble, 1 deficiency results in a spontaneous PE-like syndrome in mice, mainly by deregulating processes associated with good placentation and maternal spiral artery remodeling. Consistent with these findings, we observed a down-regulation of Gal-1 in patients suffering from early onset PE. Collectively, these results strengthen the notion that Gal-1 is required for healthy gestation and highlight Gal-1 as a valuable biomarker for early PE diagnosis.


Total tau in cerebrospinal fluid differentiates Alzheimer's disease from vascular dementia.
Tau protein is a microtubule-associated protein located in neuronal axons, which has been used in various configurations as a diagnostic marker of degenerative changes in the CNS. The aim of our study was to evaluate the use of CSF/ total tau in patients with Alzheimer-type dementia (AD) and vascular dementia (VD) compared to controls, in order to investigate. A total of 102 persons were included in the study: 58 AD patients, 24 VD patients, and 20 non-demented controls. The Alzheimer group was divided into 3 subgroups by clinical stage of the disease. CSF samples were collected by routine lumbar puncture. The level of total tau protein was determined by sensitive sandwich enzyme-linked immunosorbent assay (ELISA). CSF/total tau in the AD group was significantly higher than in the VD group (median 385.6 pg/ml vs. 101.2 pg/ml) and the controls (1.37 pg/ml). There were also significant differences among the AD stage groups in CSF total tau: highest in the group with severe dementia, intermediate in the group with moderate dementia, and lowest in the group with mild dementia. Differences in CSF total tau in all groups are not attributable to the patients' age. CSF total tau clearly and simply differentiates AD from VD. CSF total tau in the incipient stage of AD and its increase in parallel with the progression of the disease may also provide a biochemical test to monitor the development of the disease.


The 21st century role of Piver type II hysterectomy in FIGO stage IA, IB cervical cancer: a personal perspective.
Class II modified radical hysterectomy reported in 1974 by Piver, Rutledge and Smith for cervical cancer is an extended hysterectomy that has less dissection of the ureter from the paracervical tissues, ligation of the uterine vessels just medial to the ureter to ensure preservation of the distal ureteral blood supply, and less radical parametrectomy preserving the lateral parametrium. The authors present a 21st century personal perspective on the use of a type II hysterectomy based on the 1994 FIGO changes in classification of Stage IAI, IA2, IBI and IB2.


Rosmarinus officinalis L. (rosemary) extract has antibiofilm effect similar to the antifungal nystatin on Candida samples.
Candida spp. are naturally opportunistic and can promote infections. These yeasts can form biofilm, after penetration and adhesion to the biotic or abiotic surfaces. Preexisting diseases, treatments with drugs and radiation therapy, medical procedures, and parafunctional habits favor the installation of a fungal infection. Increased resistance to the available antifungals has become a concern. Therefore, alternative methods to control them have been evaluated, including the use of plant substances. In this study, the antibiofilm effect of R. officinalis L. extract was analyzed on C. albicans, C. dubliniensis, C. glabrata, C. krusei, and C. tropicalis. A phytochemical analysis of the extract was performed. Biofilms were formed for 48 h and exposed to the different concentrations of the extract (50, 100, and 200 mg/mL) for 5 min or 24 h. The effect of the plant extract was compared to the antifungal nystatin. Rosmarinus officinalis L. extract was constituted of phenols and flavonoids, highlighting the presence of chlorogenic acid derivatives in its composition. Biofilm reductions were observed after exposure to the plant extract for both periods. The plant extract provided a reduction similar to the antifungal. Thus, R. officinalis L. extract showed antibiofilm effect on Candida spp. comparable to the nystatin.


Noradrenaline is crucial for the substantia nigra dopaminergic cell maintenance.
In Parkinson's disease, degeneration of substantia nigra dopaminergic neurons is accompanied by damage on other neuronal systems. A severe denervation is for example seen in the locus coerulean noradrenergic system. Little is known about the relation between noradrenergic and dopaminergic degeneration, and the effects of noradrenergic denervation on the function of the dopaminergic neurons of substantia nigra are not fully understood. In this study, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) was injected in rats, whereafter behavior, striatal KCl-evoked dopamine and glutamate releases, and immunohistochemistry were monitored at 3 days, 3 months, and 6 months. Quantification of dopamine-beta-hydroxylase-immunoreactive nerve fiber density in the cortex revealed a tendency towards nerve fiber regeneration at 6 months. To sustain a stable noradrenergic denervation throughout the experimental timeline, the animals in the 6-month time point received an additional DSP4 injection (2 months after the first injection). Behavioral examinations utilizing rotarod revealed that DSP4 reduced the time spent on the rotarod at 3 but not at 6 months. KCl-evoked dopamine release was significantly increased at 3 days and 3 months, while the concentrations were normalized at 6 months. DSP4 treatment prolonged both time for onset and reuptake of dopamine release over time. The dopamine degeneration was confirmed by unbiased stereology, demonstrating significant loss of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra. Furthermore, striatal glutamate release was decreased after DSP4. In regards of neuroinflammation, reactive microglia were found over the substantia nigra after DSP4 treatment. In conclusion, long-term noradrenergic denervation reduces the number of dopaminergic neurons in the substantia nigra and affects the functionality of the nigrostriatal system. Thus, locus coeruleus is important for maintenance of nigral dopaminergic neurons.


Valvular and perivalvular abnormalities in end-stage renal disease.
Valvular and perivalvular involvement in end-stage renal disease (ESRD) is most commonly manifested as mitral annular calcification and aortic valve calcification. Both mitral and aortic valve calcification (MAC) occur more frequently and at younger age in those with ESRD than in those with normal renal function. Aortic valve calcification progresses to aortic stenosis more commonly and at a more accelerated rate than in the general population. Altered calcium and phosphate metabolism are thought to predispose to these valvular and perivalvular abnormalities. No treatment is necessary for MAC unless severe mitral regurgitation or stenosis occur (both are rare). Mitral valve repair or replacement and aortic valve replacement are indicated for severe symptomatic valve stenosis or regurgitation, albeit at a higher risk than in those with normal renal function. Infective endocarditis may complicate MAC or aortic stenosis in patients with ESRD and is associated with a high mortality rate in such patients.


Misidentification syndromes related to face specific area in the fusiform gyrus.
The "delusional misidentification syndromes" are a group of uncommon and varied disorders in which, in typical form, the patient thinks that a particular familiar person is someone else or a certain familiar place is a duplicate. Although first identified and considered a memory disorder by Pick, evidence in support of this has been difficult to identify. They have been most often seen in various psychotic and organic brain diseases but lesions have been generally diffuse although the right temporal lobe has been implicated. A patient was investigated who abruptly developed a disorder wherein she misidentified her husband as her deceased sister and claimed that her home was a duplicate of her real home that were typical of Frégoli syndrome and Pick's reduplicative paramnesia, respectively. A discrete area of brain damage, probably ischaemic, in this patient was seen on MRI in the anterior part of the right fusiform gyrus and a smaller area in the nearby anterior middle and inferior temporal gyri with associated parahippocampal and hippocampal atrophy. A high order nervous system function that is devoted to the identification of faces is located in the adjacent midportion of the fusiform gyrus and a similar locus for environmental scenes, termed the parahippocampal place area, is present in the bordering parahippocampal gyrus. The misidentification phenomena in this case can be explained by disruption of the connections of these highly specialised areas with the most anterior inferior and medial part of the right temporal lobe where long term memory and mechanisms for the retrieval of information that are required for the visual recognition of faces and scenes are stored.


FcγRIIb Expression Is Decreased on Naive and Marginal Zone-Like B Cells From Females With Multiple Sclerosis.
B cells are critical to the development of multiple sclerosis (MS), but the mechanisms by which they contribute to the disease are poorly defined. We hypothesised that the expression of CD32b (FcγRIIb), a receptor for the Fc region of IgG with inhibitory activities in B cells, is lower on B cell subsets from people with clinically isolated syndrome (CIS) or MS. CD32b expression was highest on post-naive IgM+ B cell subsets in healthy controls. For females with MS or CIS, significantly lower CD32b expression was identified on IgM+ B cell subsets, including naive and IgMhi MZ-like B cells, when compared with control females. Lower CD32b expression on these B cell subsets was associated with detectable anti-Epstein Barr Virus viral capsid antigen IgM antibodies, and higher serum levels of B cell activating factor. To investigate the effects of lower CD32b expression, B cells were polyclonally activated in the presence of IgG immune complexes, with or without a CD32b blocking antibody, and the expression of TNF and IL-10 in B cell subsets was assessed. The reduction of TNF but not IL-10 expression in controls mediated by IgG immune complexes was reversed by CD32b blockade in naive and IgMhi MZ-like B cells only. However, no consequence of lower CD32b expression on these cells from females with CIS or MS was detected. Our findings highlight a potential role for naive and marginal zone-like B cells in the immunopathogenesis of MS in females, which requires further investigation.


The impact of primary immunization route on the outcome of infection with SARS-CoV-2 in a hamster model of COVID-19.
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has resulted in over 6.7 million deaths worldwide. COVID-19 vaccines administered parenterally via intramuscular or subcutaneous (SC) routes have reduced the severity of respiratory infections, hospitalization rates, and overall mortality. However, there is a growing interest in developing mucosally delivered vaccines to further enhance the ease and durability of vaccination. This study compared the immune response in hamsters immunized with live SARS-CoV-2 virus via SC or intranasal (IN) routes and assessed the outcome of a subsequent IN SARS-CoV-2 challenge. Results showed that SC-immunized hamsters elicited a dose-dependent neutralizing antibody response but of a significantly lower magnitude than that observed in IN-immunized hamsters. The IN challenge with SARS-CoV-2 in SC-immunized hamsters resulted in body weight loss, increased viral load, and lung pathology than that observed in IN-immunized and IN-challenged counterparts. These results demonstrate that while SC immunization renders some degree of protection, IN immunization induces a stronger immune response and better protection against respiratory SARS-CoV-2 infection. Overall, this study provides evidence that the route of primary immunization plays a critical role in determining the severity of a subsequent respiratory infection caused by SARS-CoV-2. Furthermore, the findings suggest that IN route of immunization may be a more effective option for COVID-19 vaccines than the currently used parenteral routes. Understanding the immune response to SARS-CoV-2 elicited via different immunization routes may help guide more effective and long-lasting vaccination strategies.


Sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitudinal multicentre cohort study.
To ascertain the relationship among early (first 48 h) deep sedation, time to extubation, delirium and long-term mortality. We conducted a multicentre prospective longitudinal cohort study in 11 Malaysian hospitals including medical/surgical patients (n = 259) who were sedated and ventilated ≥24 h. Patients were followed from ICU admission up to 28 days in ICU with 4-hourly sedation and daily delirium assessments and 180-day mortality. Deep sedation was defined as Richmond Agitation Sedation Score (RASS) ≤-3. The cohort had a mean (SD) age of 53.1 (15.9) years and APACHE II score of 21.3 (8.2) with hospital and 180-day mortality of 82 (31.7%) and 110/237 (46.4%). Patients were followed for 2,657 ICU days and underwent 13,836 RASS assessments. Midazolam prescription was predominant compared to propofol, given to 241 (93%) versus 72 (28%) patients (P < 0.0001) for 966 (39.6%) versus 183 (7.5%) study days respectively. Deep sedation occurred in (182/257) 71% patients at first assessment and in 159 (61%) patients and 1,658 (59%) of all RASS assessments at 48 h. Multivariable Cox proportional hazard regression analysis adjusting for a priori assigned covariates including sedative agents, diagnosis, age, APACHE II score, operative, elective, vasopressors and dialysis showed that early deep sedation was independently associated with longer time to extubation [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.89-0.97, P = 0.003], hospital death (HR 1.11, 95% CI 1.05-1.18, P < 0.001) and 180-day mortality (HR 1.09, 95% CI 1.04-1.15, P = 0.002), but not time to delirium (HR 0.98, P = 0.23). Delirium occurred in 114 (44%) of patients. Irrespective of sedative choice, early deep sedation was independently associated with delayed extubation and higher mortality, and thus was a potentially modifiable risk in interventional trials.


17-beta estradiol inhibits oxidative stress-induced accumulation of AIF into nucleolus and PARP1-dependent cell death via estrogen receptor alpha.
Oxidative stress-induced DNA damage results in over-activation of poly(ADP-ribose) polymerase 1 (PARP1), leading to parthanatos, a newly discovered cell elimination pathway. Inhibition of PARP1-dependent cell death has shown to improve the outcome of diseases, including stroke, heart ischemia, and neurodegenerative diseases. In the present study we aimed to detect whether estrogen plays a protective role in inhibiting parthanatos. We utilized human mammary adenocarcinoma cells (MCF7) that abundantly express the estrogen receptor alpha and beta (ERα and ERβ). Parthanatos was induced by challenging the cells with hydrogen peroxide (H2O2). Microscopic imaging and molecular biological techniques, such as Western blot analysis and RNA interference, were performed. The results showed 17β estradiol (E2) protected MCF7 cells from PARP1-dependent cell death by decreasing protein PARylation, and AIF translocation into nuclei/nucleoli. Down-regulation of ERα expression by siRNA before E2 addition resulted in the failure of the E2-mediated inhibition of H2O2-induced protein PARylation and AIF nucleolar translocation. Together these data suggest that estrogen via its alpha-type receptor inhibits oxidative stress-induced, PARP1-dependent cell death. The present study provided us insight into how to apply hormone therapy in intervention of parthanatos-implicated ischemic and degenerative diseases.


Influence of the CXCL1 rs4074 A allele on alcohol induced cirrhosis and HCC in patients of European descent.
CXCL1 (CXC chemokine-ligand-1) is a ligand for CXC chemokine receptor 2 expressed on hepatic stellate cells (HSC). Thus, CXCL1 might contribute to HSC activation and fibrogenesis. In the present study, we investigated the influence of the CXCL1 rs4074 polymorphism on the occurrence of alcohol induced liver cirrhosis and hepatocellular carcinoma (HCC). The study involved 458 patients with alcoholic cirrhosis (170 with HCC), 115 alcoholics without liver disease and 342 healthy controls. All subjects were genotyped for the CXCL1 rs4074 polymorphism and CXCL1 serum levels of 132 patients were measured. In vitro CXCL1 secretion in TLR-transfected cell lines were studied by ELISA. Distribution of the CXCL1 genotypes (GG/GA/AA) was 159/219/80 in patients with alcoholic cirrhosis, 52/44/19 in alcoholic controls and 158/140/44 in healthy controls. Patients with alcohol-induced cirrhosis were significantly more often carriers of the CXCL1 rs4074 A allele (65.3%) than alcoholics without liver disease (54.8%, OR=1.55; 95%CI=1.025-2.350; p=0.04) and healthy controls (53.8%, OR=1.62; 95%CI=1.212-2.151; p=0.001). Accordingly, the frequency of the CXCL1 rs4074 A allele was significantly higher in the cirrhotic patients than in the subjects without cirrhosis (41.4% vs. 33.9%, OR=1.38, 95% CI:1.14-1.66, p=0.001). Furthermore cirrhotic carriers of the CXCL1 rs4074 A allele had significantly higher CXCL1 serum levels than carriers of the GG genotype. In contrast to sera from healthy controls, sera from patients with alcoholic cirrhosis induced CXCL1 secretion in TLR2- (p=0.016) and TLR4- (p=0.008) transfected HEK293 cells. This finding indicates that sera from patients with alcoholic cirrhosis contain soluble ligands that can induce CXCL1 production via stimulation of TLRs. The enhanced CXCL1 serum levels in carriers of the rs4074 A allele together with their increased frequency in patients with alcohol induced cirrhosis suggest the CXCL1 rs4074 A allele as a genetic risk factor for alcoholic cirrhosis.


Short vertical falls in infants.
To define injuries from short vertical falls (SVF) in infants, and to compare those with minor or no injuries to those with significant injury. Descriptive, retrospective chart review. Pediatric emergency department (PED) of an urban teaching hospital. Infants < or = 10 months treated between January 1990 and December 1992 presenting with a SVF (< or = 4 feet). 167 patients met the definition. The mean age was 5.2 months; 56% were male. The mechanisms of injury included rolling off a bed (55%), being dropped from a caretaker's arms (20%), rolling off a couch (16%), and falling from other objects (10%). The majority of patients (85 %) had minor or no injury. Significant injuries were sustained by 15% (n = 25), including 16 with a closed head injury (12 with skull fractures), two with intracranial bleed, and seven with a long bone fracture. Subsequently, the two patients with intracranial hemorrhages were confirmed as being from child abuse. After excluding cases of suspected abuse, the only characteristic found to be independently associated with significant injury was being dropped by the caretaker (odds ratio: 6.4 vs rolling or falling from furniture, 95% CI: 2.0, 21.5). The most common mechanism of a SVF was rolling off a bed. Most patients sustained minor or no injury. No child sustained an intracranial hemorrhage from a SVF. The child with intracranial injury and/or multiple injuries warrants an investigation. Being dropped appears to be a greater risk for significant injury than rolling off or falling from furniture.


An Optimized DNA Analysis Workflow for the Sampling, Extraction, and Concentration of DNA obtained from Archived Latent Fingerprints.
DNA profiles have been obtained from fingerprints, but there is limited knowledge regarding DNA analysis from archived latent fingerprints-touch DNA "sandwiched" between adhesive and paper. Thus, this study sought to comparatively analyze a variety of collection and analytical methods in an effort to seek an optimized workflow for this specific sample type. Untreated and treated archived latent fingerprints were utilized to compare different biological sampling techniques, swab diluents, DNA extraction systems, DNA concentration practices, and post-amplification purification methods. Archived latent fingerprints disassembled and sampled via direct cutting, followed by DNA extracted using the QIAamp® DNA Investigator Kit, and concentration with Centri-Sep™ columns increased the odds of obtaining an STR profile. Using the recommended DNA workflow, 9 of the 10 samples provided STR profiles, which included 7-100% of the expected STR alleles and two full profiles. Thus, with carefully selected procedures, archived latent fingerprints can be a viable DNA source for criminal investigations including cold/postconviction cases.


Altered cytoskeleton organization in platelets from patients with MYH9-related disease.
MYH9-related disease (MYH9-RD) is an autosomal dominant disorder deriving from mutations in the MYH9 gene encoding for the heavy chain of non-muscle myosin IIA, and characterized by thrombocytopenia and giant platelets. Isoform IIA of myosin is the only one expressed in platelets, but the possibility that MYH9 mutations affect the organization of contractile structures in these blood elements has never been investigated. In this work we have analyzed the composition and the agonist-induced reorganization of the platelet cytoskeleton from seven MYH9-RD patients belonging to four different families. We found that an increased amount of myosin was constitutively associated with actin in the cytoskeleton of resting MYH9-RD platelets. Upon platelet stimulation, an impaired increase in the total cytoskeletal proteins was observed. Moreover, selected membrane glycoproteins, tyrosine kinases, and small GTPases failed to interact with the cytoskeleton in agonist-stimulated MYH9-RD platelets. These results demonstrate for the first time that mutations of MYH9 result in an alteration of the composition and agonist-induced reorganization of the platelet cytoskeleton. We suggest that these abnormalities may represent the biochemical basis for the previously reported functional alterations of MYH9-RD platelets, and for the abnormal platelet formation from megakaryocytes, resulting in thrombocytopenia and giant platelets.


Emphysematous cystitis in an elderly patient with ulcerative colitis.
Emphysematous cystitis is a rare complication of lower urinary tract infections. The disease is characterized by air within the bladder wall and lumen and commonly occurs in middle-aged diabetic women. Intramural bladder gas seen on imaging is pathognomonic for this condition. The severity of the illness varies widely from cases diagnosed incidentally to patients presenting with life-threatening sepsis. We report the case of an 80-year-old non-diabetic man presenting with emphysematous cystitis after a total colectomy for ulcerative colitis.


Synergy between Cell Surface Glycosidases and Glycan-Binding Proteins Dictates the Utilization of Specific Beta(1,3)-Glucans by Human Gut Bacteroides.
The human gut microbiota (HGM) has far-reaching impacts on human health and nutrition, which are fueled primarily by the metabolism of otherwise indigestible complex carbohydrates commonly known as dietary fiber. However, the molecular basis of the ability of individual taxa of the HGM to address specific dietary glycan structures remains largely unclear. In particular, the utilization of β(1,3)-glucans, which are widespread in the human diet as yeast, seaweed, and plant cell walls, had not previously been resolved. Through a systems-based approach, here we show that the symbiont Bacteroides uniformis deploys a single, exemplar polysaccharide utilization locus (PUL) to access yeast β(1,3)-glucan, brown seaweed β(1,3)-glucan (laminarin), and cereal mixed-linkage β(1,3)/β(1,4)-glucan. Combined biochemical, enzymatic, and structural analysis of PUL-encoded glycoside hydrolases (GHs) and surface glycan-binding proteins (SGBPs) illuminates a concerted molecular system by which B. uniformis recognizes and saccharifies these distinct β-glucans. Strikingly, the functional characterization of homologous β(1,3)-glucan utilization loci (1,3GUL) in other Bacteroides further demonstrated that the ability of individual taxa to utilize β(1,3)-glucan variants and/or β(1,3)/β(1,4)-glucans arises combinatorially from the individual specificities of SGBPs and GHs at the cell surface, which feed corresponding signals to periplasmic hybrid two-component sensors (HTCSs) via TonB-dependent transporters (TBDTs). These data reveal the importance of cooperativity in the adaptive evolution of GH and SGBP cohorts to address individual polysaccharide structures. We anticipate that this fine-grained knowledge of PUL function will inform metabolic network analysis and proactive manipulation of the HGM. Indeed, a survey of 2,441 public human metagenomes revealed the international, yet individual-specific, distribution of each 1,3GUL.IMPORTANCEBacteroidetes are a dominant phylum of the human gut microbiota (HGM) that target otherwise indigestible dietary fiber with an arsenal of polysaccharide utilization loci (PULs), each of which is dedicated to the utilization of a specific complex carbohydrate. Here, we provide novel insight into this paradigm through functional characterization of homologous PULs from three autochthonous Bacteroides species, which target the family of dietary β(1,3)-glucans. Through detailed biochemical and protein structural analysis, we observed an unexpected diversity in the substrate specificity of PUL glycosidases and glycan-binding proteins with regard to β(1,3)-glucan linkage and branching patterns. In combination, these individual enzyme and protein specificities support taxon-specific growth on individual β(1,3)-glucans. This detailed metabolic insight, together with a comprehensive survey of individual 1,3GULs across human populations, further expands the fundamental roadmap of the HGM, with potential application to the future development of microbial intervention therapies.


Conservation genetics of the threatened plant species Physaria filiformis (Missouri bladderpod) reveals strong genetic structure and a possible cryptic species.
Understanding genetic diversity and structure in a rare species is critical for prioritizing both in situ and ex situ conservation efforts. One such rare species is Physaria filiformis (Brassicaceae), a threatened, winter annual plant species. The species has a naturally fragmented distribution, occupying three different soil types spread across four disjunct geographical locations in Missouri and Arkansas. The goals of this study were to understand: (1) whether factors associated with fragmentation and small population size (i.e., inbreeding, genetic drift or genetic bottlenecks) have reduced levels of genetic diversity, (2) how genetic variation is structured and which factors have influenced genetic structure, and (3) how much extant genetic variation of P. filiformis is currently publicly protected and the implications for the development of conservation strategies to protect its genetic diversity. Using 16 microsatellite markers, we genotyped individuals from 20 populations of P. filiformis from across its geographical range and one population of Physaria gracilis for comparison and analyzed genetic diversity and structure. Populations of P. filiformis showed comparable levels of genetic diversity to its congener, except a single population in northwest Arkansas showed evidence of a genetic bottleneck and two populations in the Ouachita Mountains of Arkansas showed lower genetic variation, consistent with genetic drift. Populations showed isolation by distance, indicating that migration is geographically limited, and analyses of genetic structure grouped individuals into seven geographically structured genetic clusters, with geographic location/spatial separation showing a strong influence on genetic structure. At least one population is protected for all genetic clusters except one in north-central Arkansas, which should therefore be prioritized for protection. Populations in the Ouachita Mountains were genetically divergent from the rest of P. filiformis; future morphological analyses are needed to identify whether it merits recognition as a new, extremely rare species.


Psychiatric comorbidity assessed in Korean children and adolescents who screen positive for Internet addiction.
This study aimed to evaluate clinical comorbidity in children and adolescents with Internet addiction by using structured interview. The study was performed in 2 stages. We screened for the presence of Internet addiction among 455 children (mean +/- SD age = 11.0 +/- 0.9 years) and 836 adolescents (mean +/- SD age = 15.8 +/- 0.8 years) using Young's Internet Addiction Scale. These subjects also completed a measure of psychopathology for comparison between addicted and nonaddicted subjects. Sixty-three children (13.8%) and 170 adolescents (20.3%) screened positive for Internet addiction. Of these, 12 children (male, N = 9; female, N = 3) and 12 adolescents (male, N = 11; female, N = 1) were randomly selected for evaluation of current psychiatric diagnoses. Structured interviews used were K-SADS-PL-K for children and SCID-IV for adolescents. Data were collected and interviews were conducted from August 2003 through October 2004. In the child group, 7 were diagnosed with attention-deficit/hyperactivity disorder (ADHD) not otherwise specified including those with subthreshold levels. Mean DuPaul's ADHD Rating Scale scores were more than 20% higher than the mean in Korean children for 6 subjects. In the adolescent group, 3 subjects had major depressive disorder, 1 had schizophrenia, and 1 had obsessive-compulsive disorder. By structured interview, we found that Internet-addicted subjects had various comorbid psychiatric disorders. The most closely related comorbidities differ with age. Though we can not conclude that Internet addiction is a cause or consequence of these disorders, clinicians must consider the possibility of age-specific comorbid psychiatric disorders in cases of Internet addiction.


Elucidation of the structural basis for ligand binding and translocation in conserved insect odorant receptor co-receptors.
In numerous insects, the olfactory receptor family forms a unique class of heteromeric cation channels. Recent progress in resolving the odorant receptor structures offers unprecedented opportunities for deciphering their molecular mechanisms of ligand recognition. Unexpectedly, these structures in apo or ligand-bound states did not reveal the pathway taken by the ligands between the extracellular space and the deep internal cavities. By combining molecular modeling with electrophysiological recordings, we identified amino acids involved in the dynamic entry pathway and the binding of VUAA1 to Drosophila melanogaster's odorant receptor co-receptor (Orco). Our results provide evidence for the exact location of the agonist binding site and a detailed and original mechanism of ligand translocation controlled by a network of conserved residues. These findings would explain the particularly high selectivity of Orcos for their ligands.


Dual-targeting nanotherapeutics antagonize hyperinsulinemia-promoted tumor growth via activating cell autophagy.
Hyperinsulinemia, a concomitant symptom in type 2 diabetes mellitus (T2DM) promotes the migration, invasion and proliferation of tumors by inhibiting autophagy. Therefore, it is necessary to search for antitumor drugs that can effectively antagonize hyperinsulinemia by promoting autophagy. In this study, dual-targeting modified selenium nanoparticles (u/A-SeNPs) were proposed as a biocompatible tumor chemotherapeutic drug to antagonize high insulin. The modification of chitosan (CS) and grafting targeted peptides (uPA/ACPP) allowed SeNPs to exert better selectivity and higher antitumor activity. The nanotherapeutics entered tumor cells through receptor-mediated endocytosis and produced excessive ROS. Meanwhile, u/A-SeNPs significantly increased the level of autophagy in tumor cells, as detected by monodansylcadaverine (MDC) and mRFP-GFP-LC3. U/A-SeNPs cause mitochondrial fragmentation to induce the cell apoptosis via the synergistic action of overproduced ROS and activated autophagy. In conclusion, this study proposes a feasible method for the synthesis of dual-targeting nanomedicines, and it also provides a new strategy for the application of Se-based nanotherapeutics in tumor therapy under hyperinsulinemia conditions.


Steroidogenesis-activator polypeptide isolated from a rat Leydig cell tumor.
A cycloheximide-sensitive protein responsive to adenosine 3',5'-monophosphate has been postulated to participate in the regulation of cholesterol side-chain cleavage activity in steroidogenic tissues. Such a steroidogenesis activator polypeptide (SAP) had been isolated from rat adrenocortical tissue and partially characterized. Now a polypeptide with comparable chromatographic behavior and biological activity has been purified from the rat H-540 Leydig cell tumor in quantities sufficient for amino acid sequencing. The activator contains 30 amino acid residues and has a molecular weight of 3215. The synthetic construct based on this sequence is virtually equipotent with native H-540 tumor SAP in an adrenal mitochondrial cholesterol side-chain cleavage assay. Hormonal regulation of the intracellular concentration of this activator may control the rate of cholesterol metabolism in steroidogenic organs.


Influence of aging on murine neutrophil and macrophage function against Candida albicans.
Previous work by our group showed that aged C57BL/6 mice develop an altered innate and adaptive immune response to Candida albicans and are more susceptible to systemic primary candidiasis. In this work, we used young (2-3 months old) and aged (18-20 months old) C57BL/6 mice to study in vitro the influence of aging on (1) the fungicidal activity of neutrophils and macrophages, (2) the production of cytokines by resident peritoneal macrophages in response to C. albicans, and (3) cell surface Toll-like receptor (TLR) 2 expression on resident peritoneal macrophages. Our results indicate that murine phagocytes have a fungicidal activity well preserved with aging. In vitro production of proinflammatory cytokines (IL-6, IL-1beta, and tumor necrosis factor-alpha and chemokines (MIP-2) by purified (CD11b(+)) peritoneal macrophages in response to yeasts and hyphae of C. albicans was significantly lower in aged mice as compared with young mice. However, the production of IL-10 by macrophages, in response to C. albicans, was similar in both young and aged animals. Moreover, baseline TLR2 surface expression level was lower on aged macrophages than on control macrophages. Taken together, these data indicate that the increased susceptibility to C. albicans disseminated infections in aged mice is correlated with defects in TLR2 expression and in cytokine production, but not with an impaired fungicidal activity.


Narrative discourse impairments in Persian-speaking persons with traumatic brain injury: a pilot study.
Studies have shown the presence of narrative discourse difficulties in persons with traumatic brain injury (TBI), even in those who do not suffer from aphasia. Yet, there still exist inconsistencies between the results of different studies, in particular at the microlinguistic level. Moreover, a limited number of languages have been studied in this regard. Therefore, this study aimed at examining these skills in Persian-speaking individuals with TBI. The purpose of this pilot study was to analyse the microlinguistic and macrolinguistic skills of these individuals to determine impaired linguistic measures at different levels of narrative discourse. Fourteen non-aphasic Persian-speaking persons with TBI (9 with severe TBI and 5 with moderate TBI), aged 19-40 years (mean = 25.84, SD = 5.69), and 61 age-matched healthy adults completed a narrative task. Measures of language productivity, clause density, verbal error ratio, and cohesion ratio were calculated. Also, test-retest and inter-rater reliability coefficients were analysed. The TBI group was impaired in some microlinguistic and all macrolinguistic measures compared to their control peers. The results of this study suggest that multi-level narrative discourse analyses of Persian-speaking individuals with TBI may be useful for speech/language pathologists wishing to evaluate communication disorders in persons with TBI.


Review of Hereditary and Acquired Rare Choreas.
Movement disorders are often a prominent part of the phenotype of many neurologic rare diseases. In order to promote awareness and diagnosis of these rare diseases, the International Parkinson's and Movement Disorders Society Rare Movement Disorders Study Group provides updates on rare movement disorders. In this narrative review, we discuss the differential diagnosis of the rare disorders that can cause chorea. Although the most common causes of chorea are hereditary, it is critical to identify acquired or symptomatic choreas since these are potentially treatable conditions. Disorders of metabolism and mitochondrial cytopathies can also be associated with chorea. The present review discusses clues to the diagnosis of chorea of various etiologies. Authors propose algorithms to help the clinician in the diagnosis of these rare disorders.


Relationship between alcohol abuse and low back pain.
One hundred and forty-two consecutive referrals attending a low back pain clinic were assessed with questionnaires and blood tests for their alcohol consumption and the severity of their low back pain. Alcohol abuse was found by questionnaires in 11% of patients and 24% had abnormal blood tests. These are higher than reported in the general population. However, the level of alcohol consumption or presence of abnormal tests did not correlate with the severity of the low back pain as assessed by the degree of disability. Nevertheless, the increased consumption of alcohol may contribute to the syndrome complex.


Heterogeneity in [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography of non-small cell lung carcinoma and its relationship to metabolic parameters and pathologic staging.
To investigate the relationships between tumor heterogeneity, assessed by texture analysis of [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) images, metabolic parameters, and pathologic staging in patients with non-small cell lung carcinoma (NSCLC). A retrospective analysis of 38 patients with histologically confirmed NSCLC who underwent staging FDG-PET/computed tomography was performed. Tumor images were segmented using a standardized uptake value (SUV) cutoff of 2.5. Five textural features, related to the heterogeneity of gray-level distribution, were computed (energy, entropy, contrast, homogeneity, and correlation). Additionally, metabolic parameters such as SUVmax, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG), as well as pathologic staging, histologic subtype, and tumor diameter, were obtained. Finally, a correlation analysis was carried out. Of 38 tumors, 63.2% were epidermoid and 36.8% were adenocarcinomas. The mean ± standard deviation values of MTV and TLG were 30.47 ± 25.17 mL and 197.81 ± 251.11 g, respectively. There was a positive relationship of all metabolic parameters (SUVmax, SUVmean, MTV, and TLG) with entropy, correlation, and homogeneity and a negative relationship with energy and contrast. The T component of the pathologic TNM staging (pT) was similarly correlated with these textural parameters. Textural features associated with tumor heterogeneity were shown to be related to global metabolic parameters and pathologic staging.


[Primary surgical care of pelvic fractures associated with perineal laceration].
Unstable fractures of the pelvic ring, associated to perineal lacerations are severe injuries occurring during high-energy trauma. High rates of septic complications and mortality have been reported with these injuries. Current treatment guidelines, while dealing with open pelvic fractures or dislocations are discussed, based on a current review of the literature and on our local experience. At our institution, 55 unstable type B or C fractures of the pelvic ring were treated by osteosynthesis between 1991 and 1997. Of these, 11 patients presented with an associated perineal laceration (20%). Simultaneously to the immediate pelvic ring fixation, a diversion colostomy was performed in all these patients. Repeated wound debridements and wide spectrum antibioprophylaxis were associated. Of these 11 patients presenting an open pelvic fracture, only one died of pelvic sepsis at three weeks. 10 patients survived (91%) and went on to bony union, without any local infectious complications. Aggressive multidisciplinary initial surgical management is a rule when dealing with this type of injuries, immediate colostomy and careful wound debridement must be associated to the initial osteosynthesis.


Comparison of nonsurgical periodontal therapy with oral hygiene instruction alone for chronic periodontitis.
We evaluated changes in clinical variables and microbiological profiles of periodontopathogens among 56 patients with moderate to severe CP who were randomly assigned to oral hygiene instruction (OHI; n = 28) or nonsurgical periodontal treatment (NSPT; n = 28). Periodontal variables were assessed and subgingival plaque samples were obtained from deep pockets (≥5 mm) at baseline and 3 months after treatment. Real-time polymerase chain reaction was used to quantify Actinobacillus actinomycetemcomitans, Tannerella forsythia, Porphyromonas gingivalis, and Prevotella intermedia. All clinical variables significantly improved in both groups. Improvements in gingival bleeding index (GBI), probing pocket depth (PPD), and periodontal attachment loss (PAL) were significantly greater at 3 months after treatment in the NSPT group. At baseline, the prevalences of all pathogens were high. Significant reductions in microbial count were observed for A. actinomycetemcomitans and T. forsythia (P ≤ 0.05) in the NSPT group. None of the improvements in clinical variables was associated with changes in microbiological profiles. At 3 months after treatment, NSPT was associated with significantly greater improvements in GBI, PPD, and PAL as compared with OHI. A. actinomycetemcomitans and T. forsythia counts were significantly lower in the NSPT group.


Risk factors of infectious complication after ureteroscopic procedures of the upper urinary tract.
Ureteroscopic procedures are being commonly performed in urology, but only a few clinical studies have been conducted on infectious complications after these procedures, and overall understanding on the preoperative use of prophylactic antibiotics is insufficient. This study examined the incidence rate of infectious complications and the risk factors affecting incidence after ureteroscopic procedures. We retrospectively reviewed the medical records of 531 patients who underwent ureteroscopy and ureteroscopic lithotripsy in our hospital, including age, sex, past history, comorbidity, urine analysis, urine culture, blood test, hydronephrosis, urethral catheter or ureteral stent, and percutaneous nephrostomy placement from January 2002 to December 2011. A total of 20 patients (3.8%) contracted infectious complications after various procedures in the upper urinary tract. Preoperative bacteriuria, hydronephrosis, and the placement of a urethral catheter or ureteral stent, and percutaneous nephrostomy are significant risk factors of infectious complication. No significant differences were shown in the types and start time of prophylactic antibiotics. Diagnostic ureteroscopy exhibited a higher incidence rate of infectious complications compared to ureteroscopic lithotripsy.


Laboratory intercomparison of the ozone absorption coefficients in the mid-infrared (10 microm) and ultraviolet (300-350 nm) spectral regions.
For the measurement of atmospheric ozone concentrations, the mid-infrared and ultraviolet regions are both used by ground-, air-, or satellite-borne instruments. In this study we report the first laboratory intercomparison of the ozone absorption coefficients using simultaneous measurements in these spectral regions. The intercomparison shows good agreement (around 98.5%) between the HITRAN 2000 recommendation for the mid-infrared and the most reference measurements in the ultraviolet regions, whereas systematic differences of about 5.5% are observed when using the recommendation of HITRAN2003 for the mid-infrared. Possible reasons for this discrepancy are discussed. Future measurements are clearly needed to resolve this issue.


Stress response after race and endurance training sessions and competitions in Arabian horses.
Assuring a high level of animal welfare is a critical aspect of contemporary animal husbandry. Equine athletes begin their careers at a very young age when they are still developing and they are both physically and mentally immature. Lack of scientific knowledge of the stress related to horse racing impedes the development of optimal training programs to attain equilibrium between the best sport results and optimal welfare. This study aimed to determine the influence of the intensity and type of physical activity on peripheral blood cortisol concentration. Thirty untrained Arabians, 9 endurance and 21 race horses were enrolled in this longitudinal study. Blood samples were analysed every 3-weeks in 4 training sessions and 2 races in racing horses and monthly after 2 training sessions and 1 competition in endurance horses. Cortisol concentration was measured at rest and 30 min. after physical effort. Racing horses were divided into two groups of the best and the worst performers. Cortisol concentration increased significantly after training and competition, however both in racing and endurance horses the increase was more intensive after competition. In the racing horses, cortisol concentration tended to gradually increase after the subsequent trainings during the racing season, however the starting gate did not appear to exert any impact on cortisol concentration. The best performing race horses appeared to have a lesser increase in cortisol concentration after the race than the worst performing horses, however the cortisol concentration after the race was not significantly different between these two groups of horses. This study suggests that an optimal training program can induce a stress response which is likely not to have any harmful impact on an athlete's welfare. The more intense effort associated with competition events, both in race and endurance horses, results in a greater stress response, indicating that these kinds of events should be limited to assure animal welfare. Finally, better performance horses adapt more readily to physical activity as they experience less increase of serum cortisol concentration after the race.


A freeze-fracture study of avian epiphyseal cartilage differentiation.
The morphological features of avian epiphyseal cartilage have been investigated by freeze-fracture techniques. Progressive changes occurred in both the cells and the matrix during differentiation. Chondrocytes changed in shape from small flattened cells with few, short cellular processes, to enlarged ovoid cells with numerous long processes often associated with extracellular vesicles. In the matrix these vesicles appeared first in the cellular lacunae, then in the extralacunar matrix, becoming larger and more numerous. Large membrane-associated particles (MAPS) were seen on the p faces of the plasmalemma. These became progressively concentrated on and around the cellular processes, with few large MAPS being seen on the e face. Similar distribution of MAPS was seen in the matrix vesicles. Domains of hydrated proteoglycan aggregates were manifest as regular fracture patterns in the extralacunar matrix of the upper regions of the plate. Collagen fibrils progressively increased in size and state of aggregation, often being associated with matrix vesicles and in the end, with long plate-like mineral crystals. These findings, while in basic agreement with patterns observed with TEM, reveal important new features concerning cellular and matrix structure during cartilage differentiation.


Polymorphonuclear leukocyte dysfunction associated with feline leukaemia virus infection.
The chemiluminescent characteristics of enriched (greater than 95%) peripheral blood polymorphonuclear leukocyte populations (PMN) from normal and feline leukaemia virus (FeLV)-infected cats were investigated. FeLV-infected cats demonstrated a significantly lower (P less than 0.001) PMN chemiluminescent response when compared to the response of normal age-matched controls. Normal PMN treated with FeLV-infected cat serum exhibited a depressed response in comparison to control cells. A titration of serum from infected cats supplemented with normal serum revealed a titratable suppression of chemiluminescence with increasing concentration of serum from the infected cats. However, PMN from FeLV-infected cats treated with normal serum displayed a slight increase in chemiluminescence over the same cells in autologous serum. The addition of inactivated FeLV to normal PMN caused a titratable decrease in chemiluminescence.


Nickel-catalyzed allylic substitution of simple alkenes.
This report describes a nickel-catalyzed allylic substitution process of simple alkenes whereby an important structural motif, a 1,4-diene, was prepared. The key to success is the use of an appropriate nickel-phosphine complex and a stoichiometric amount of silyl triflate. Reactions of 1-alkyl-substituted alkenes consistently provided 1,1-disubstituted alkenes with high selectivity. Insight into the reaction mechanism as well as miscellaneous application of the developed catalytic process is also documented.


Financial Incentive Does Not Affect P300 in the Complex Trial Protocol (CTP) Version of the Concealed Information Test (CIT) in Malingering Detection. II. Uninstructed Subjects.
Well-known research showed that the skin conductance response (SCR) of the Autonomic Nervous System (ANS) in the Concealed Information Test (CIT) is usually augmented in participants who are financially and motivationally incentivized to beat the CIT. This is not what happens with Reaction Time (RT)-based CITs, P300 CITs based on the 3-stimulus protocol, nor on the P300-based complex trial protocol for detection of malingering (however these tests differ from forensic CITs). The present report follows up the Rosenfeld et al. (1, 2) study of motivated malingerers instructed how to beat the test, with uninstructed motivated (paid and unpaid) and unmotivated ("simple malingering") subjects, using episodic and semantic memory probes. The Test of Memory Malingering (TOMM) validated behavioral differences among groups. The "CIT effect" (probe-minus-irrelevant P300 differences) did not differ among incentive groups, although as previously, semantic memory-evoked P300s exceeded episodic memory evoked P300s. An effect of specific test-beating instructions was found to enhance the CIT effect for semantic information.


Synergistic regulation of Pseudomonas aeruginosa-induced cytokine production in human monocytes by mannose receptor and TLR2.
The immune response to pathogen is regulated by a combination of specific PRR, which are involved in pathogen recognition. Pseudomonas aeruginosa, a bacterium that causes life-threatening disease in immuno-compromised host, is recognized by distinct members of the TLR family. We have previously shown that viable P. aeruginosa bacteria are recognized by human monocytes mainly through TLR2. Using ligand-specific blocking antibodies, we herein show that the mannose receptor (MR), a phagocytic receptor for unopsonized P. aeruginosa bacteria, contributes equally to TLR2 in proinflammatory cytokine production by human monocytes in response to P. aeruginosa infection. Synergy of both receptors totally controls the immune response. Viable P. aeruginosa bacteria activate NF-kappaB and MAPK pathways and enhance TLR2-mediated signaling in MR-transfected human embryonic kidney 293 cells. Moreover, MR follows the same kinetics and colocalizes with TLR2 in the endosome during in vivo infection of human macrophages with P. aeruginosa. The studies provide the first demonstration of a significant role for MR, synergistic with TLR2, in activating a proinflammatory response to P. aeruginosa infection.


Triterpenoids from Aglaia abbreviata exert cytotoxicity and multidrug resistant reversal effect in MCF-7/ADM cells via reactive oxygen species induction and P-glycoprotein inhibition.
Triterpenoids from the Aglaia have been shown cytotoxicity on a broad spectrum of human tumor cells. In the present study, we extracted triterpenoids AA-5 (1) and AA-6 (2) from stems of Aglaia abbreviata, and studied their cytotoxicity in multidrug resistant (MDR) MCF-7/ADM cells. After 48 h treatment, AA-5 (1) and AA-6 (2) significantly increased mitochondrial-mediated apoptosis by enhancing reactive oxygen species (ROS) with depressed mitochondrial membrane potential and caspase-9 activities. The drug efflux transporter P-glycoprotein (P-gp) and the intracellular antioxidant systems, involving Glutathione S-Transferase π, Glutathione and heme oxygenase-1, were also inhibited via the ROS-depressed Akt/NF-E2-related factor 2 pathway. Furthermore, 2 h-treatment of AA-6 (2) at non-toxic concentrations exhibited MDR reversal effects with no alteration on P-gp expression but increased drug accumulation ability. AA-6 alos demonstrated synergetic effects with classic anti-tumor agents. Moreover, computational modeling studies showed that AA-6 (2) might bind to the modulator site on P-gp and act as an inhibitor, not a substrate of P-gp. Therefore, AA-5 (1) and AA-6 (2) may be effective anti-tumor and reversal agents for the further development of therapeutics against MDR breast cancer.


Introduction to the Thematic Minireview Series: Brain glycogen metabolism.
The synthesis of glycogen allows for efficient intracellular storage of glucose molecules in a soluble form that can be rapidly released to enter glycolysis in response to energy demand. Intensive studies of glucose and glycogen metabolism, predominantly in skeletal muscle and liver, have produced innumerable insights into the mechanisms of hormone action, resulting in the award of several Nobel Prizes over the last one hundred years. Glycogen is actually present in all cells and tissues, albeit at much lower levels than found in muscle or liver. However, metabolic and physiological roles of glycogen in other tissues are poorly understood. This series of Minireviews summarizes what is known about the enzymes involved in brain glycogen metabolism and studies that have linked glycogen metabolism to multiple brain functions involving metabolic communication between astrocytes and neurons. Recent studies unexpectedly linking some forms of epilepsy to mutations in two poorly understood proteins involved in glycogen metabolism are also reviewed.


Formation of photoreceptors in larval and adult goldfish.
Histogenesis of the photoreceptor layer in the retina of goldfish was studied morphometrically and with thymidine radioautography at the light microscopic level. At hatching, the photoreceptor layer is poorly differentiated. The cells in the outer nuclear layer that are postmitotic' at hatching differentiate into cones. Two to 3 days after hatching, rod nuclei appear in the outer nuclear layer , and rods begin to differentiate. Rods and rod nuclei accumulate across the retina during larval and juvenile life. It is proposed that rods are generated in the outer nuclear layer by dividing progenitor cells that may be analogous to subventricular cells. Rod progenitors appear to derive from clusters of undifferentiated cells in the inner nuclear layer, which are called neurogenic clusters. Some of these cells apparently migrate across the outer plexiform layer from the inner to the outer nuclear layer and then divide to produce rods. The ontogenetic sequence of photoreceptor development in the larval retina is recapitulated continuously in the circumferential growth zone at the margin of the juvenile and adult retina. New rods continue to be inserted, but at a slower rate, throughout the adult retina; this may explain how the density of rods is maintained constant despite the expansion of the retinal surface that accompanies growth of the eye.


Thyroid surgery and voice-related outcomes.
Vocal dysfunction in patients with thyroid pathology has been poorly documented, and dysfunction after thyroid surgery is generally reported in terms of recurrent laryngeal nerve or external laryngeal nerve palsy. But voice dysfunction is more complex than simply nerve integrity. The present study reports the incidence of dysphonia in patients presenting for thyroid surgery, and relates postoperative changes in vocal function to recurrent and external laryngeal nerve function, and the surgical handling of the strap muscles. Fifty patients were assessed by Visipitch before and after thyroidectomy. Following surgery the patients filled out a questionnaire. Overall 26 of 44 patients had no subjective postoperative voice change, while 10 reported subjective deterioration and eight reported subjective improvement in voicing. Postoperative objective assessment of these patients found that 17 were the same, eight refused to come for testing because they felt their voice had not changed, 13 were better and six were worse. Following surgery two patients (4.5%) had temporary recurrent laryngeal nerve palsies (2.5% of nerves at risk), and four patients (10%) suffered external laryngeal nerve palsies. Division of strap muscles was not detrimental to voicing. Six patients were lost to follow-up. Fifteen patients (34%) presented with vocal abnormalities, six (40%) of whom improved postoperatively. Patients may have voicing abnormalities before thyroid surgery is performed. Surgery may improve or worsen the voice irrespective of the pre-operative voice status.


Macropodid herpesviruses 1 and 2 occupy unexpected molecular phylogenic positions within the Alphaherpesvirinae.
The molecular phylogeny of macropodid herpesviruses 1 and 2 (MaHV-1 and -2) has been investigated by cloning and sequencing the genes encoding glycoprotein B from both viruses. Phylogenetic reconstructions based on the putative amino acid sequences of glycoprotein B indicate that MaHV-1 and -2 are most closely related to the subfamily Alphaherpesvirinae. Within the Alphaherpesvirinae, MaHV-1 and -2 are closely associated with those herpesviruses that infect primates. This phylogenetic relationship does not fit the constraints of the proposed co-evolution theory described for other members of the Alphaherpesvirinae which have mammalian hosts.


Probabilistic Learning by Positive and Negative Reinforcement in Generalized Anxiety Disorder.
This experiment examined learning tendencies in generalized anxiety disorder (GAD) using reinforcement feedback for probabilistic outcomes. One hundred sixty-six GAD and 105 non-GAD participants were randomized to a computerized probabilistic learning task that used either negative or positive reinforcement. Participants chose between stimuli with specific probabilities of reinforcement to learn which of each pair had the highest probability. Reinforced choices either removed an angry face (negative reinforcement) or made a happy face appear (positive reinforcement). Results showed that those with GAD learned the correct probabilistic choices at a slower rate over time and to a lesser degree than control participants regardless of reinforcement type. Estimations of the likelihood of receiving a good outcome posttask were also more inaccurate for those with GAD, especially when true likelihoods were high. Furthermore, compared with control participants, those with GAD reported lower perceived reinforcement sensitivity, higher behavioral inhibition sensitivity, and higher undesirable feelings toward probabilistic learning.


Optimal model-free prediction from multivariate time series.
Forecasting a time series from multivariate predictors constitutes a challenging problem, especially using model-free approaches. Most techniques, such as nearest-neighbor prediction, quickly suffer from the curse of dimensionality and overfitting for more than a few predictors which has limited their application mostly to the univariate case. Therefore, selection strategies are needed that harness the available information as efficiently as possible. Since often the right combination of predictors matters, ideally all subsets of possible predictors should be tested for their predictive power, but the exponentially growing number of combinations makes such an approach computationally prohibitive. Here a prediction scheme that overcomes this strong limitation is introduced utilizing a causal preselection step which drastically reduces the number of possible predictors to the most predictive set of causal drivers making a globally optimal search scheme tractable. The information-theoretic optimality is derived and practical selection criteria are discussed. As demonstrated for multivariate nonlinear stochastic delay processes, the optimal scheme can even be less computationally expensive than commonly used suboptimal schemes like forward selection. The method suggests a general framework to apply the optimal model-free approach to select variables and subsequently fit a model to further improve a prediction or learn statistical dependencies. The performance of this framework is illustrated on a climatological index of El Niño Southern Oscillation.