β-alanine supplementation improves in-vivo fresh and fatigued skeletal muscle relaxation speed.
In fresh muscle, supplementation with the rate-limiting precursor of carnosine, β-alanine (BA), results in a decline in muscle half-relaxation time (HRT) potentially via alterations to calcium (Ca2+) handling. Accumulation of hydrogen cation (H+) has been shown to impact Ca2+ signalling during muscular contraction, carnosine has the potential to serve as a cytoplasmic regulator of Ca2+ and H+ coupling, since it binds to both ions. The present study examined the effect of BA supplementation on intrinsic in-vivo isometric knee extensor force production and muscle contractility in both fresh and fatigued human skeletal muscle assessed during voluntary and electrically evoked (nerve and superficial muscle stimulation) contractions. Twenty-three males completed two experimental sessions, pre- and post- 28 day supplementation with 6.4 g.day-1 of BA (n = 12) or placebo (PLA; n = 11). Isometric force was recorded during a series of voluntary and electrically evoked knee extensor contractions. BA supplementation had no effect on voluntary or electrically evoked isometric force production, or twitch electromechanical delay and time-to-peak tension. There was a significant decline in muscle HRT in fresh and fatigued muscle conditions during both resting (3 ± 13%; 19 ± 26%) and potentiated (1 ± 15%; 2 ± 20%) twitch contractions. The mechanism for reduced HRT in fresh and fatigued skeletal muscle following BA supplementation is unclear. Due to the importance of muscle relaxation on total energy consumption, especially during short, repeated contractions, BA supplementation may prove to be beneficial in minimising contractile slowing induced by fatigue. The trial is registered with Clinicaltrials.gov, ID number NCT02819505.


High levels of photosystem I subunit II (PsaD) mRNA result in the accumulation of the PsaD polypeptide only in the presence of light.
The light-regulated mRNA and polypeptide accumulation of the nuclear encoded subunit II (PsaD) of the photosystem I reaction center was studied during the greening of etiolated spinach seedlings. Upon exposure to continuous white light, the mRNA, detected at low levels in etiolated seedlings, accumulated in a specific pattern. In contrast, the PsaD subunit could not be detected in the etiolated seedlings; the polypeptide could first be detected in thylakoid membranes approximately 4 h after exposure to continuous light. A pulse of red light induced the expression of the PsaD mRNA, but the polypeptide could not be detected unless the seedlings were exposed to light. In the light (but not in the dark), the PsaD mRNA was found associated with the polysomal fraction. Taken together, the data suggest a dual regulatory mechanism in which both the level of mRNA and the presence of light control the accumulation of the PsaD polypeptide.


Hypoxia predisposes neonatal rat ventricular myocytes to apoptosis induced by activation of the Fas (CD95/Apo-1) receptor: Fas activation and apoptosis in hypoxic myocytes.
Since apoptosis is an important contributor to heart diseases in which ischemia and hypoxia are key elements, we tested the hypothesis that hypoxia predisposes neonatal rat ventricular myocytes (NRVM) to Fas-mediated apoptosis, by shifting the balance between antiapoptotic and proapoptotic proteins towards the latter. Normoxic or hypoxic (22 h, 1% O(2)) cultured NRVM were exposed to recombinant Fas L (rFasL) for 7 h, and apoptosis measured thereafter. Whereas in normoxic NRVM, rFasL did not cause apoptosis measured by the TUNEL assay (4.8+/-0.5% in control versus 4.5+/-0.9% in rFasL), in hypoxic cultures rFasL increased the background apoptosis level by 100%. That Fas was functional in normoxic NRVM, despite its inability to mediate apoptosis, was evidenced by the finding that Fas activation increased the diastolic [Ca(2+)](i) levels measured by Fura 2 fluorescence, and caused arrhythmias. In support of our working hypothesis, hypoxia increased Fas expression by 200% (measured by quantitative Western blot), and the expression of the proapoptotic proteins ARTS and FADD by 323 and 250%, respectively, and decreased the expression of the antiapoptotic proteins ARC and FLIP by 90 and 60%, respectively. By upregulating Fas expression and key proapoptotic proteins, and by downregulating antiapoptotic proteins, hypoxia predisposes ventricular myocytes to Fas-induced apoptosis.


The need for a Rehabilitation Model to address the disparities of public healthcare for people living with HIV in South Africa.
Rehabilitation in the context of HIV management in Africa is still a neglected field which holds great promise for the improvement of the quality of life as well as integration of people living with HIV back into their communities and homes. However, rehabilitation has not been incorporated into HIV care despite the fact that a large number of people living with HIV experience disability. The dearth of literature and lack of models of care to roll out rehabilitation for people living with HIV in Africa are astounding. Well-resourced countries have emerging approaches on the management of disability in the context of HIV. However, epidemic countries are still lacking such an approach neglecting the devastating effects of disability on individual livelihoods and antiretroviral treatment adherence. Thus, rehabilitation needs to be integrated into the response to HIV. This article advocates for the development and implementation of a model of care to guide rehabilitation of people living with HIV in South Africa.


Microbiota and host immune responses: a love-hate relationship.
A complex relationship between the microbiota and the host emerges early at birth and continues throughout life. The microbiota includes the prokaryotes, viruses and eukaryotes living among us, all of which interact to different extents with various organs and tissues in the body, including the immune system. Although the microbiota is most dense in the lower intestine, its influence on host immunity extends beyond the gastrointestinal tract. These interactions with the immune system operate through the actions of various microbial structures and metabolites, with outcomes ranging from beneficial to deleterious for the host. These differential outcomes are dictated by host factors, environment, and the type of microbes or products present in a specific ecosystem. It is also becoming clear that the microbes are in turn affected and respond to the host immune system. Disruption of this complex dialogue between host and microbiota can lead to immune pathologies such as inflammatory bowel diseases, diabetes and obesity. This review will discuss recent advances regarding the ways in which the host immune system and microbiota interact and communicate with one another.


Impaired expression of CYP2D6 in intermediate metabolizers carrying the *41 allele caused by the intronic SNP 2988G>A: evidence for modulation of splicing events.
We investigated the molecular basis for low expression and activity of CYP2D6 associated with the CYP2D6*41 allele in about 10-15% of Caucasians with intermediate metabolizer phenotype. With respect to two previously described polymorphisms in the promoter (-1584C>G) and in intron 6 (2988G>A; c.985+39G>A), the three most frequent functional alleles have the distinct haplotypes 2D6*1[CG], 2D6*2[GG] and 2D6*41[CA], respectively. Reporter gene analyses in transiently transfected HepG2 and Huh7 hepatoma cells did not indicate changes in transcription rate by these polymorphisms. By reverse-transcription polymerase chain reaction analysis of liver RNA of genotyped patients, however, we discovered that the 2988G>A change was associated with increased levels of a nonfunctional splice variant lacking exon 6. Quantification by denaturing high-performance liquid chromatography revealed up to 7.3-fold increased levels of the splice variant and up to 2.9-fold less functional transcript in carriers of 2D6*41, in good concordance with concomitant changes in immunoquantified CYP2D6 protein. Recombinant expression of the entire genomic sequence coding for 2D6*41, 2D6*2 and 2D6*1 alleles but lacking the upstream region in COS-1 and Huh7 cell lines resulted in two-fold to five-fold reduced levels of CYP2D6 mRNA containing exon 6, apoprotein and enzyme activity of 2D6*41. These experiments establish the causal relationship between the intron 6 single-nucleotide polymorphism 2988G>A and the low expression phenotype associated with allele 2D6*41. These data improve the CYP2D6 genotype-phenotype relationship and they demonstrate that major phenotype changes occurring in large population subgroups can be caused by intronic polymorphisms outside of splice site consensus sequences.


Nitric oxide agents and apomorphine-induced rat behaviors.
Nitric oxide (NO) may alter dopamine release in the brain. Activation of D2-dopamine receptors may suppress NO synthase, and inhibition of NO synthase prevents behaviors induced by psychostimulants. We have investigated the modulatory actions of the precursor of NO synthesis (L-arginine) and the broad-spectrum NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on apomorphine-induced behaviors in the rat. Apomorphine was injected subcutaneously, and behaviors induced by the drug were examined in the presence or absence of intracerebroventricular administration of L-arginine and L-NAME. Our data indicate that L-arginine or L-NAME treatment decreased licking and yawning, but not penile erection induced by apomorphine. Apomorphine-induced behaviors may be modulated by NO levels.


13C isotopic abundances in natural nutrients: a newly formulated test meal for non-invasive diagnosis of type 2 diabetes.
A new method to replace commercially prepared 13C-labelled glucose with naturally available 13C-enriched substrates could result in promotion of the clinical applicability of the isotopic breath test for detection of type 2 diabetes (T2D). Variation of the carbon-13 isotope in human breath depends on the 13C enrichment in the diet taken by subjects. Here, we formulated a new test meal comprising naturally available 13C-enriched foods and subsequently administered it to non-diabetic control (NDC) subjects and those with T2D. We found that the new test meal-derived 13C enrichment of breath CO2 was significantly lower in T2D compared with NDC. Furthermore, from our observations T2D exhibited higher isotopic enrichment of oxygen-18 (18O) in breath CO2 compared with NDC following ingestion of the new meal. We determined the optimal diagnostic cut-off values of 13C (i.e. δ 13C‰ = 7.5‰) and 18O (i.e. δ 18O‰ = 3.5‰) isotopes in breath CO2 for precise classification of T2D and NDC. Our new method involving the administration of naturally 13C-abundant nutrients showed a typical diagnostic sensitivity and specificity of about 95%, suggesting a valid and potentially robust global method devoid of any synthetically manufactured commercial 13C-enriched glucose which thus may serve as an alternative diagnostic tool for routine clinical applications.


Recombination in Perovskite Solar Cells: Significance of Grain Boundaries, Interface Traps, and Defect Ions.
Trap-assisted recombination, despite being lower as compared with traditional inorganic solar cells, is still the dominant recombination mechanism in perovskite solar cells (PSCs) and limits their efficiency. We investigate the attributes of the primary trap-assisted recombination channels (grain boundaries and interfaces) and their correlation to defect ions in PSCs. We achieve this by using a validated device model to fit the simulations to the experimental data of efficient vacuum-deposited p-i-n and n-i-p CH3NH3PbI3 solar cells, including the light intensity dependence of the open-circuit voltage and fill factor. We find that, despite the presence of traps at interfaces and grain boundaries (GBs), their neutral (when filled with photogenerated charges) disposition along with the long-lived nature of holes leads to the high performance of PSCs. The sign of the traps (when filled) is of little importance in efficient solar cells with compact morphologies (fused GBs, low trap density). On the other hand, solar cells with noncompact morphologies (open GBs, high trap density) are sensitive to the sign of the traps and hence to the cell preparation methods. Even in the presence of traps at GBs, trap-assisted recombination at interfaces (between the transport layers and the perovskite) is the dominant loss mechanism. We find a direct correlation between the density of traps, the density of mobile ionic defects, and the degree of hysteresis observed in the current-voltage (J-V) characteristics. The presence of defect states or mobile ions not only limits the device performance but also plays a role in the J-V hysteresis.


Access to health care after welfare reform.
This research uses data from a longitudinal statewide study of Oregon families leaving Temporary Assistance to Needy Families (TANF) to identify: 1) the trends in insurance coverage over time; 2) the role of health insurance coverage in predicting whether respondents received needed medical care; and 3) the relationship between access to care and physical and mental health. Data were obtained from 637 families seven months after leaving welfare for work; 552 of these families were re-interviewed one year later. The data reveal that 40% of TANF leavers were uninsured at wave 2 and suggest that significant access barriers exist, which may be associated with poor health outcomes.


Treadmill exercise improves depression-like symptoms by enhancing serotonergic function through upregulation of 5-HT1A expression in the olfactory bulbectomized rats.
The olfactory bulbectomy (OBX) is a well-known method inducing animal model of depression. Depression is associated with dysfunction of serotonin (5-hydroxytryptamine, 5-HT) system. In the present study, antidepressive effect of treadmill exercise was investigated using olfactory bulbectomized rats. After bilateral bulbectomy, the rats in the treadmill exercise groups were subjected to run on a treadmill for 30 min once a day during 28 days. Increased immobility time and decreased fast time in the forced swim test were observed in the olfactory bulbectomized rats. Sucrose preference in the sucrose preference test was decreased and activity in the open field test was also increased in the olfactory bulbectomized rats. Treadmill exercise decreased immobility time and activity and increased fast time and sucrose preference in the olfactory bulbectomized rats. Expressions of 5-HT and tryptophan hydroxylase (TPH) in the dorsal raphe of rats were suppressed by OBX and treadmill exercise increased the expressions of 5-HT and TPH in the olfactory bulbectomized rats. Serotonin receptor type 1A (5-HT1A) expression in the dorsal raphe was reduced by OBX and treadmill exercise increased 5-HT1A expression in the olfactory bulbectomized rats. In the present study, treadmill exercise ameliorated OBX-induced depressive symptoms. The antidepressive effect of treadmill exercise might be ascribed to the enhancement of serotonergic function through upregulation of 5-HT1A expression in the dorsal raphe.


Frailty and the Effect of Catheter Ablation in the Elderly Population With Atrial Fibrillation - A Real-World Analysis.
It is unclear whether catheter ablation is beneficial for frail elderly patients with atrial fibrillation (AF). This study evaluated the effect of ablation on outcomes in frail elderly patients with AF.Methods and Results:From the Korean National Health Insurance Service database, 194,928 newly diagnosed AF patients were treated with ablation or medical therapy (rhythm or rate control) between 2005 and 2015. Among these patients, the study included 1,818 (ablation; n=119) frail and 1,907 (ablation; n=230) non-frail elderly (≥75 years) patients. Propensity score matching was used to correct for differences between groups. During 28 months (median) follow up, the risk of all-cause death, composite outcome (all-cause death, heart failure admission, stroke/systemic embolism, and sudden cardiac arrest), and each outcome did not change after ablation in frail elderly patients. However, in non-frail elderly patients, ablation was associated with a lower risk of all-cause death (3.5 and 6.2 per 100 person-years; hazard ratio [HR] 0.48; 95% confidence interval [CI] 0.30-0.79; P=0.004), and composite outcome (6.9 and 11.2 per 100 person-years; HR 0.54; 95% CI 0.38-0.75; P<0.001). Ablation may be associated with a lower risk of death and composite outcome in non-frail elderly, but the beneficial effect of ablation was not significant in frail elderly patients with AF. The effect of frailty on the outcome of ablation should be evaluated in further studies.


Topographic study of cervical condyloma and intraepithelial neoplasia.
In this study of 101 cervical conization specimens, the location and the size of condyloma and intraepithelial neoplasia (dysplasia and carcinoma in situ) were mapped using the last endocervical gland as the marker for the original squamocolumnar junction. Condylomatous changes were identified in 85% of cervices affected by the intraepithelial neoplasia, and were in direct contact with 68% of intraepithelial neoplasms. The proximal location of intraepithelial neoplasia in relation to the condyloma can be explained by the occurrence of neoplasia just proximal to the condyloma and subsequent expansion of neoplasia towards the cervical canal. This study adds topographic evidence linking cervical condyloma to the development of intraepithelial neoplasia.


Efficacy and safety of leuprorelin acetate 6-month depot in prostate cancer patients: a Phase III, randomized, open-label, parallel-group, comparative study in Japan.
Leuprorelin acetate (TAP-144-SR) is commonly used worldwide in prostate cancer patients. This study was conducted to assess the non-inferiority of a 6-month depot formulation of TAP-144-SR (TAP-144-SR [6M]) 22.5 mg to a 3-month depot formulation of TAP-144-SR (TAP-144-SR [3M]) 11.25 mg in prostate cancer patients in Japan. This was a 48-week Phase III, open-label, parallel-group comparative study. TAP-144-SR (6M) 22.5 mg (6M group) and TAP-144-SR (3M) 11.25 mg (3M group) were administered to 81 and 79 subjects, respectively. The primary endpoint was the rate of serum testosterone suppression to the castrate level (≤100 ng/dl). Serum testosterone of all subjects excluding one subject in the 3M group was suppressed to the castrate level throughout 48 weeks. The estimated between-group difference (6M group - 3M group) in suppression rate was 1.3% (95% confidence interval: -3.4, 6.8), and its lower confidence interval was more than -10% of the pre-determined allowable limit value to judge the non-inferiority. The prostate-specific antigen concentrations were stable throughout the study in both groups. Progressive disease in the best overall response based on the Response Evaluation Criteria In Solid Tumors was 0.0% for the 6M group and 2.6% for the 3M group. Adverse events occurred in 92.6% in the 6M group and 89.9% in the 3M group. Adverse events leading to discontinuation were reported in 2.5% in the 6M group and 3.8% in the 3M group. TAP-144-SR (6M) was not inferior to TAP-144-SR (3M) for the suppressive effect on serum testosterone level. TAP-144-SR (6M) was also as well tolerated as TAP-144-SR (3M).


Heparan sulfate mimicry: a synthetic glycoconjugate that recognizes the heparin binding domain of interferon-gamma inhibits the cytokine activity.
Cell-associated heparan sulfate (HS) is endowed with the remarkable ability to bind numerous proteins. As such, it represents a unique system that integrates signaling from circulating ligands with cellular receptors. This polysaccharide is extraordinary complex, and examples that define the structure-function relationship of HS are limited. In particular, it remains difficult to understand the structures by which HS interact with proteins. Among them, interferon-gamma (IFNgamma), a dimeric cytokine, binds to a complex oligosaccharide motif encompassing a N-acetylated glucosamine-rich domain and two highly sulfated sequences, each of which binds to one IFNgamma monomer. Based on this template, we have synthesized a set of glycoconjugate mimetics and evaluated their ability to interact with IFNgamma. One of these molecules, composed of two authentic N-sulfated octasaccharides linked to each other through a 50-Angstroms-long spacer termed 2O(10), displays high affinity for the cytokine and inhibits IFNgamma-HS binding with an IC(50) of 35-40 nm. Interestingly, this molecule also inhibits the binding of IFNgamma to its cellular receptor. Thus, in addition to its ability to delocalize the cytokine from cell surface-associated HS, this compound has direct anti-IFNgamma activity. Altogether, our results represent the first synthetic HS-like molecule that targets a cytokine, strongly validating the HS structural determinants for IFNgamma recognition, providing a new strategy to inhibit IFNgamma in a number of diseases in which the cytokine has been identified as a target, and reinforcing the view that it is possible to create"tailor-made"sequences based on the HS template to isolate therapeutic activities.


Cardio-metabolic risk factors in Iranian children: where we are and the others?
Rising obesity incidence and its complications have lead to change of our view about cardio-metabolic risk factors and need of reassessment of these complications in childhood age. The aim of current study was to evaluate prevalence of obesity and related cardio-metabolic risk factors of children. This was a cross-sectional study in a representative sample of 12 years old children in Rasht, the biggest city in north of Iran. Participants were interviewed and examined by a trained research team and demographic characteristics, detailed examination (height - weight - blood pressure) were recorded. Blood samples were drawn for biochemical testing including Fasting blood sugar, Triglyceride, Cholesterol, HDL & LDL. Data analysis was done using SPSS software. Total participants were 858 children and 550(64%) were male. Prevalence of underweight, normal weight, overweight, obese were 22.5%, 54.4%, 11.3%, 11.8%, respectively. The prevalence of cardio-metabolic risk factors included hypercholesterolemia (6.7%), hypertriglyceridemia (33.6%), high LDL (5.9%), low HDL (28 %), high systolic (7.6%) & diastolic blood pressure (10.6%) (> percentile) and abnormal carbohydrate metabolism (12%) revealed hypertriglyceridemia as the most common dyslipidemia. Correlation analysis didn't show significant correlation between BMI & FBS but LDL, Cholesterol and TG had week positive correlation with BMI (Pearson correlation: 0.161, 0.285, 0.222 respectively, p value <0.001). Obesity and dyslipidemia are common problems in this area and we should note to screen cardiometabolic risk factors in addition of obesity, especially in children with rapid weight gain. This study highly recommended more investigation to evaluate final effect of these factors in adulthood.


Clinical importance of carbapenem hypersensitivity in patients with self-reported and documented penicillin allergy.
The risk of carbapenem hypersensitivity in patients with self-reported or documented penicillin allergy needs to be determined so that practitioners can make better-informed decisions regarding antibiotic therapy for this patient population. The risk of cross-reactivity between penicillin and carbapenem antibiotics initially was reported to approach 50%. Recent retrospective studies have suggested that the clinical risk of cross-hypersensitivity between these two drug classes is 9.2-11%, which is significantly lower than initially reported. Patients whose history of penicillin allergy is self-reported and is not type 1 may be at moderate risk for hypersensitivity when treated with a carbapenem antibiotic. The risk of hypersensitivity appears to be higher in patients whose penicillin allergy was documented by a health care provider, those with several antibiotic allergies, and those with a positive penicillin skin test result or a history of type 1 penicillin hypersensitivity.


Sevoflurane for controlled hypotension during spinal surgery: preliminary experience in five adolescents.
The physical properties of sevoflurane suggest that it may be a suitable agent for controlled hypotension. With its low blood:gas partition coefficient of 0.69, it has a rapid onset of action making it easy to rapidly control blood pressure. The current report outlines preliminary experience with sevoflurane for controlled hypotension during posterior spinal fusion in five adolescents. The patients ranged in age from 12 to 16 years and in weight from 49 to to 72kg. The duration of controlled hypotension varied from two to three h. The expired sevoflurane concentration required to maintain the mean arterial pressure (MAP) at 55 to 65 mmHg varied from 2 to 4%. With sevoflurane, there was an increase in heart rate from baseline of 74 +/- 7 beats.min-1 to a maximum of 83 +/- 13 beats.min-1 (P = 0.038). One patient required three intravenous doses of esmolol (10mg each) for a heart rate in excess of 100 beats.min-1. Estimated blood loss varied from 300 to 850 ml. No patient received homologous blood. No excessive hypotension was noted with sevoflurane. No patient required calcium, alpha adrenergic agonists, or ephedrine for excessive hypotension. When controlled hypotension was no longer necessary, the sevoflurane concentration was decreased to 1%. After decreasing the sevoflurane to 1%, the time to return of the MAP to baseline varied from 4 to 8 min (5.6 +/- 1.8 min).


Head and body sway in response to vertical visual stimulation.
Postural responses differed according to the stimulus direction, i.e. vertical visual stimulation induced head rather than trunk displacements. Accordingly, it could be that center of foot pressure (COP) responses tended to underestimate the postural sway during visual stimulation. To investigate head and body sway in response to vertical visual surround motion, and to examine the correlation between the displacements of head and body segments derived from video-motion analysis and COP measurements. Postural sway was assessed in 10 young female subjects by video-motion analysis of four different head and body segments, and by use of force-plate posturography. Head and body sway in the pitch plane was induced by rotating a random pattern of dots about the subject's inter-aural axis at a constant acceleration of 1 degree/s(2) or a constant velocity of 60 degrees/s in darkness. Generally, head displacement was greater than that of other body parts during vertical optokinetic stimulation (OKS). In most subjects, maximum head displacements were induced in the same direction as the visual motion. Downward OKS induced a forward head and body sway. The COP trajectory correlated well with the displacements of each head and body segment during downward OKS. In contrast, postural responses to upward OKS were complicated in terms of their time course. The correlation coefficient between each head and body segment and the COP varied among individuals for upward OKS.


PAs in orthopedics in the VHA's community-based outpatient clinics.
In the Veterans Health Administration (VHA) system, most orthopedic care takes place in the VA medical centers (VAMCs). Because most patients receiving orthopedic care were referred by adult medicine providers, more widely deploying physician assistants (PAs) in orthopedic medicine might help offset this workload. An orthopedic medicine demonstration project recruited, trained, and positioned PAs in community-based outpatient clinics (CBOCs) to improve access to care. The project involved surgeons at the Houston VAMC instructing five newly employed PAs in a wide range of orthopedic evaluation and management strategies before their assignment to a CBOC. An administrative assessment compared encounter data pre- and postproject (2012 and 2014) to determine if this strategy modified orthopedic workload and improved patient access to care. By 2014, orthopedic patient visit volume had increased 31%-10% at the VAMC and 21% at the five CBOCs. Overall, the five deployed PAs managed 28% of all orthopedic encounters spread over 1 year and only 3.2% of visits required VAMC referral for further evaluation or treatment. During the project, the total volume of patient visits increased throughout the Houston VAMC region but access to care for this specialty service also increased, with more veteran musculoskeletal care being met at the five CBOCs, off-loading visit demand centrally. The adaptability and flexibility of new roles has been identified as one of the defining characteristics of PAs. That the VHA can take advantage of this role malleability suggests that employing PAs is useful in meeting medical service needs of veterans.


Treating Leaky Syndrome in the Over 65s: Progress and Challenges.
As we age, our organ functions gradually decline. Circulating factors in the blood and the integrity of organ barriers can become dysfunctional, resulting in a condition known as leaky syndrome. This condition involves the unregulated exchange or leakage of components between organs. However, the triggers of leaky syndrome, as well as its role in aging-related disorders and illnesses, remain largely unknown. In this editorial, we discuss potential mechanisms that originate from the gut and resident microbes (microbiome) to contribute in leaky syndrome. Furthermore, we explore how the food we consume can impact the development of leaky syndrome, potentially influencing the biology of aging and challenges to diagnose the leaky gut condition accurately and clinically.


Preschool physics: Using the invisible property of weight in causal reasoning tasks.
Causal reasoning is an important aspect of scientific thinking. Even young human children can use causal reasoning to explain observations, make predictions, and design actions to bring about specific outcomes in the physical world. Weight is an interesting type of cause because it is an invisible property. Here, we tested preschool children with causal problem-solving tasks that assessed their understanding of weight. In an experimental setting, 2- to 5-year-old children completed three different tasks in which they had to use weight to produce physical effects-an object displacement task, a balance-scale task, and a tower-building task. The results showed that the children's understanding of how to use object weight to produce specific object-to-object causal outcomes improved as a function of age, with 4- and 5-year-olds showing above-chance performance on all three tasks. The younger children's performance was more variable. The pattern of results provides theoretical insights into which aspects of weight processing are particularly difficult for preschool children and why they find it difficult.


Nephron-sparing tumorectomy for a large benign renal mass: a case of massive bilateral renal angiomyolipomas associated with tuberous sclerosis.
A case of massive bilateral angiomyolipomas (AML) associated with tuberous sclerosis in a 33-year-old woman is reported. She was hospitalized because she had been experiencing abdominal fullness and epigastralgia. Several imaging studies revealed massive bilateral renal tumors and she was diagnosed as having renal AML associated with tuberous sclerosis. Left nephrectomy was carried out after renal arterial embolization for intratumor hemorrhage. Two years after left nephrectomy, nephron-sparing surgery (tumorectomy) for right AML was done because of an increase in the size of the right renal AML and she hoped for a future pregnancy. The left kidney with AML weighed 5700 g and the right AML weighed 1700 g. Postoperative serous creatinine did not differ from that before operation and an increase in the size of the residual tumor was not observed 8 months after operation. We consider that tumorectomy is an effective therapy in patients with a very large tumor involving a solitary kidney.


Emerging Artificial Neuron Devices for Probabilistic Computing.
In recent decades, artificial intelligence has been successively employed in the fields of finance, commerce, and other industries. However, imitating high-level brain functions, such as imagination and inference, pose several challenges as they are relevant to a particular type of noise in a biological neuron network. Probabilistic computing algorithms based on restricted Boltzmann machine and Bayesian inference that use silicon electronics have progressed significantly in terms of mimicking probabilistic inference. However, the quasi-random noise generated from additional circuits or algorithms presents a major challenge for silicon electronics to realize the true stochasticity of biological neuron systems. Artificial neurons based on emerging devices, such as memristors and ferroelectric field-effect transistors with inherent stochasticity can produce uncertain non-linear output spikes, which may be the key to make machine learning closer to the human brain. In this article, we present a comprehensive review of the recent advances in the emerging stochastic artificial neurons (SANs) in terms of probabilistic computing. We briefly introduce the biological neurons, neuron models, and silicon neurons before presenting the detailed working mechanisms of various SANs. Finally, the merits and demerits of silicon-based and emerging neurons are discussed, and the outlook for SANs is presented.


Development and validation of a pretreatment nomogram to predict overall survival in gastric cancer.
Pretreatment clinical staging is essential to select therapy. However, there have been no published pretreatment gastric cancer nomograms constructed using pretreatment clinical prognostic factors, including in nonresection patients. We aimed to develop a new pretreatment gastric cancer nomogram for individualized prediction of overall survival (OS). The nomogram was developed using data of 5231 Japanese gastric cancer patients, and it was created with a Cox regression model. Fifteen clinical variables, which were obtained at pretreatment, were collected and registered. Data of two independent cohorts of patients from Seoul St. Mary's Hospital (1001 patients), and the University of Verona (389 patients) formed the external validation cohorts. The model was validated internally and externally using measures of discrimination (Harrell's C-index), calibration, and decision curve analysis. The developed nomogram showed good discrimination, with a C-index of 0.855; that of the American Joint Committee on Cancer (AJCC) clinical stage was 0.819. In the external validation procedure, the C-indexes were 0.856 (AJCC, 0.795) in the Seoul St. Mary's cohort and 0.714 (AJCC, 0.648) in the University of Verona cohort. The nomogram performed well in the calibration and decision curve analyses when applied to both the internal and external validation cohorts. A stage-specific subset survival analysis of the three risk groups calculated using the nomogram also showed the superiority of nomogram-prediction when compared to AJCC. This new pretreatment model accurately predicts OS in gastric cancer and can be used for patient counseling in clinical practice and stratification in clinical trials.


c-Maf regulates pluripotency genes, proliferation/self-renewal, and lineage commitment in ROS-mediated senescence of human mesenchymal stem cells.
Mesenchymal stem cells (MSCs) are therapeutically relevant multilineage and immunomodulatory progenitors. Ex vivo expansion of these rare cells is necessary for clinical application and can result in detrimental senescent effects, with mechanisms still largely unknown. We found that vigorous ex vivo expansion of human adipose tissue-derived MSCs (hAMSCs) results in proliferative decline, cell cycle arrest, and altered differentiation capacity. This senescent phenotype was associated with reactive oxygen species (ROS) accumulation, and with increased expression of G1 cell -cycle inhibitors- p15INK4b and p16INK4a - but decreased expression of pluripotency genes-Oct-4, Sox-2, Nanog, and c-Myc-as well as c-Maf a co-factor of MSC lineage-specific transcription factor and sensitive to oxidative stress. These global changes in the transcriptional and functional programs of proliferation, differentiation, and self-renewal were all mediated by ROS-induced suppression of c-Maf, as evidenced by binding of c-Maf to promoter regions of multiple relevant genes in hAMSCs which could be reduced by exogenous ROS. Our findings implicate the strong effects of ROS on multiple stem cell functions with a central role for c-Maf in stem cell senescence.


Organic and conservation agriculture promote ecosystem multifunctionality.
Ecosystems provide multiple services to humans. However, agricultural systems are usually evaluated on their productivity and economic performance, and a systematic and quantitative assessment of the multifunctionality of agroecosystems including environmental services is missing. Using a long-term farming system experiment, we evaluated and compared the agronomic, economic, and ecological performance of the most widespread arable cropping systems in Europe: organic, conservation, and conventional agriculture. We analyzed 43 agroecosystem properties and determined overall agroecosystem multifunctionality. We show that organic and conservation agriculture promoted ecosystem multifunctionality, especially by enhancing regulating and supporting services, including biodiversity preservation, soil and water quality, and climate mitigation. In contrast, conventional cropping showed reduced multifunctionality but delivered highest yield. Organic production resulted in higher economic performance, thanks to higher product prices and additional support payments. Our results demonstrate that different cropping systems provide opposing services, enforcing the productivity-environmental protection dilemma for agroecosystem functioning.


Winter cover crops on processing tomato yield, quality, pest pressure, nitrogen availability, and profit margins.
Much of cover crop research to date focuses on key indicators of impact without considering the implications over multiple years, in the absence of a systems-based approach. To evaluate the effect of three years of autumn cover crops on subsequent processing tomato (Solanum lycopersicum L.) production in 2010 and 2011, a field split-split-plot factorial design trial with effects of cover crop type, urea ammonium nitrate fertilizer rate (0 or 140 kg N ha-1 preplant broadcast incorporated) and tomato cultivar (early vs. late) was conducted. The main plot factor, cover crop, included a no cover crop control, oat (Avena sativa L.), winter cereal rye (hereafter referred to as rye) (Secale cereale L.), oilseed radish (OSR) (Raphanus sativus L. var. oleiferus Metzg Stokes), and mix of OSR and rye (OSR + rye) treatments. Cover crop biomass of 0.5 to 2.8 and 1.7 to 3.1 Mg ha-1 was attained in early Oct. and the following early May, respectively. In general, OSR increased soil mineral N during cover crop growth and into the succeeding summer tomato growing season, while the remaining cover crops did not differ from the no cover crop control. The lack of a cover crop by N rate interaction in soil and plant N analyses at harvest suggests that growers may not need to modify N fertilizer rates to tomatoes based on cover crop type. Processing tomato fruit quality at harvest (rots, insect or disease damage, Agtron colour, pH, or natural tomato soluble solids (NTSS)) was not affected by cover crop type. In both years, marketable yield in the no cover crop treatment was lower or not statistically different than all planted cover crops. Partial profit margins over both years were 1320 $ ha-1 higher with OSR and $960 higher with oat compared to the no cover crop control. Thus, results from a systems-based approach suggest that the cover crops tested had no observed negative impact on processing tomato production and have the potential to increase marketable yield and profit margins.


[Detection of toxin-producing types of Pasteurella multocida--a comparison of methods].
28 Pasteurella multocida strains were examined for production of toxin by 6 different methods. Identical results were obtained using a mice lethality test, a tissue cell culture assay and an ELISA. Different results were received with a dot-blot-immunoassay (1 strain), using a gene probe (6 strains) and a guinea pig skin test (8 strains). Corresponding differences were detected with 2 strains only. Tissue culture, ELISA and dot-blot-immunoassay are effective methods for the diagnosis of toxin-producing Pasteurella multocida strains. Animal experiments should be an exception.


Enhanced immunization techniques to obtain highly specific monoclonal antibodies.
Despite fast advances in genomics and proteomics, monoclonal antibodies (mAbs) are still a valuable tool for areas such as the evolution of basic research in stem cells and cancer, for immunophenotyping cell populations, diagnosing and prognosis of diseases, and for immunotherapy. To summarize different subtractive immunization approaches successfully used for the production of highly specific antibodies, we identified scientific articles in NCBI PubMed using the following search terms: subtractive immunization, monoclonal antibody, tolerization, neonatal, high-zone tolerance, masking immunization. Patent records were also consulted. From the list of results, we included all available reports, from 1985 to present, that used any enhanced immunization technique to produce either polyclonal or monoclonal antibodies. Our examination yielded direct evidence that these enhanced immunization techniques are efficient in obtaining specific antibodies to rare epitopes, with different applications, such as to identify food contaminants or tumor cells.


Protective effects of lysozyme chloride and reduced glutathione on betel quid chewing-produced gastric oxidative stress and haemorrhagic ulcer in rats.
The pathogenic mechanisms underlying betel quid chewing (BQC)-induced gastric haemorrhagic ulcer are totally unknown. This study first demonstrated that BQC produced gastric haemorrhagic ulcer via oxidative stress that could be protected by lysozyme chloride and glutathione in rats. Male Wistar rats were fed with regular pellet food or BQC-containing diets. After 1-90 days rats were deprived of food for 24 h. Rat stomachs were irrigated for 3 h with normal saline or simulated gastric juice. Rats were killed and gastric specimens were harvested. A BQC-feeding period-dependent exacerbation of gastric parameters, such as enhanced acid back-diffusion, mucosal lipid peroxide generation, as well as related decreased glutathione levels and mucus content, were observed. Gastric juice caused a further aggravation of these ulcerogenic parameters. Daily intragastric lysozyme chloride or glutathione dose-dependently inhibited exacerbation of various ulcerogenic parameters in those BQC-fed rats. In conclusion, BQC can produce gastric haemorrhagic ulcer in rats via oxidative stress that could be ameliorated by lysozyme chloride and glutathione.


The association of microtubules with tight junctions is promoted by cingulin phosphorylation by AMPK.
Epithelial cells characteristically have noncentrosomal microtubules that are arranged in the apicobasal direction. In this paper, we examined cell sheets formed by an epithelial (Eph4) cell line by structure illumination microscopy and found a previously not clearly described planar apical network of noncentrosomal microtubules (MTs) in which the sides of the MT bundles were associated with tight junctions (TJs). In a gel overlay assay with taxol-stabilized MTs, cingulin showed strong binding to MTs, and a domain analysis showed that this binding occurred through cingulin's N-terminal region. The association of planar apical MTs with TJs was compromised by cingulin knockdown (KD) or the expression of dephosphomimetic mutants of cingulin at its adenosine monophosphate-activated protein kinase (AMPK) target sites, whereas phosphorylation at these sites facilitated cingulin-tubulin binding. In addition, although wild-type colonies formed spheres in 3D culture, the cingulin KD cells had anisotropic shapes. These findings collectively suggest that the regulated cingulin-MT association has a specific role in TJ-related epithelial morphogenesis that is sensitive to metabolic homeostasis-related AMPK activity.


A role for Dictyostelium racE in cortical tension and cleavage furrow progression.
The small GTPase racE is essential for cytokinesis in Dictyostelium. We found that this requirement is restricted to cells grown in suspension. When attached to a substrate, racE null cells form an actomyosin contractile ring and complete cytokinesis normally. Nonetheless, racE null cells fail completely in cytokinesis when in suspension. To understand this conditional requirement for racE, we developed a method to observe cytokinesis in suspension. Using this approach, we found that racE null cells attempt cytokinesis in suspension by forming a contractile ring and cleavage furrow. However, the cells form multiple blebs and fail in cytokinesis by regression of the cleavage furrow. We believe this phenotype is caused by the extremely low level of cortical tension found in racE null cells compared to wild-type cells. The reduced cortical tension of racE null cells is not caused by a decrease in their content of F-actin. Instead, mitotic racE null cells contain abnormal F-actin aggregates. These results suggest that racE is essential for the organization of the cortical cytoskeleton to maintain proper cortical integrity. This function of racE is independent of attachment to a substrate, but can be bypassed by other signaling pathways induced by adhesion to a substrate.


Chest-wall reconstruction in case of infection of the operative site: is there any interest in titanium rib osteosynthesis?
To describe the management of thoracic reconstructions in the presence of primary chest-wall infection (PCWI) or secondary deep chest-wall infection (SCWI), focussing on local tolerance of a titanium rib osteosynthesis system. PCWI included infected chest wall tumours (CWT), infected T3 non-small-cell lung carcinoma (NSCLC) and open flail chest. SCWI was defined by deep infection of previous thoracic-wall reconstructions. Infection was identified by preoperative bacterial analysis of the tumour or surgical site. In PCWI, a one-step procedure combined extensive resection of infected tissues and rigid reconstruction of the defect; skeletal rigidity was achieved using titanium implants. In SCWI, we removed all synthetic material except titanium implants. In both groups, the surgical field was thoroughly cleaned and implants were wrapped or covered by flaps. From January 2005 to December 2011, 11 patients (54 ± 10.2 years) with either PCWI (3 CWT, 3 T3 NSCLC, 1 open flail chest) or SCWI (3 CWT, 1 funnel chest) were treated. Infection was polymicrobial in all but 1 case. Bacteria observed in PCWI patients were multidrug resistant. In PCWI, we resected 4.2 ± 0.6 ribs en bloc with the lung (n = 5), the skin and the pectoralis major and then used mesh and 2.1 ± 1.2 titanium implants for reconstruction (n = 6). The mean defect was 1154.4 ± 318 cm(3). Surgical SCWI management removed polytetrafluoroethylene-mesh and preserved the titanium implants. A Vicryl mesh (n = 3) and greater omentum flap (n = 3) were added. One of the 2 postoperative deaths in the PCWI group was related to infection recurrence. No other patient had infection at the 6-month follow-up with leucocyte-labelled scintigraphy. Titanium rib osteosynthesis is reliable in two complex and life-threatening situations: PCWIs and SCWIs. In combination with a flap, this allows rapid, reliable, rigid reconstruction of infected full-thickness chest-wall defects in a single-step procedure.


Procurement and workbench procedures in preparation of pancreatic allografts. Factors essential for a successful pancreas transplant.
The rapidly developing field of pancreas allotransplantation can be regarded as an excellent school of surgery in which the topics of meticulous surgical technique and attention to detail by virtue of their significance strongly outweigh all other topics. The growing experience of the rather grave complications after pancreas transplantation points to the need for consistent use of meticulous techniques during organ procurement and application of workbench procedures just prior to transplantation. In addition, with the further development of the extra-renal transplant programs, the procurement of multiple organs from the same donor is becoming more common and the pancreatic team is more frequently faced with a less than optimal situation in regard to the vascular supply of the pancreatic graft. It, therefore, becomes imperative to carefully evaluate the vasculature and to make the necessary modifications prior to transplantation, since the best surgical techniques will not outweigh the consequences of a suboptimal blood supply, which will compromise the viability of any segment of the delicate pancreaticoduodenal graft.


Mitochondrial staining allows robust elimination of apoptotic and damaged cells during cell sorting.
High-speed fluorescence-activated cell sorting is relevant for a plethora of applications, such as PCR-based techniques, microarrays, cloning, and propagation of selected cell populations. We suggest a simple cell-sorting technique to eliminate early and late apoptotic and necrotic cells, with good signal-to-noise ratio and a high-purity yield. The mitochondrial potential dye, TMRE (tetramethylrhodamine ethyl ester perchlorate), was used to separate viable and non-apoptotic cells from the cell sorting samples. TMRE staining is reversible and does not affect cell proliferation and viability. Sorted TMRE(+) cells contained a negligible percentage of apoptotic and damaged cells and had a higher proliferative potential as compared with their counterpart cells, sorted on the basis of staining with DNA viability dye. This novel sorting technique using TMRE does not interfere with subsequent functional assays and is a method of choice for the enrichment of functionally active, unbiased cell populations.


[Transcortical sensory aphasia produced by lesions of the anterior basal ganglia area].
We reported three cases of an aphasic syndrome caused by unusual lesion distribution. Our patients, language disorders could be summarized as transcortical sensory aphasia and showed following symptoms; (1) fluent paraphasic verbal output, (2) anomia which was not facilitated by cueing, (3) impaired comprehension of spoken language, (4) preserved capacity of repetition, (5) preserved ability of reading aloud with impaired comprehension of the written material and (6) agraphia. In addition, all had no associated physical neurological signs such as hemiparesis or hemianopsia. All were right handed. All three cases showed the similar lesion distribution by computed tomographic scanning of the brain. All had low density areas in the anterior portion of the left basal ganglia including the head of the caudate nucleus, the anterior portion of the putamen, the anterior portion of the anterior limb of the internal capsule and the nearby white matter. Case 2 also had the small right hemisphere lesion in the white matter near the anterior portion of the lateral ventricle. Transcortical sensory aphasia with this lesion distribution has not been reported. We attributed the causative damage to lesions of the white matter and not to lesions of the basal ganglia per se. It was also speculated that fluent aphasia can be produced by the anteriorly situated white matter lesion if issuing fibers from the Broca's area were spared. Finally a possible anatomoclinical correlation for "transcortical alexia" (preserved oral reading and impaired reading comprehension) was attempted. The symptom is probably a reflection of the fact that the posterior speech area including the angular gyrus was left intact.


Neuropeptide S: a novel regulator of pain-related amygdala plasticity and behaviors.
Amygdala plasticity is an important contributor to the emotional-affective dimension of pain. Recently discovered neuropeptide S (NPS) has anxiolytic properties through actions in the amygdala. Behavioral data also suggest antinociceptive effects of centrally acting NPS, but site and mechanism of action remain to be determined. This is the first electrophysiological analysis of pain-related NPS effects in the brain. We combined whole cell patch-clamp recordings in brain slices and behavioral assays to test the hypothesis that NPS activates synaptic inhibition of amygdala output to suppress pain behavior in an arthritis pain model. Recordings of neurons in the laterocapsular division of the central nucleus (CeLC), which serves pain-related amygdala output functions, show that NPS inhibited the enhanced excitatory drive [monosynaptic excitatory postsynaptic currents (EPSCs)] from the basolateral amygdala (BLA) in the pain state. As shown by miniature EPSC analysis, the inhibitory effect of NPS did not involve direct postsynaptic action on CeLC neurons but rather a presynaptic, action potential-dependent network mechanism. Indeed, NPS increased external capsule (EC)-driven synaptic inhibition of CeLC neurons through PKA-dependent facilitatory postsynaptic action on a cluster of inhibitory intercalated (ITC) cells. NPS had no effect on BLA neurons. High-frequency stimulation (HFS) of excitatory EC inputs to ITC cells also inhibited synaptic activation of CeLC neurons, providing further evidence that ITC activation can control amygdala output. The cellular mechanisms by which EC-driven synaptic inhibition controls CeLC output remain to be determined. Administration of NPS into ITC, but not CeLC, also inhibited vocalizations and anxiety-like behavior in arthritic rats. A selective NPS receptor antagonist ([d-Cys(tBu)(5)]NPS) blocked electrophysiological and behavioral effects of NPS. Thus NPS is a novel tool to control amygdala output and pain-related affective behaviors through a direct action on inhibitory ITC cells.


Dynamic Nuclear Polarization of Long-Lived Nuclear Spin States in Methyl Groups.
We have induced hyperpolarized long-lived states in compounds containing 13C-bearing methyl groups by dynamic nuclear polarization (DNP) at cryogenic temperatures, followed by dissolution with a warm solvent. The hyperpolarized methyl long-lived states give rise to enhanced antiphase 13C NMR signals in solution, which often persist for times much longer than the 13C and 1H spin-lattice relaxation times under the same conditions. The DNP-induced effects are similar to quantum-rotor-induced polarization (QRIP) but are observed in a wider range of compounds because they do not depend critically on the height of the rotational barrier. We interpret our observations with a model in which nuclear Zeeman and methyl tunnelling reservoirs adopt an approximately uniform temperature, under DNP conditions. The generation of hyperpolarized NMR signals that persist for relatively long times in a range of methyl-bearing substances may be important for applications such as investigations of metabolism, enzymatic reactions, protein-ligand binding, drug screening, and molecular imaging.


Antigen detection and immunological typing of Haemophilus ducreyi with a specific rabbit polyclonal serum.
A rabbit polyclonal serum was raised against the 29-kDa species-specific marker, as well as the 30- to 34-kDa immunotype-specific markers of Haemophilus ducreyi described elsewhere (E. Roggen, S. De Breucker, E. Van Dyck, and P. Piot, Infect. Immun. 60:590-595, 1992). These antigens were purified from a cocktail of H. ducreyi isolates by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The immune serum reacted in enzyme-linked immunosorbent assay (ELISA) preferentially with H. ducreyi, at a titer as high as 50,000. To make it specific to H. ducreyi, nonspecific antibodies were removed by adsorption on a mixture of Haemophilus spp., Escherichia coli, Candida albicans, and Corynebacterium spp. In the 29- to 34-kDa region of immunoblot profiles from H. ducreyi isolates (n = 450), the adsorbed serum revealed essentially the same antigens as did a pool of well-characterized human sera. Yet, eight different immunotypes were observed. With this rabbit polyclonal serum, an ELISA-based antigen detection test was developed. The adsorbed serum reacted specifically with all H. ducreyi isolates tested (n = 450), but not with other bacterial species (n = 15). This test was evaluated with a limited number of clinical specimens from African patients with culture-proven chancroid and no evidence for any other ulcerating etiology (n = 10) and a number of chancroid-negative control patients from Belgium (n = 20). Within this context, the test yielded a sensitivity and specificity of 100%.


Accumulation of Hsp70/Hsc70 molecular chaperone regulator BAG-1 on COPI-coated structures in gastric epithelial cells.
The multifunctional protein BAG-1 binds to molecular chaperones Hsc70/Hsp70 and regulates their activity. While a role for BAG-1 in regulating Hsc70 chaperone activity is firmly established in vitro, physiological roles of this regulation remain obscure. Here we show that BAG-1 is highly expressed in gastrointestinal epithelial cells and accumulates at the Golgi apparatus, probably through interaction with COPI coated structure. Subcellular fractionation of gastric mucosa revealed that BAG-1 was mainly recovered in the Golgi-enriched fractions. Confocal immunofluorescence studies revealed that BAG-1 was overlapped with a cis-Golgi matrix protein GM130 and a COPI component beta-COP in the vicinity of the Golgi. In response to brefeldin A, which blocks recruitment of COPI coats to the Golgi membrane, BAG-1 was dispersed throughout the cytoplasm as beta-COP was. Extensive overlap of BAG-1 immunofluorescence with beta-COP was still observed when cells were treated with nocodazole, which depolymerizes microtubules and induces fragmentation of the Golgi stacks. Immunoelectron microscopy revealed that BAG-1 signals were predominantly found on vesicular membrane structures adjacent to Golgi stacks, but not on mitochondrial membrane. Taken together, we suggest that BAG-1 is targeted to the COPI coated structures, implying its contribution toward the COPI vesicular transport in gastrointestinal epithelial cells.


Optical trapping and surgery of living yeast cells using a single laser.
We present optical trapping and surgery of living yeast cells using two operational modes of a single laser. We used a focused laser beam operating in continuous-wave mode for noninvasive optical trapping and manipulation of single yeast cell. We verified that such operational mode of the laser does not cause any destructive effect on yeast cell wall. By changing the operation of the laser to femtosecond-pulsed mode, we show that a tightly focused beam dissects the yeast cell walls via nonlinear absorption. Lastly, using the combined technique of optical microsurgery and trapping, we demonstrate intracellular organelle extraction and manipulation from a yeast cell. The technique established here will be useful as an efficient method for both surgery and manipulation of living cells using a single laser beam.


α-Amino Acid Rich Photophytonic Nanoparticles of Algal Origin Serendipitously Reveal Antimigratory Property against Cancer.
Spheroidal nanoparticles of algal ("phytonic") origin were synthesized and composed of carbonaceous architectures and surface-rich oxygenated functional groups. Nanoparticles were negatively charged and efficiently luminescent after ultraviolet-range excitation and called as "photophytonic" nanoparticles. A multitude of analytical techniques confirmed the rich profusion of hydroxyl, carboxylate, and amines at the nanoscale, while spectroscopic investigation indicated the presence of α-amines, a signature functionality present in amino acids. Confirmed via a series of biological assays, i.e., growth regression, antimigration, and protein-regression studies, photophytonic nanoparticles serendipitously revealed remarkable anticancer activity against various stages of breast cancer cells, barring the need for an encapsulated drug. We report that nanoparticles derived from algal biomass exhibit intrinsic antimigratory properties against cancer, likely due to the rich abundance of α-amino acids.


Hsp70 chaperone systems: diversity of cellular functions and mechanism of action.
Hsp70 chaperone systems play an essential role in the life cycle of many proteins not only in an hostile environment but also under normal growth conditions. In the course of evolution the diversification of functions was accompanied by an amplification of components of the Hsp70 system. Here strategies are reviewed how different Hsp70 systems work independently or cooperate with each other in a functional network to perform their housekeeping tasks even under stress conditions. We further discuss how co-chaperones which act as targeting factors regulate the cycle of substrate binding and release upon which the Hsp70 chaperone activity depends.


The Biological Function of POLA2 in Hepatocellular Carcinoma.
The role and prognostic value of POLA2 in liver cancer were comprehensively analyzed through TCGA, GEO, and ICGC databases, and the role of POLA2 in liver cancer cells and the regulatory mechanism involved were further verified through cell experiments. Hepatocellular carcinoma (HCC) is the most prevalent malignancy with high morbidity and mortality. Consequently, it is critical to identify robust and reliable predictive biomarkers and therapeutic targets for HCC patients. POLA2 is involved in the regulation of various tumors, but the specific role of POLA2 in HCC has not been reported. The regulatory role and prognostic value of POLA2 in HCC were determined by bioinformatics techniques and cell experiments. The specific role and prognostic value of POLA2 in HCC were comprehensively analyzed by combining the expression data of POLA2 in TCGA, GEO, and ICGC databases and clinical data. In clinical samples, the expression of POLA2 in liver cancer was verified by QPCR. Further, the regulatory role of POLA2 in HCC was explored through cell experiments such as CCK-8, clonal formation experiment, EDU cell proliferation experiment, and flow cytometry. In terms of mechanism exploration, western blot was used to verify the specific regulatory mechanism that POLA2 participated in. Finally, the relationship between POLA2 and immune invasion of HCC was analyzed by using the TIMER database. A POLA2 expression and prognosis analysis of HCC patients was conducted using the TCGA, GEO, and ICGC databases. We hypothesized that POLA2 might be one of the key factors contributing to the HCC progression. According to a combined analysis of TCGA, ICGC, and GEO databases, POLA2 was highly expressed in HCC. This was further confirmed in clinical samples using the qPCR. POLA2 knockdown was also performed in vitro on HCC cell lines to study the changes in their biological behavior. We confirmed that POLA2 was associated with HCC proliferation by CCK-8, Colony Formation, and EDU assay. We verified the POLA2's involvement in cell cycle regulation using flow techniques. The relationship between POLA2 and PI3K/AKT/mTOR pathway was explored using Western Blotting experiments regarding its mechanism. Further analysis revealed that the POLA2 expression was significantly associated with HCC immune infiltration. Our study demonstrated POLA2's importance in HCC development and progression and its potential role as a biomarker for disease progression on multiple levels. POLA2 has an important role in regulating the cell cycle and cell proliferation. By interfering with the cell cycle and proliferation, HCC cell growth is inhibited. Furthermore, POLA2 expression was significantly associated with immune infiltration. POLA2 may play a role in HCC immunotherapy based on its correlation with several immune cell types' genetic markers. The findings of this study are expected to lead to new anticancer strategies for HCC.


Eccentric overload differences between loads and training variables on flywheel training.
There is considerable debate about the existence of a real eccentric overload in flywheel exercises. This study aimed to analyse the differences in concentric: eccentric mechanical output ratios between different loads and variables in the flywheel squat exercise. Twenty physically active men (22.9 ± 2.2 years, height: 1.8 ± 0.1 m, weight: 79.6 ± 8.2 kg) performed a loading test using five moments of inertia. Angular speed was measured using a rotary encoder, while the vertical force was measured using force plates. For each variable (angular speed, angular acceleration, power, vertical force, and torque), mean and peak values were calculated for concentric and eccentric phases to allow comparisons across the loads. We tested the possible differences in Load × Phase (concentric and eccentric) and Load × Variable. The level of significance was established as p < 0.05. A significant Load × Phase interaction was found in mean angular speed, peak vertical force, peak angular acceleration, peak power and peak torque. Higher eccentric overload values were observed with speed-derived variables (angular speed, angular acceleration and power). In conclusion, speed-derived peak variables and lower loads are more likely to show an eccentric overload and can be used to monitor responses to flywheel training.


Hormone release and behavior during suckling and milking in Gir, Gir x Holstein, and Holstein cows.
There are several different milking management systems in Latin America, because Gir cattle are reputed to be easily stressed and not well adapted to machine-milking. This paper, therefore, provides an overview of hormone release and behavior during suckling and milking in Gir cows and their cross-bred offspring. Several experiments were performed to study oxytocin release during exclusive suckling or exclusive hand- and machine-milking, oxytocin, and prolactin release during a mixed suckling-milking system and oxytocin release after weaning. Cortisol concentrations and behavior were also examined. Concentration of oxytocin, released during suckling, and both types of milking were high, but the maximum concentration measured during suckling was significantly greater than that observed during exclusive milking. In the mixed suckling-milking system, the greatest oxytocin and prolactin releases were measured during suckling. Cortisol concentrations measured before, during, and after milking demonstrated that Gir x Holstein and Holstein cows were not stressed. On the other hand, although Gir had greater concentrations of cortisol, the percentage of residual milk for Gir cows was less than for dairy cows exposed to different stressful situations. In general, Gir cows and their crossbred offspring adapted to machine-milking, although these breeds can react negatively to milkers. Gir, Gir x Holstein, and Holstein cows all had similar cortisol levels during and after milking.


Fluconazole Resistance Candida albicans in Females With Recurrent Vaginitis and Pir1 Overexpression.
Some genes may be associated with Candida albicans resistance to azoles. Pir1 gene is described as responsible to induce resistance in C. albicans. The current study aimed to find the relationship between fluconazole resistance and Pir1 protein (Pir1p) overexpression in the females with recurrent C. albicans vaginitis requiring longer fluconazole therapy. A total of 52l vaginal samples were obtained from the females with C. albicans vaginitis. The azole susceptibility phenotype was determined according to the Clinical Laboratory for Standards Institute (CLSI) protocol for disk diffusion method and inhibition zone for fluconazole. Expression of pir1 gene and fluconazole -resistance were evaluated using polymerase chain reaction (PCR) in C. albicans. In the 52 isolates, 49 (94%) were resistant to fluconazole. Overexpression of Pir1 gene was detected in 47 (96%) fluconazole-resistant C. albicans isolates. The findings show fluconazole -resistance in C. albicans isolates with overexpression of Pir1p.


Recurrence After Resection of Pancreatic Cancer: Can Radiomics Predict Patients at Greatest Risk of Liver Metastasis?
Liver metastasis (LM) after pancreatic ductal adenocarcinoma (PDAC) resection is common but difficult to predict and has grave prognosis. We combined preoperative clinicopathological variables and quantitative analysis of computed tomography (CT) imaging to predict early LM. We retrospectively evaluated patients with PDAC submitted to resection between 2005 and 2014 and identified clinicopathological variables associated with early LM. We performed liver radiomic analysis on preoperative contrast-enhanced CT scans and developed a logistic regression classifier to predict early LM (< 6 months). In 688 resected PDAC patients, there were 516 recurrences (75%). The cumulative incidence of LM at 5 years was 41%, and patients who developed LM first (n = 194) had the lowest 1-year overall survival (OS) (34%), compared with 322 patients who developed extrahepatic recurrence first (61%). Independent predictors of time to LM included poor tumor differentiation (hazard ratio (HR) = 2.30; P < 0.001), large tumor size (HR = 1.17 per 2-cm increase; P = 0.048), lymphovascular invasion (HR = 1.50; P = 0.015), and liver Fibrosis-4 score (HR = 0.89 per 1-unit increase; P = 0.029) on multivariate analysis. A model using radiomic variables that reflect hepatic parenchymal heterogeneity identified patients at risk for early LM with an area under the receiver operating characteristic curve (AUC) of 0.71; the performance of the model was improved by incorporating preoperative clinicopathological variables (tumor size and differentiation status; AUC = 0.74, negative predictive value (NPV) = 0.86). We confirm the adverse survival impact of early LM after resection of PDAC. We further show that a model using radiomic data from preoperative imaging combined with tumor-related variables has great potential for identifying patients at high risk for LM and may help guide treatment selection.


Interpreting phylogenetic placements for taxonomic assignment of environmental DNA.
Taxonomic assignment of operational taxonomic units (OTUs) is an important bioinformatics step in analyzing environmental sequencing data. Pairwise alignment and phylogenetic-placement methods represent two alternative approaches to taxonomic assignments, but their results can differ. Here we used available colpodean ciliate OTUs from forest soils to compare the taxonomic assignments of VSEARCH (which performs pairwise alignments) and EPA-ng (which performs phylogenetic placements). We showed that when there are differences in taxonomic assignments between pairwise alignments and phylogenetic placements at the subtaxon level, there is a low pairwise similarity of the OTUs to the reference database. We then showcase how the output of EPA-ng can be further evaluated using GAPPA to assess the taxonomic assignments when there exist multiple equally likely placements of an OTU, by taking into account the sum over the likelihood weights of the OTU placements within a subtaxon, and the branch distances between equally likely placement locations. We also inferred the evolutionary and ecological characteristics of the colpodean OTUs using their placements within subtaxa. This study demonstrates how to fully analyze the output of EPA-ng, by using GAPPA in conjunction with knowledge of the taxonomic diversity of the clade of interest.


Knockdown of phosphodiesterase 4D inhibits nasopharyngeal carcinoma proliferation via the epidermal growth factor receptor signaling pathway.
Phosphodiesterase 4D (PDE4D) is a subtype of metallohydrolases, and it has been reported that PDE4D functions as a proliferation promoting factor in certain types of cancer, including head and neck cancer. The present study first investigated the function of PDE4D in nasopharyngeal carcinoma (NPC). Western blot analysis was applied to detect PDE4D expression in NPC samples and cells. A lentiviral infection technique was used to stabilize the knockdown of PDE4D, which was subsequently examined in vitro and in vivo. The results showed that PDE4D was overexpressed in the NPC tissues and cells. Knockdown of PDE4D inhibited the growth of CNE2 and 5-8F, inducing cell cycle arrest in the G0/G1 phase in CNE2. These effects could be reversed by epidermal growth factor (EGF) stimulation. Furthermore, knockdown of PDE4D significantly inhibited the phosphorylation of epidermal growth factor receptor (EGFR) and AKT. The results were further validated in an NPC xenograft in nude mice. In conclusion, this study demonstrated that PDE4D may function as a proliferation promoting factor in NPC, by affecting the EGFR/PI3K/AKT signaling pathway. Therefore, the targeting of PDE4D may be a rational strategy in the treatment of NPC.


Changes in the Quality of Life of Patients with Left Ventricular Assist Device and their Caregivers in Japan: Retrospective Observational Study.
Left ventricular assist devices (LVAD) improve quality of life (QOL) in many patients with end-stage severe heart failure, but not in some patients. In addition, the burden on caregivers is expected to increase after LVAD patients are discharged. Our study aimed to investigate the impact of LVAD on the QOL of patients and caregivers. Thirty-two LVAD patients were assessed for changes in QOL, mental status, and activity level using the Euro QOL (EQ-5D-5L), Short Form 12 (SF-12), Minnesota Living with Heart Failure Questionnaire, Hospital Anxiety and Depression Scale (HADS), and Frenchay Activities Index. Twenty-four caregivers were assessed for changes in QOL, mental status, and burden of care using the EQ-5D-5L, SF-12, HADS, and Burden Index of Caregiver (BIC-11). The LVAD patients and caregivers responded contemporaneously regarding two points: pre-and post-LVAD. Patients' physical and mental QOL was significantly improved, but not social QOL and activity level. Caregivers' QOL and burden of care did not change, and anxiety was reduced (p = 0.028). The patients were divided into two groups based on whether EQ-5D-5L was improved: twelve patients in the unimproved group (UG) and twenty patients in the improved group (IG). In the UG, 50% had LVAD-related strokes (p = 0.001, IG: 0%), and their social QOL decreased (p = 0.023). The activity levels improved in the IG. Multi-dimensional analyses on the QOL in LVAD patients yielded mixed results. Anticipated benefits derived from LVAD therapy may be limited by LVAD-related complications such as stroke that negatively impacts on the QOL.


Incomplete dabigatran reversal with idarucizumab.
With increasing use of direct oral anticoagulants (DOACs), urgent reversal of these agents becomes a growing concern. Idarucizumab is a humanized monoclonal antibody fragment that specifically binds to dabigatran with higher affinity than thrombin, rapidly neutralizing its anticoagulant effect without increased risk of thrombosis. We describe two cases in which the recommended dose of idarucizumab was unsuccessful in completely reversing the anticoagulant effects of dabigatran. Both of these patients were noted to have supratherapeutic international normalized ratios (INRs) and high dabigatran concentrations. In the first case, an 86-year-old male underwent an emergent procedure and experienced excessive hemorrhaging refractory to blood product repletion, idarucizumab, and factor eight inhibitor bypass activity (FEIBA). In the second case, a 62-year-old female in shock was found to have elevated dabigatran concentrations despite two doses of idarucizumab, continuous renal replacement therapy (CRRT), blood product repletion, and FEIBA. Both patients ultimately expired from their coagulopathies. These cases illustrate the potential for incomplete reversal of dabigatran with the recommended 5 g of idarucizumab and emphasize the importance of early detection of dabigatran toxicity. While direct dabigatran serum concentrations are not readily available, the INR may be a useful surrogate marker for supratherapeutic dabigatran concentrations.


Assessment of a Novel Vitamin D3 Formulation with Nanostructured Lipid Carriers for Transdermal Delivery.
Develop and assess a transdermal emulsion loaded with nanostructured lipid carriers for vitamin D3 supplementation. Vitamin D3 loaded nanostructured lipid carriers, produced via high shear homogenization and ultrasonication, were assessed for their particle size, distribution, morphology, zeta potential, entrapment efficiency, and cytotoxicity. They were incorporated into a transdermal vehicle, and the stability and ex vivo permeation were evaluated. Spherical nanoparticles were developed with a particle size of 192.5 nm, a polydispersity index of 0.13, a zeta potential of -29.0 mV, and an entrapment efficiency of 99.75%. They were stable (particle size and distribution) for 15 days when stored in a refrigerator, and for 30 days at room temperature and 32°C. The nanoparticles decreased the drug cytotoxicity against fibroblasts, as shown by IC50 (nanoparticle: 32.48 μg mL-1 vitamin D3: 16.73 μg mL-1). The emulsion loaded with nanoparticles minimized the degradation of vitamin D3 when compared with the nanoparticle dispersion. Additionally, the emulsion provided the skin permeation of vitamin D3 following the recommended daily allowance. To the best of our knowledge, this is the first study to use nanostructured lipid carriers for transdermal delivery of vitamin D. The developed formulation is a promising strategy to overcome the vitamin D3 variable oral bioavailability. It also represents a comfortable route of administration; thus it could be beneficial for patients and clinicians. However, further studies are needed to allow the permeation of larger amounts of vitamin D3, and the combination of these nanoparticles with microneedles would be interesting.


Blink nystagmus.
A pattern of eye movement similar to vestibular nystagmus associated with blink is characterized. This artifact can be seen in asymptomatic, otologically normal subjects and is considered to have different meaning than lateral conjugate deviation of the eyes on forced closure of the lids (Cogan sign). Since this nystagmus artifact is most evident during electronystagmographic testing for spontaneous and semispontaneous nystagmus, its importance can be overestimated. Simultaneous monitoring of horizontal and vertical eye movement presently provides a definitive means of identification.


Alternative use of 5' exons in the specification of Ly-5 isoforms distinguishing hematopoietic cell lineages.
Previous inferences that Ly-5 glycoprotein isoforms of murine hematopoietic cells are generated by alternative splicing of primary transcripts of a single Ly-5 gene are supported by the present study. A cDNA library was prepared from B cells by extension from primer representing a known T-cell cDNA sequence. Three different Ly-5 clones from this library included sequences missing in T-cell cDNA clones. From the constitution of cDNA clones and of the Ly-5 gene, and from S1 nuclease mapping, it is concluded that at least two exons, provisionally numbered Ex-6(B) and Ex-7(B), in the 5'-proximal region are mainly represented in mRNA of the B-cell lines examined but not of the T-cell lines examined. Also, exons 1 and 2 appear to be used alternatively in different species of B-cell mRNA and probably also in different species of T-cell mRNA.


Argon plasma coagulation and electrosurgery for benign endobronchial tumors.
Benign endobronchial tumors are a rare entity capable of causing significant symptoms. Endobronchial tumor destruction has the potential for relieving symptoms while sparing the patient from invasive surgical resection. Although Nd:YAG laser has been successfully used, other less costly approaches such as argon plasma coagulation (APC) and electrocautery, may be effective alternatives for the bronchoscopic treatment of benign endobronchial tumors. A retrospective medical chart review was conducted at a single academic center in the United States from the period of January 2005 through December 2011 to collect a minimum of 10 cases for review. Eligibility criteria included diagnosis of a benign endobronchial tumor and age over 18 years. Our institution's pathology database was searched by specific benign tumor and the results were further refined based on an endobronchial location. The bronchoscopic procedure log was also searched and identified procedures were cross referenced with the medical record to confirm eligibility. Ten patients with pathologically confirmed benign endobronchial tumors were identified. All patients achieved tumor regression with APC in combination with electrocautery or cryotherapy. Majority of the procedures (75%) were performed with flexible bronchoscopy and 55% were performed under moderate sedation. APC is an effective method for tumor devitalization and reduction in tumor size, making it a viable and less costly therapeutic option for the treatment of benign endobronchial tumors.


Acute release of thyrotropin in the newborn.
Measurements of serum thyrotropin (TSH) concentrations were conducted in maternal and fetal blood during labor and delivery and the early postnatal and neonatal periods. Mean TSH concentration was significantly higher in cord blood (9.5 muU/ml) than maternal blood (3.9 muU/ml), a finding suggesting a fetal-maternal TSH gradient at term. Serum TSH concentration in the newborn increased rapidly to mean levels of 60 muU/ml at 10 min and 86 muU/ml at 30 min of age. Between 30 min and 3-4 hr serum levels decreased rapidly, then fell more gradually to a mean concentration of 13 muU/ml at 48 hr. The half-time of the decrease in serum TSH concentration between 30 and 90 min was 77 min, a value slightly greater than the half-time of disappearance of radioiodinated TSH measured in adults. This indicates that the early high rate of TSH secretion in the newborn ceases by 30 min, and that the rapid rise and fall in serum TSH concentrations may represent release of stored pituitary TSH. A more chronic TSH hypersecretion persisted throughout the first 24-48 hr of extrauterine life. Measurements of serum PBI concentrations were conducted in a separate group of maternal and cord blood samples and in the newborn infants during the first 48 hr of extrauterine life to relate the TSH and serum hormonal iodine concentration changes. Serum protein-bound iodine (PBI) concentrations were similar in maternal and cord blood, increased significantly by 4 hr of age in the newborn, and peaked at about 24 hr, presumably in response to the TSH hypersecretion. The pattern of TSH hypersecretion was similar in infants delivered vaginally and by caesarean section. Maternal serum TSH concentrations were stable throughout the perinatal period. Warming the infants at 99-103 degrees F during the first 3 hr of life did not prevent the early, acute release of thyrotropin. Cooling of warm infants at room temperature (72-78 degrees F) between 3 and 4 hr resulted in a decrease in mean rectal temperature of 3.3 degrees F and produced a significant increment in serum TSH concentration. These data suggest that the mechanism of the early, acute release of thyrotropin in the newborn may involve a potent stimulus other than cooling. However, the increase in serum TSH stimulated by delayed (3-4 hr) cooling indicates that neonatal hyperthyroxinemia is, at least, augmented by extrauterine cooling. Thus, cold exposure is capable of increasing TSH secretion in humans.


[Uncomplicated urinary tract infections. Antimicrobial susceptibility study in Navarre].
Urinary tract infection (UTI) is a high prevalence infection at the community level. In order to improve the adequacy of the empirical therapy, we evaluated the etiology and the resistance pattern of the main uropathogens responsible for community acquired UTI in Navarre. Retrospective study (2014-2016) in which we included microorganisms recovered with significant counts from samples of patients with community-acquired UTI. The global etiology and etiology according to age and sex was analyzed. Antimicrobial resistance was studied with urotopathogens isolated in 2016. Escherichia coli was the most frequently isolated microorganism both in the population (60.8%) and in each of the groups analyzed according to age and sex. The sensitivity of E. coli was: nitrofurantoin 97.4%, fosfomycin 96.5% amoxicillin-clavulanic acid 83.8%, trimethoprim-sulfamethoxazole 68.3%, quinolones 63.4% and amoxicillin 41.9%. Pooled sensitivity shows that the sensitivity to fosfomycin was 83.4% in men <15 years, 89.4% in women <15 years and 81.9% in women between 15-65 years; and to nitrofurantoin was 86.7% in women <15 years and 82.2% in women between 15-65 years. E. coli continues to be the most frequent microorganism in community-acquired UTI with a rate of sensitivity to fosfomycin and nitrofurantoin above 95%. The empirical treatment of UTI in our environment should not include amoxicillin, amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole or quinolones. Fosfomycin may be empirically used in the treatment of uncomplicated cystitis in men younger than 15 years and in women under 65 years, and nitrofurantoin may be used empirically in women under 65 years.


Mechanism of decrease in plasma renin activity during volume expansion.
The importance of filtered load of sodium and extracellular volume expansion (ECVE( per se on plasma renin activity (PRA) was studied in two groups of hydropenic dogs. Group I protocol consisted of bilateral ureteral obstruction (UO) followed by isotonic ECVE and finally UO release. During UO, PRA rose significantly above control (15.4 leads to 41.7 ng/ml per h). Superimposition of ECVE did not significantly alter PRA, but UO release returned PRA toward control (24.8 ng/ml per h). Fractional sodium excretion (FE(Na)) after UO release was higher than control (0.6 leads to 12.6%). In group II, ECVE preceded UO and caused a fall in PRA below control (16.8 leads to 4.8 ng/ml per h). FE(Na) was significantly increased over control (0.3 leads to 14.7%). Superimposition of UO reversed the fall in PRA to a value not significantly different from control. On release of UO PRA fell, but not significantly, whereas FE(Na) fell to 12.6%, a value not different from that during ECVE alone. The results indicate that filtration is required for ECVE to elicit a fall in PRA, under the present experimental condition.


Isolation and molecular characterization of Orf virus from natural outbreaks in goats of Assam.
Outbreaks of contagious ecthyma (caused by a Parapox virus) in goats were investigated in 6 districts of Assam, a north eastern state of India. Diagnosis of the disease was carried out employing both standard virological as well as molecular methods. Four representative isolates from different places were selected for phylogenetic analysis. The major envelop protein (B2L) of Orf virus was targeted for molecular analysis. The sequencing and phylogenetic analysis of the selected sequences at nucleotide level revealed that the Orf virus isolates were closely related to each other (97.6-100 %) and showed highest similarity to the Orf virus isolate 82/04 (98.4 %), reported from Shahjahanpur, India. The data will provide an insight in transmission of the virus from northern to North eastern part of the country.


Localizing Optic Disc in Retinal Image Automatically with Entropy Based Algorithm.
Examining retinal image continuously plays an important role in determining human eye health; with any variation present in this image, it may be resulting from some disease. Therefore, there is a need for computer-aided scanning for retinal image to perform this task automatically and accurately. The fundamental step in this task is identification of the retina elements; optical disk localization is the most important one in this identification. Different optical disc localization algorithms have been suggested, such as an algorithm that would be proposed in this paper. The assumption is based on the fact that optical disc area has rich information, so its entropy value is more significant in this area. The suggested algorithm has recursive steps for testing the entropy of different patches in image; sliding window technique is used to get these patches in a specific way. The results of practical work were obtained using different common data set, which achieved good accuracy in trivial computation time. Finally, this paper consists of four sections: a section for introduction containing the related works, a section for methodology and material, a section for practical work with results, and a section for conclusion.


Iridium-192 interstitial brachytherapy as adjunctive treatment for canine cutaneous mast cell tumors.
Eleven dogs with cutaneous mast cell tumors (MCTs) were treated with surgery and iridium-192 ((192)Ir) interstitial brachytherapy. Minimum tumor doses ranged from 47.2 to 63.3 Gy. Treated tumors were classified as grade II (n=7) or III (n=4). Five dogs had recurrences with a median progression-free interval of 1391 days, and six dogs had no recurrence at a median follow-up time of 942 days. Acute adverse effects were well tolerated, and late effects were mild. One dog developed a second tumor of a different cell type in the radiation treatment field.


Metabolic effects of amino acid solutions infused for renal protection during therapy with radiolabelled somatostatin analogues.
Infusion of amino acids (AAs) can reduce renal uptake of radiolabelled somatostatin analogues resulting in a lower kidney exposure during peptide radiotherapy of patients with neuroendocrine tumours. In this study, we investigated the metabolic effects related to the infusion of large amounts of amino acids in patients undergoing positron emission tomography (PET) studies with [(86)Y]DOTA(0)-D-Phe(1)-Tyr(3)-octreotide. Twenty-four patients, in four consecutive groups of six, received a 4 h infusion of 120 g of mixed AAs and, in addition, either a 4 h infusion of 50 g of L-lysine (n = 6), a 10 h infusion of 240 g of mixed AAs (n = 6), a 4 h infusion of 50 g of L-lysine + L-arginine (Lys-Arg; n = 6) or no infusion (control; n = 6) in randomly ordered crossover studies. A number of clinical and biochemical parameters in blood and urine were measured over 24 h, including calculation of creatinine clearance, tubular reabsorption of inorganic phosphate (TRP) and fractional urate excretion. No clinical side effects occurred during the infusions except for nausea and vomiting under mixed AAs. Patients in the latter group showed an increase in serum urea, whereas patients receiving L-lysine showed an increase in serum potassium and chloride. Inorganic phosphate levels dropped at 2.5 h in all groups except controls, and a significant decrease in TRP was observed with mixed AAs but not with L-lysine or Lys-Arg. Although infusion of AA solutions can improve the effect of therapy by allowing the administration of higher doses of radiolabelled somatostatin analogues, each preparation has specific sides effects that should be taken into account with this type of therapy.


The Cell Surface Markers Expression in Postmenopausal Women and Relation to Obesity and Bone Status.
The age-related changes and hormonal deprivation in postmenopausal women are associated with the immune response alteration. The excessive fat accumulation, local and systemic inflammation may lead to dysregulation in immune function and relevant health problems, including obesity and osteoporosis. We analyzed the expression of cell surface markers in the venous blood specimens, stained with fluorophores-conjugated monoclonal antibodies and analysed by multicolour flow cytometry. The significant changes of cytotoxic, naive, and memory T-lymphocytes, plasmacytoid dendritic cells (DCs) were in postmenopausal women versus fertile women. Body mass index (BMI) affected markedly the cell surface expression of CD265/RANK. Osteoporosis is linked to reduced percentage of plasmacytoid DCs, and elevated natural Treg cells (p < 0.05). The confounding factors such as women age, BMI, bone mineral density (BMD), waist size and tissue fat affect the expression of RANK on myeloid DCs and CD40L on T-lymphocytes that might be the immunophenotypic modulators after menopause.


Effect of plant VOCs and light intensity on growth and reproduction performance of an invasive and a native Phytolacca species in China.
Invasive plants often pose great threats to the growth of co-occurring native plant species. Identifying environmental factors that facilitate exotic plant invasion and native species decline are important. In this study, we measured the effects of plant volatile organic compounds (VOCs), light intensity, and their interactions on the growth and reproduction performance of indigenous Phytolacca acinosa, and invasive Phytolacca americana, which has largely replaced the former in China. VOCs of invasive P. americana and low light levels both had negative effects on P. acinosa morphological and reproductive traits (stem length, average leaf number, total number, and length of racemes), and biomass allocation (total biomass, and leaf and flower mass fraction); low light also affected photosynthesis-related trait (specific leaf area) of P. acinosa. In contrast, VOCs of P. acinosa had no significant effect on P. americana, but low light levels adversely affected its morphological and reproductive traits (stem length, total number, and length of racemes) and biomass allocation (total biomass, stem, and leaf mass fraction). Interactions between plant VOCs and light intensity had no significant effects on P. acinosa or P. americana. Under all experimental treatments, stem length, average leaf area, total number, and length of racemes, Root/Shoot ratio, root and flower mass fraction of P. americana were higher than those of P. acinosa, while average leaf number, specific leaf area, and leaf mass fraction was lower. These results indicated that P. acinosa was sensitive to P. americana VOCs and low light, which might affect the growth of sympatric P. acinosa. P. americana was negatively influenced by low light, but higher plant height and more reproductive organ resource allocation relative to sympatric P. acinosa might contribute to invasion success.


Computational modeling of chemo-bio-mechanical coupling: a systems-biology approach toward wound healing.
Wound healing is a synchronized cascade of chemical, biological, and mechanical phenomena, which act in concert to restore the damaged tissue. An imbalance between these events can induce painful scarring. Despite intense efforts to decipher the mechanisms of wound healing, the role of mechanics remains poorly understood. Here, we establish a computational systems biology model to identify the chemical, biological, and mechanical mechanisms of scar formation. First, we introduce the generic problem of coupled chemo-bio-mechanics. Then, we introduce the model problem of wound healing in terms of a particular chemical signal, inflammation, a particular biological cell type, fibroblasts, and a particular mechanical model, isotropic hyperelasticity. We explore the cross-talk between chemical, biological, and mechanical signals and show that all three fields have a significant impact on scar formation. Our model is the first step toward rigorous multiscale, multifield modeling in wound healing. Our formulation has the potential to improve effective wound management and optimize treatment on an individualized patient-specific basis.


Heterogeneity of dehydrogenases of Stenotrophomonas maltophilia showing dye-linked activity with polypropylene glycols.
Distinct enzyme activities were found in extracts from Stenotrophomonas maltophilia showing dye-linked oxidation of polypropylene glycols. The activities were induced when polypropylene glycols served as sole carbon and energy sources for the bacterium. In the logarithmic phase, most of the enzyme activities (88%) were found in the cytoplasm. In the stationary phase, more than half of the activities (54%) were found on the membrane, but significant activities were also distributed in the periplasm (34%) and the cytoplasm (12%). The enzyme activities differed from each other in their localization, time of induction in the growth cycle, specificity toward electron acceptor, and electrophoresis mobility.


Revising Working Models Across Time: Relationship Situations That Enhance Attachment Security.
We propose the Attachment Security Enhancement Model (ASEM) to suggest how romantic relationships can promote chronic attachment security. One part of the ASEM examines partner responses that protect relationships from the erosive effects of immediate insecurity, but such responses may not necessarily address underlying insecurities in a person's mental models. Therefore, a second part of the ASEM examines relationship situations that foster more secure mental models. Both parts may work in tandem. We posit that attachment anxiety should decline most in situations that foster greater personal confidence and more secure mental models of the self. In contrast, attachment avoidance should decline most in situations that involve positive dependence and foster more secure models of close others. The ASEM integrates research and theory, suggests novel directions for future research, and has practical implications, all of which center on the idea that adult attachment orientations are an emergent property of close relationships.