Three-Dimensional Blood Vessel Model with Temperature-Indicating Function for Evaluation of Thermal Damage during Surgery.
Surgical simulators have recently attracted attention because they enable the evaluation of the surgical skills of medical doctors and the performance of medical devices. However, thermal damage to the human body during surgery is difficult to evaluate using conventional surgical simulators. In this study, we propose a functional surgical model with a temperature-indicating function for the evaluation of thermal damage during surgery. The simulator is made of a composite material of polydimethylsiloxane and a thermochromic dye, which produces an irreversible color change as the temperature increases. Using this material, we fabricated a three-dimensional blood vessel model using the lost-wax process. We succeeded in fabricating a renal vessel model for simulation of catheter ablation. Increases in the temperature of the materials can be measured by image analysis of their color change. The maximum measurement error of the temperature was approximately -1.6 °C/+2.4 °C within the range of 60 °C to 100 °C.


Collaboration is Critical: Working Together to Optimize Health in Our Communities.
Clinical care accounts for only 20% of health outcomes, with social determinants of health including environment, health behaviors, and economics accounting for the remaining 80%. Providers ought to address social determinants of health and, more and more are joining community partnerships to do so.


Orthotopic ileal bladder substitute after radical cystectomy: urodynamic features.
Urodynamic investigation was performed in 12 men, 3 to 8 months after cystoprostatectomy for bladder cancer and bladder substitution, using a detubularized ileal segment as described by Studer-Zingg. All patients underwent a standard urodynamic evaluation and extramural ambulatory urodynamic monitoring (e.a.m.). Ten patients were continent by day and 3 were incontinent during the night to a degree that necessitated use of a condom catheter. Three patients awakened every 3 hours to void and 6 had to void 1-2 times nightly. The residual urine was over 100 ml in 3 patients; it was low or absent in the remainder. Micturition was achieved by straining, with a maximum flow rate of 13 ml per second or greater, except in 2 patients. In 2 patients a urethral narrowing was found at the urethro-ileal anastomosis, and in 1 of them an incoordination between the neobladder and the pelvic floor required the use of a urethral catheter and a subsequent protocol of pelvic floor rehabilitation. The incidence of nocturnal incontinence was 56.6%. In 2 patients urethral pressure profile revealed hypotonia, with a maximum urethral closure pressure (MUCP) < 45 cm H2O. During e.a.m. study pressure values in the neobladder usually ranged below 15 cm H2O and exceeded 35 cm H2O in only 1 patient who complained of daytime and nocturnal incontinence. Neobladder compliance was normal in all cases. In order to achieve a complete rehabilitation after operation, the patient should be instructed to follow a careful training in order to prevent overdistention of the neobladder by voiding at regular intervals and to obtain continence.


An increase in a long noncoding RNA ANRIL in peripheral plasma is an indicator of stable angina.
Stable angina develops during physical activity or stress, and it is typically an aspect of Coronary Heart Disease (CHD) that can lead to arrhythmia, heart failure and even sudden death. ANRIL, an Antisense Noncoding RNA gene in the INK4 Locus, is associated with multiple disorders including CHD; however, expressional levels of ANRIL in between patients with stable angina and myocardial infarction, one of the acute coronary syndrome, have not been clarified yet. The authors enrolled 62 patients with myocardial infarction and 59 with stable angina before primary percutaneous coronary intervention, as well as 48 healthy volunteers. Their peripheral blood was collected for analysis of ANRIL and cardiac troponin I, a traditional diagnostic index of CHD by real-time PCR. The data showed that ANRIL is a better diagnostic indicator than cardiac troponin I in patients with stable angina and that the levels of ANRIL are higher in patients with stable angina than those with the myocardial infarction. The levels of ANRIL in peripheral plasma could be used as a good biomarker for stable angina.


Sex-related expression of 20alpha-hydroxysteroid dehydrogenase mRNA in the adult mouse.
The enzyme 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) catalyzes the conversion of progesterone into its inactive form, 20alpha-hydroxyprogesterone. To gain information about the exact sites of 20alpha-HSD mRNA expression, we performed in situ hybridization using a (35)S-labeled cRNA probe in tissues of adult mice of both sexes. 20alpha-HSD mRNA was expressed in both male and female gonads. In the ovary, high expression was found in luteal cells of corpora lutea, while much lower expression could be detected in granulosa cells of growing follicles. In the testis, a specific hybridization signal was detected only in Leydig cells. In the female reproductive tract, 20alpha-HSD mRNA was found in the epithelial cells of the uterine cervix. In the adrenal cortex, only the zona reticularis exhibited specific radiolabeling, the expression being very high in the female and very low in the male. In the skin, specific labeling was restricted to sebaceous glands, the hybridization signal being much higher in the female than in the male. In the liver, 20alpha-HSD mRNA was found in hepatocytes, with a higher degree of expression in the female. In the kidney, specific labeling was observed in the epithelial cells of distal convoluted tubules, the signal being also much more striking in the female than in the male. In non-reproductive tissues, it clearly appears that the expression of 20alpha-HSD mRNA is higher in the female than in the male, suggesting that 20alpha-HSD may play an important role in reducing the intracellular concentration of progesterone originating from the circulation at a much higher level in the female.


Evaluation of contact lenses by microbial enumeration and protein determination.
Contact lenses worn for varying periods of time (from 1 to 48 months) were subjected to microbiological examination by plate counts and protein determination. Seventy percent of the lenses displayed bacterial colony counts below 120 colony-forming units (CFU)/lens, 28 percent were in the range of 140 to 9060 CFU/lens, and one lens was contaminated with greater than 6 x 10(4) CFU/lens. Fungal contaminants were detected in three lens specimens in the range of 220 to 760 CFU/lens. Protein accumulation showed wide variation of up to 1.2 mg of protein per lens. Statistical analysis indicated highly significant associations (p less than 0.001) between the bacterial colony counts obtained with three different media. Some significant associations were found between the protein concentration and bacterial counts. The data did not indicate statistically significant relations between the above variables and either the water content or the length of wear of the contact lenses.


Autosomal recessive severe combined immunodeficiency of Jack Russell terriers.
Because of unexplained mortality among 33 sibling offspring of a single pair of dogs, a family of Jack Russell Terriers was investigated. Twelve pups, 5 male and 7 female, died between 8 and 14 weeks of age. Six of those animals died in the field within 50 hours following vaccination with modified live vaccines. Subsequent histopathologic examination revealed the absence of splenic white pulp in 4 dogs and hepatic inclusions diagnostic for adenoviral infection in 2 dogs. Two additional litters yielded 2 pups with the same splenic and hepatic lesions. These observations led to a detailed study of 7 siblings whelped specifically for this investigation. Four of these 7 siblings had a profound lymphopenia and a decrease in serum immunoglobulins. Six of these dogs were necropsied at 7 weeks of age, and 4 of them had marked hypoplasia of all lymphoid tissue. The affected pups had an 86% decrease in mean thymic weight, with poor corticomedullary differentiation, and very few CD3-positive (T cell) thymocytes were detected immunohistochemically. However, the affected thymic tissue stained intensely with a immunochemical stain for cytokeratin. The other affected lymphoid tissues were identified histologically only by stromal architectural characteristics. Lymph nodes lacked both CD3 and CD79a (B cell) positive cells. The analyzed breeding data were consistent with an autosomal recessive mode of inheritance. This canine severe combined immunodeficiency has immunologic and pathologic features similar to those observed in immunodeficient C.B-17 mice and Arabian horses.


Effect of fever or respiratory symptoms on leaving without being seen during the COVID-19 pandemic in South Korea.
Coronavirus disease 2019 (COVID-19) has notably altered the emergency department isolation protocol, imposing stricter requirements on probable infectious disease patients that enter the department. This has caused adverse effects, such as an increased rate of leave without being seen (LWBS). This study describes the effect of fever/respiratory symptoms as the main cause of isolation regarding LWBS after the COVID-19 pandemic. We retrospectively analyzed emergency department visits before (March to July 2019) and after (March to July 2020) the COVID-19 pandemic. Patients were grouped based on existing fever or respiratory symptoms, with the LWBS rate as the primary outcome. Logistic regression analysis was used to identify the risk factors of LWBS. Logistic regression was performed using interaction terminology (fever/respiratory symptom patient [FRP] × post-COVID-19) to determine the interaction between patients with FRPs and the COVID-19 pandemic period. A total of 60,290 patients were included (34,492 in the pre-COVID-19, and 25,298 in the post-COVID-19 group). The proportion of FRPs decreased significantly after the pandemic (P < 0.001), while the LWBS rate in FRPs significantly increased from 2.8% to 19.2% (P < 0.001). Both FRPs (odds ratio, 1.76; 95% confidence interval, 1.59-1.84 (P < 0.001) and the COVID-19 period (odds ratio, 2.29; 95% confidence interval, 2.15-2.44; P < 0.001) were significantly associated with increased LWBS. Additionally, there was a significant interaction between the incidence of LWBS in FRPs and the COVID-19 pandemic period (P < 0.001). The LWBS rate has increased in FRPs after the COVID-19 pandemic; additionally, the effect observed was disproportionate compared with that of nonfever/respiratory symptom patients.


Tsunami disaster victim identification in Sri Lanka: legal aspects.
Natural hazards amounting to disasters have almost become an endemic phenomenon during past decades throughout the globe, particularly affecting less resourced countries. The capabilities of the affected nations are stretched to the maximum in most of the disasters, thereby exposing deficiencies at various levels of the disaster mitigation mechanisms. A key factor identified through the human experience of all previous disaster scenarios is the requisite of effective and integrated local, national and regional disaster management mechanisms. The national and regional legal framework in this context can supplement disaster management enormously by drafting and implementing practical legislation which can be activated in disaster situations to co-ordinate the relief missions and minimize the damage. Thus, the existing legal systems and legislation at national and regional levels should be modified accordingly to yield proper disaster management policies. However, many less resourced countries are still lacking functional disaster management mechanisms in local legislation and are consequently highly vulnerable to heavy casualties in disasters. Sri Lanka is a typical example of a state which had an ineffective disaster management mechanism, not strengthened by legislation, when the Asian tsunami struck the country in December 2004, despite having frequently been affected by natural and man-made hazards during the past three decades. The net effect was total disarray in disaster victim identification, leading to drastic and irreparable consequences.


Dendrite-free lithium deposition via self-healing electrostatic shield mechanism.
Rechargeable lithium metal batteries are considered the "Holy Grail" of energy storage systems. Unfortunately, uncontrollable dendritic lithium growth inherent in these batteries (upon repeated charge/discharge cycling) has prevented their practical application over the past 40 years. We show a novel mechanism that can fundamentally alter dendrite formation. At low concentrations, selected cations (such as cesium or rubidium ions) exhibit an effective reduction potential below the standard reduction potential of lithium ions. During lithium deposition, these additive cations form a positively charged electrostatic shield around the initial growth tip of the protuberances without reduction and deposition of the additives. This forces further deposition of lithium to adjacent regions of the anode and eliminates dendrite formation in lithium metal batteries. This strategy may also prevent dendrite growth in lithium-ion batteries as well as other metal batteries and transform the surface uniformity of coatings deposited in many general electrodeposition processes.


[Hemangioma: complications].
Hemangioma (HMG) is a benign tumour of the child generally evolving to spontaneous regression. Sometimes this evolution can become complicated in a more or less serious way according to its localization or of its importance. If local complications are, in the most of cases, without gravity, complications of a general nature like thrombopenia or cardiac failure may compromise the vital prognosis. There are in addition serious forms where, according to its localization or its importance, the HMG can compromise the aesthetic, or functional even vital outcome.


Optional vena cava filters for patients with high thromboembolic risk: questions to be answered.
The use of vena cava filters has increased rapidly over the past few years to more than 140,000 filters inserted worldwide in 2003. Continued improvements in filter design have increased the safety of intravascular caval filtration. Although there are many factors attributed to this increase, the most significant contributing factor has been the development of optional vena cava filters. That is, filters that can be left as a permanent device or can be removed endovascularly at a later date. Three filters are approved for removal in the United States, the Günther Tulip, the OptEase, and the Recovery. Recent reports have demonstrated the safety and feasibility of these devices in appropriate patients, but a number of questions have arisen regarding their use.


Hereditary Cerebral Small Vessel Diseases and Stroke: A Guide for Diagnosis and Management.
Cerebral small vessel diseases represent a frequent cause of stroke and cognitive or motor disability in adults. A small proportion of cerebral small vessel diseases is attributable to monogenic conditions. Since the characterization in the late 1990s of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, several other monogenic conditions leading to adult-onset ischemic or hemorrhagic stroke have been described. In this practical guide, we summarize the key features that should elicit the differential diagnosis of a hereditary cerebral small vessel diseases in adult stroke patients, describe the main clinical and imaging characteristics of the major hereditary cerebral small vessel diseases that can manifest as stroke, and provide general recommendations for the clinical management of affected patients and their relatives.


Retinal Changes After Posterior Cerebral Artery Infarctions Display Different Patterns of the Nasal und Temporal Sector in a Case Series.
Background: Visual field defects are a common and disabling consequence of stroke and a negative prognostic factor of patient's quality of life. They result from lesions in different parts of the visual system, most commonly the visual cortex and optic radiation. An important pathophysiological mechanism is transsynaptic retrograde degeneration (TRD). Methods: In a case series 21 patients with posterior cerebral artery (PCA) territory infarctions were analyzed by spectral-domain optical coherence tomography (SD-OCT) and multifocal visual evoked potentials (mfVEPs) cross-sectionally and longitudinally for up to 6 months. In OCT, symptomatic affected nasal and temporal sectors and corresponding visual fields in mfVEPs were compared to the contralateral side. Results: SD-OCT revealed a significant reduction (-2.92 ±2.53 μm, mean ± SD) of the symptomatic nasal macular retinal nerve fiber layer (RNFL) thickness and of the symptomatic temporal peripapillary RNFL after 6 months compared to baseline whereas the symptomatic temporal macular quadrant already showed a significantly thinner RNFL at baseline. The mfVEP first peak latency at baseline was significantly different (nasal visual field +11.69 ±11.17 ms, mean ± SD; temporal visual field +16.63 ±7.97 ms, mean ± SD) on the symptomatic compared to the asymptomatic field. The nasal visual fields partly recovered in amplitude and first peak latency of mfVEPs over the following 6 months compared to baseline. Conclusion: The dynamics of OCT and mfVEP outcomes for degeneration and recovery after PCA infarction differ between the nasal and temporal retinal sector. We postulate that retinal sectors may differ in their temporal pattern of TRD over time after retrogeniculate cerebral infarction.


Improved Deep Learning Network Based in combination with Cost-sensitive Learning for Early Detection of Ovarian Cancer in Color Ultrasound Detecting System.
With the development of theories and technologies in medical imaging, most of the tumors can be detected in the early stage. However, the nature of ovarian cysts lacks accurate judgement, leading to that many patients with benign nodules still need Fine Needle Aspiration (FNA) biopsies or surgeries, increasing the physical pain and mental pressure of patients as well as unnecessary medical health care costs. Therefore, we present an image diagnosis system for classifying the ovarian cysts in color ultrasound images, which novelly applies the image features fused by both high-level features from deep learning network and low-level features from texture descriptor. Firstly, the ultrasound images are enhanced to improve the quality of training data set and the rotation invariant uniform local binary pattern (ULBP) features are extracted from each of the images as the low-level texture features. Then the high-level deep features extracted by the fine-tuned GoogLeNet neural network and the low-level ULBP features are normalized and cascaded as one fusion feature that can represent both the semantic context and the texture patterns distributed in the image. Finally, the fusion features are input to the Cost-sensitive Random Forest classifier to classify the images into "malignant" and "benign". The high-level features extracted by the deep neural network from the medical ultrasound image can reflect the visual features of the lesion region, while the low-level texture features can describe the edges, direction and distribution of intensities. Experimental results indicate that the combination of the two types of features can describe the differences between the lesion regions and other regions, and the differences between lesions regions of malignant and benign ovarian cysts.


Trajectories of Substance Use among Child Welfare-Involved Youth: Longitudinal Associations with Child Maltreatment History and Emotional/Behavior Problems.
Maltreated children experience a variety of adverse outcomes including substance use problems. Although previous research indicated that there may be distinct trajectories of substance use among these youth, studies have examined them as if they were a single homogeneous group. The goals of this study were to explore substance use trajectories among child welfare-involved youth and to identify characteristics that distinguish substance use trajectories. Data from the National Survey of Child and Adolescent Well-Being (NSCAW II) were used. Multilevel latent growth mixture modeling (MLGMM) was performed using a subsample of 625 youth from ages 11-17 years investigated for maltreatment in 2008-2009. Measures included self-reported use of substance use during the previous 30 days, demographic characteristics, maltreatment history, placement in out-of-home care, and behavioral health problems. MLGMM identified two distinct substance use trajectory classes including High Stable Substance Use and Rapid Progression Use. Findings suggest that the experience of physical abuse is the key factor that distinguishes the two groups. When the effects of class-specific covariates were examined, results suggest that involvement in substance use behavior and its escalation vary between groups and are affected by youth's different previous experiences. Conclusions/Importance: The results have important implications for understanding individual differences in substance use behavior over time and how these differences were shaped by youth's experiences of family adversity. Study findings may be helpful for developing and enhancing the effectiveness of interventions targeted at decreasing substance use behaviors in child welfare-involved youth.


[A case of solitary ectopic medullary carcinoma in the right submandibular region].
A 77-year-old woman consulted our hospital because of an indolent mass in the right submandibular region, which developed approximately 4 months previously. Ultrasonography revealed a 19.5×9.2 mm homogeneous low echoic mass in the submandibular region and a 9.8×3.1 mm low echoic mass in the left thyroid lobe. Blood examinations revealed high levels of carcinoembryonic antigen (CEA) and calcitonin. Analysis of the cytological specimens obtained from the submandibular tumors indicated class IV disease. First, we resected the mandibular tumor for diagnosis, and the specimen showed medullary carcinoma. Later, the patient underwent left thyroid lobe resection. The pathological diagnosis was adenomatous goiter. We report a rare case of ectopic medullary carcinoma in the right mandibular region.


Immunogold quantitation of immunoglobulin light chains in renal amyloidosis and kappa light chain nephropathy.
By quantitative immunoelectron microscopy using protein A-gold, the authors compared the content and distribution of immunoglobulin light chain (LC) antigens in glomeruli from 11 cases of renal amyloidosis with that in two cases of kappa LC glomerulopathy and two cases of diabetic glomerulosclerosis. In a supplementary study and using a similar immunogold technique, the authors identified amyloid A in deparaffinized renal tissue from three of the 11 cases of renal amyloidosis. Each patient had similar clinical manifestations (chronic renal failure with proteinuria) and similar glomerular morphology (thickened glomerular basement membranes and nodular expansion of the mesangium). In 12 cases (10 amyloid, 2 kappa LC), immunoelectron microscopy localized LC antigens over the glomerular deposits and allowed indirect tissue quantitation of each LC antigen to the various cellular and interstitial compartments. In 6 of the 11 cases of renal amyloidosis, the amyloid labeled only for lambda, and in one, only for kappa. In one patient with Waldenström's macroglobulinemia, who had a biclonal gammopathy, both LC were identified in the amyloid. In two cases, both of whom had a history of chronic suppurative lung disease, both LC antigens as well as amyloid A were localized to the amyloid fibrils. In only one case, in which glomerular amyloid labeled for amyloid A, the amyloid did not label for either LC. Whereas lambda LC-derived fibrils often appeared as spicules in the glomerular subepithelial space, other amyloid deposits usually accumulated in the subendothelial zone and did not form spicules. The epimembranous location of spicules suggested that the amyloid precursor protein transformed into amyloid fibrils after filtration into the urinary space. Presence of epimembranous spicules may explain the more severe proteinuric renal failure and the more rapid progression to glomerulosclerosis described in primary amyloidosis.


Control of renin secretion from rat juxtaglomerular cells by cAMP-specific phosphodiesterases.
We tested the hypothesis that cGMP stimulates renin release through inhibition of the cAMP-specific phosphodiesterase 3 (PDE3) in isolated rat juxtaglomerular (JG) cells. In addition, we assessed the involvement of PDE4 in JG-cell function. JG cells expressed PDE3A and PDE3B, and the PDE3 inhibitor trequinsin increased cellular cAMP content, enhanced forskolin-induced cAMP formation, and stimulated renin release from incubated and superfused JG cells. Trequinsin-mediated stimulation of renin release was inhibited by the permeable protein kinase A antagonist Rp-8-CPT-cAMPS. PDE4C was also expressed, and the PDE4 inhibitor rolipram enhanced cellular cAMP content. Dialysis of single JG cells with cAMP in whole-cell patch-clamp experiments led to concentration-dependent, biphasic changes in cell membrane capacitance (C(m)) with a marked increase in C(m) at 1 micromol/L, no net change at 10 micromol/L, and a decrease at 100 micromol/L cAMP. cGMP also had a dual effect on C(m) at 10-fold higher concentration compared with cAMP. Trequinsin, milrinone, and rolipram mimicked the effect of cAMP on C(m). Trequinsin, cAMP, and cGMP enhanced outward current 2- to 3-fold at positive membrane potentials. The effects of cAMP, cGMP, and trequinsin on C(m) and cell currents were abolished by inhibition of protein kinase A with Rp-cAMPs. We conclude that degradation of cAMP by PDE3 and PDE4 contributes to regulation of renin release from JG cells. Our data provide evidence at the cellular level that stimulation of renin release by cGMP involves inhibition of PDE3 resulting in enhanced cAMP formation and activation of the cAMP sensitive protein kinase.


Non-Peptidergic Nociceptive Neurons Are Essential for Mechanical Inflammatory Hypersensitivity in Mice.
Small nerve fibers that bind the isolectin B4 (IB4+ C-fibers) are a subpopulation of primary afferent neurons that are involved in nociceptive sensory transduction and do not express the neuropeptides substance P and calcitonin-gene related peptide (CGRP). Several studies have attempted to elucidate the functional role of IB4+-nociceptors in different models of pain. However, a functional characterization of the non-peptidergic nociceptors in mediating mechanical inflammatory hypersensitivity in mice is still lacking. To this end, in the present study, the neurotoxin IB4-Saporin (IB4-Sap) was employed to ablate non-peptidergic C-fibers. Firstly, we showed that intrathecal (i.t.) administration of IB4-Sap in mice depleted non-peptidergic C-fibers, since it decreased the expression of purinoceptor 3 (P2X3) and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the dorsal root ganglia (DRGs) as well as IB4 labelling in the spinal cord. Non-peptidergic C-fibers depletion did not alter the mechanical nociceptive threshold, but it inhibited the mechanical inflammatory hypersensitivity induced by glial cell-derived neurotrophic factor (GDNF), but not nerve growth factor (NGF). Depletion of non-peptidergic C-fibers abrogated mechanical inflammatory hypersensitivity induced by carrageenan. Finally, it was found that the inflammatory mediators PGE2 and epinephrine produced a mechanical inflammatory hypersensitivity that was also blocked by depletion of non-peptidergic C-fibers. These data suggest that IB4-positive nociceptive nerve fibers are not involved in normal mechanical nociception but are sensitised by inflammatory stimuli and play a crucial role in mediating mechanical inflammatory hypersensitivity.


Analysis of strain-specific plasmid sequences from Coxiella burnetii.
Acute isolates of Coxiella burnetii possess a 36-kbp plasmid termed QpH1. DNA hybridizations show that QpH1 contains approximately 6-kbp region of DNA which is not present in the QpRS plasmid from chronic isolates. This QpH1-specific region of DNA contains the contiguous EcoRI fragments G, E, and D. The GED region was found to possess seven open reading frames (ORF's) coding for proteins ranging from 5.5 to 42.3 kDa in molecular mass when subcloned and expressed in vitro. Summing the predicted ORF's accounts for 95% of the GED coding potential. E. coli expression produced a stable 42.3-kDa protein from the pHIN19 subclone of GED. The ORF of the 42.3-kDa protein, termed cbhE', has been localized on GED by both in vitro transcription/translation and DNA sequencing. The cbhE' gene is estimated as 1142 bp in length with a putative promoter region of TCAACT (-35)-N16-TAAAAT (-10)-N14-AGAAGGA (Shine-Dalgarno)-N10-ATG.


Nonbiomorphic Passively Adaptive Swimming Robot Enables Agile Propulsion in Cluttered Aquatic Environments.
Aquatic swimmers, whether natural or artificial, leverage their maneuverability and morphological adaptability to operate successfully in diverse, complex underwater environments. Maneuverability allows swimmers the agility to change speed and direction within a constrained operating space, while morphological adaptability allows their bodies to deform as they avoid obstacles and pass through narrow gaps. In this work, we design a soft, modular, nonbiomorphic swimming robot that emulates the maneuverability and adaptability of biological swimmers. This tethered swimming robot is actuated by a two degree-of-freedom (2-DOF) cable-driven mechanism that enables not only common maneuvers, such as undulatory surging and pitch/yaw rotations, but also a roll rotation maneuver that is steady and controllable. This simple 2-DOF system demonstrates full 3D swimming abilities in a space-constrained underwater test bed. The soft compliant body and passive foldable fins of the swimming robot lend to its morphological adaptability, allowing it to move through narrow gaps, channels, and tunnels and to avoid obstacles without the need for a low-level feedback control strategy. The passive adaptability and maneuvering capabilities of our swimming robot offer a new approach to achieving underwater navigation in complex real-world settings.


Maladaptation to Acute Metal Exposure in Resurrected Daphnia ambigua Clones after Decades of Increasing Contamination.
Human environmental impacts have driven some of the strongest and fastest phenotypic changes recorded in wild animal populations. Across populations, this variation is often adaptive, because populations evolve fitness advantages in response to human-modified environments. Yet some populations fail to adapt to changing environments. Evidenced by declines in relative fitness, such seemingly maladaptive outcomes are less common but may be more likely in human-modified contexts. Further, our ability to investigate the dynamics of these adaptive and maladaptive responses over time is typically limited in natural systems. I combined resurrection ecology and paleolimnology approaches to examine evolutionary responses of the freshwater zooplankter Daphnia to exposure to heavy metal contamination over the past 50-75 years, using animals hatched from diapausing egg banks. In contrast to the predicted trend of adaptation to metal exposure over time, I observed an increase in sensitivity to both copper and cadmium exposure associated with increasing historic contamination. This potentially maladaptive trend occurred in Daphnia populations in three lakes. Given that the release of toxicants such as heavy metals is widespread and that other researchers have observed local maladaptation to toxicant exposure, it is important to understand the drivers and implications of this pattern.


[Depression and anxiety symptom severity in a group of children with epilepsy and related factors].
The aim of this study was to assess the anxiety and depression symptom severity in a group of epileptic children and compare the results to healthy controls. Additionally, the frequency of psychiatric disorders in epileptic children was also assessed. The study compared 30 children, ranging in age from 8 to 16 years with epileptic disorder who attended a children's neurology clinic, with healthy controls using the State-Trait Anxiety Inventory and Children's Depression Inventory scores and suicidal ideation. The MINI was administered to epileptic patients to determine the frequency of psychiatric disorders in this clinical group. State anxiety scores of the epilepsy group were significantly higher compared to controls. No significant differences were found between patients and controls in terms of trait anxiety and depression scores. In all 3 scales boys scored significantly higher than girls. No significant relationships were found between symptom severity, duration of epilepsy, age of seizure onset and depression and anxiety scores. Psychiatric assessments with the MINI identified psychiatric disorders in 26.7% of epileptic patients. Two epileptic patients reported past suicidal attempts however, only 2 patients were receiving psychiatric treatment. Psychiatric disorders were frequently observed in the group of epileptic patients. Psychiatric disorders occurred more frequently in boys compared to girls in this group. Clinicians should be more aware of accompanying psychiatric symptoms in epileptic patients and take the necessary precautions in the early period of the illness in an effort to prevent future mental health problems.


Stress, breakfast cereal consumption and objective signs of upper respiratory tract illnesses.
Recent research has shown that both negative life events and breakfast cereal consumption are associated with the incidence and severity of subjective symptoms of upper respiratory tract illnesses (URTIs) Two studies were conducted to examine whether objective markers of illness were also associated with stress and breakfast cereal consumption. The results from the first study showed that regular breakfast cereal consumption was associated with lower sub-lingual temperatures in volunteers with URTIs. Stress had no effect on temperature. In the second study nasal secretion weight was lower in regular breakfast cereal consumers but was not influenced by stress. These studies suggest that breakfast cereal consumption is associated with reduced illness severity and that this does not reflect stress levels. Further research is now required to determine whether such results are directly due to cereal consumption or reflect correlated attributes, such as other aspects of the diet.


Prevalence and Molecular Subtyping of Blastocystis from Patients with Irritable Bowel Syndrome, Inflammatory Bowel Disease and Chronic Urticaria in Iran.
Blastocystis is a parasite that colonizes in the human intestine. Its clinical features include diarrhea, abdominal pain, or urticarial and irritable bowel syndrome (IBS). Spite of being significant genetic diversity and numerous subtypes within the genus there were no associations between its subtypes and symptomatology. Aim of this project was subtyping of the protozoa in 184 Iranian people with history of IBS/IBD (n = 74) or chronic urticaria (n = 59) and individuals referred to general clinic (n = 51). Microscopic and molecular examinations used for identifying and subtyping of Blastocystis. Overall, frequency of the parasite was 24.46% while, 29.41% of people who referred to general clinic, 20.27%, and 25.42% of IBS/IBD and urticarial cases were infected, respectively. Subtyping result showed that 28.89% of all people were infected with Blastocystis sp. while the prevalence of ST3, ST2 and ST1 were 22.22%, 22.22%, and 17.78%, respectively. Blastocystis sp., was identified in most IBS/IBD cases (46.7%) followed with ST2 and ST3 (13.3 and 13.3, respectively). Whereas, in chronic urticaria group ST2(33.3%) was the major subtype and most individuals in control group were infected with ST3 (33.3%). Pearson's Chi Square test showed no significant differences between the parasite or subtype prevalence and diseases (p > 0.05). Given significant factors have effect on clinical signs including host or parasite genetics, microbiota, as well as environmental factors, it seems that further studies are needed to find out different markers of host susceptibility to diverse parasite genotypes in patients with irritable bowel syndrome or urticaria.


[Camptocormia, a rare form of motor system disorders in Parkinson's disease].
Camptocormia is characterized by pronounced forward flexion of the thoracolumbar spine, which increases while walking and disappears in recumbent position. The clinical spectrum of the described disorders with concomitant camptocormia is heterogenous. It was described for the first time in idiopathic Parkinson's disease in 1999. The pathophysiology of this phenomenon remains unclear but seems to be not related to antiparkinsonian treatment. The authors present the case of a 54 years old woman, with idiopathic Parkinson disease diagnosed 5 years ago. The rapid progression of the disease was associated with good response to Levodopa therapy, although the dose had to be increased up to 1400 mg/d (with peripheral decarboxylase and COMT inhibitor). After 5 years she developed painful spasms of paraspinal muscles which resulted in trunk flexion. The clinical picture resembled the described cases of camptocormia. There was no correlation between the appearance of camptocormia and the regime of levodopa administration (time or dosage). Therefore, one can conclude, that presumably camptocormia is not a form of dystonia of the trunk but, the result of till now unclear other factors (dysfunction in other non-dopaminergic nigrostriatal projections?).


Assay for aflatoxin production by the genera Aspergillus and Penicillium.
A total of 260 isolates, including 43 species of Penicillium and 7 species of Aspergillus, were screened for their ability to produce aflatoxin on rice. Chloroform extracts were analyzed by thin-layer chromatography. None of the isolates produced aflatoxin. Certain species of Penicillium produced fluorescent substances that either were similar in R(F) or were of similar color to B and G aflatoxins. These substances were subsequently proved not to be aflatoxin by two-dimensional chromatography, by reaction with iodine fumes, or by both methods.


Endemic Lake Baikal sponges from deep water. 2: Taxonomy and Bathymetric Distribution.
Unique samples of deep-water sponges of Lake Baikal were collected between 120 and 1450 m depth and their taxonomy and bathymetric distribution were studied. Based on morphological studies with scanning electron microscopy (SEM) and molecular analyses (CO1, ITS) we describe a new species, Baikalospongia abyssalis sp. nov. Spicule morphology of this new species is similar to Palaeoephydatia sp., a species previously known only from fossils in Late Pliocene (3.2-2.8 mya) sediments. Other sponge samples collected were identified as Baikalospongia intermedia intermedia, B. intermedia profundalis, B. bacillifera, B. fungiformis, B. martinsoni and Swartschewskia papyracea, all from the family Lubomirskiidae. Sponge specimens with giant spicules, identified as B. fungiformis, were found at great depths. B.i. intermedia and B. i. profundalis are dominating species at great depth. Light is a limiting factor for distribution of Lubomirskia baicalensis, possibly due to its symbiosis with photosynthetic protists. The current study extends our knowledge on the distribution boundaries of Lubomirskiidae at great depths.


Bilateral subthalamic deep brain stimulation initial impact on nonmotor and motor symptoms in Parkinson's disease: An open prospective single institution study.
Numerous studies document significant improvement in motor symptoms in patients with Parkinson's disease (PD) after deep brain stimulation of the subthalamic nucleus (STN-DBS). However, little is known about the initial effects of STN-DBS on nonmotor domains.Our objective was to elucidate the initial effects of STN-DBS on non-motor and motor symptoms in PD patients in a 4-month follow-up.This open prospective study followed 24 patients with PD who underwent STN-DBS. The patients were examined using dedicated rating scales preoperatively and at 1 and 4 months following STN-DBS to determine initial changes in motor and nonmotor symptoms. Patients at month 1 after STN-DBS had significantly reduced the Parkinson's disease Questionnaire scores (P = .018) and Scales for Outcomes in Parkinson's disease - Autonomic scores (P = .002); these scores had increased at Month 4 after DBS-STN. Nonmotor Symptoms Scale for Parkinson's Disease had improved significantly at Month 1 (P < .001); at Month 4, it remained significantly lower than before stimulation (P = .036). There was no significant difference in The Parkinson's Disease Sleep Scaleat Month 1 and significant improvement at Month 4 (P = .026). There were no significant changes in The Female Sexual Function Index or International Index of Erectile Function. Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III scores show significant improvements at Month 1 (P < .001) and at Month 4 (P < .001).STN-DBS in patients with advanced PD clearly improves not only motor symptoms, but also several domains of nonmotor functions, namely sleep, autonomic functions and quality of life quickly following the start of stimulation.


Exocytic trafficking pathways in plants: why and how they are redirected.
The membrane trafficking system is responsible for precise transportation and localization of proteins, lipids, and polysaccharides among single membrane-bound organelles, the plasma membrane, and the extracellular space. While the exocytic trafficking pathway is considered to be a default transport pathway in many organisms, including land plants, research has shown that evolutionary processes led to an increase in the number of machinery components involved in the plant exocytic pathway. This study provides an overview of the diversification of exocytic trafficking pathways in plants, which mediate the formation and maintenance of cell polarity, interaction with symbiotic and pathogenic microbes, and cytokinesis. To fulfill these functions, distinct strategies have been employed to reroute secretory/exocytic transport during land plant evolution.


Leukocyte DNA damage after multi-detector row CT: a quantitative biomarker of low-level radiation exposure.
To prospectively determine if gammaH2AX (phosphorylated form of H2AX histone variant)-based visualization and quantification of DNA damage induced in peripheral blood mononuclear cells (PBMCs) can be used to estimate the radiation dose received by adult patients who undergo multidetector computed tomography (CT). After institutional review board approval and written informed patient consent were obtained, eight women and five men (mean age, 63.8 years) who would be undergoing chest-abdominal-pelvic CT or chest CT only were recruited. Venous blood samples obtained before scanning were exposed to different radiation doses in vitro and incubated for 5-30 minutes to obtain reference values of gammaH2AX focus yield. Additional blood samples were taken 5-30 minutes after CT. Leukocytes were isolated, fixed, and stained for gammaH2AX expression. The gammaH2AX focus yields were determined with fluorescence microscopy, and the radiation doses delivered during CT were estimated by comparing post-CT focus yields with in vitro pre-CT focus yields. These CT radiation doses were compared with doses calculated by using phantom dosimetry and Monte Carlo data sets. Data were analyzed by using linear regression, the dispersion index test, and the contaminated Poisson method. Compared with the gammaH2AX focus yields in blood samples taken before CT (0.06 focus per cell+/-0.01 [mean+/-standard error of mean]), the yields in blood samples taken 5 minutes after chest-abdominal-pelvic CT (0.52 focus per cell+/-0.02) were 8-10-fold higher and corresponded to a mean radiation dose of 16.4 mGy (95% confidence interval: 15.1, 17.7). The mean yield of 0.24 focus per cell+/-0.04 in one patient after chest CT corresponded to a mean radiation dose of 6.3 mGy+/-1.4. In comparison, phantom dosimetry-calculated total blood doses were 13.85 mGy with whole-body CT and 5.16 mGy with chest CT. gammaH2AX focus yield in blood cells may be a useful quantitative biomarker of human low-level radiation exposure.


Methotrexate in the therapeutic pathway of patients with psoriasis. Analysis of clinical practice data and comparison with guidelines.
Psoriasis is an inflammatory skin disease with a chronic-relapsing course. It is estimated that the prevalence in Italy is 3%. An adequate model of taking care of the patient with psoriasis allows the patient to benefit from the most suitable treatment option for his health needs. In this position statement the observations, criticalities and proposals for improvement of the Pso-Path Working Group, composed by health economists, clinicians and patients, on the diagnostic-therapeutic pathway of the patient with psoriasis have been collected. In particular, the deviation of clinical practice from the current Guidelines for the management of patients with psoriasis, which recommend the use of biologic drugs in case of non-response, intolerance or contraindication to Methotrexate or Cyclosporine, was evaluated. A Working Group was convened whose participants were asked to express their thoughts on the diagnostic and therapeutic pathway of the patient with psoriasis, bringing out critical elements and proposals for improvement, based on their experiences. This position statement summarizes the experiences and consensus between clinicians and patients on actions to optimize the management of patients with psoriasis undergoing biological treatment. Compared to the epidemiological data currently available, it is believed that only a small percentage of patients with psoriasis are treated with systemic drugs. The perception of clinicians, according to their experience, confirms the data emerging from the National Report "National Observatory on the Use of Medicines" (Osmed) compiled by AIFA in 2015, according to which more than 77% of patients with psoriasis are started to treatment with biological drugs without a previous use of Methotrexate or Cyclosporine for at least 3 months. The Pso-Path Working Group concluded that it would be desirable to incentivize, through the formalization of regional guidelines, the creation of a network system that promotes not only a greater awareness, at the territorial level, of the importance and impact of the disease and the possible paths, but also the collaboration and connection between all the actors involved in the overall care of the patient.


Serosurvey of anti-Toxocara antibodies and associated risk factors in domestic dogs and cats owners in Karaj, Alborz Province of Iran.
Toxocariasis is a zoonotic parasitic infection with important public health considerations. The aim of the study was to assess the prevalence of anti-Toxocara species antibodies and associated risk factors in domestic dogs and cats referred by their owners to veterinary clinics located in Karaj, Alborz Province, Iran. A cross-sectional study involving 540 owners of dogs and cats was conducted between July - December 2020. A questionnaire administered by direct interviews was used to collect socio-demographic information and data on associated risk factors. Blood samples were collected and tested by indirect enzyme-linked immunosorbent assay (ELISA). The overall sero-prevalence of toxocariasis among the 540 participants was 16.7% (90 of 540). When participants included in the sample were classified by age, those aged 10-29 years demonstrated higher Toxocara infection prevalence than other groups (45.6%, 41 of 90). Univariate analysis revealed that the pet owners who had contact with soil [adjusted odds ratio (AOR) = 7.61, 95% CI: 6.06-9.24, P = 0.028], practiced handwashing after contact with dogs and cats (AOR = 2.42, 95% CI: 1.15-4.85, P = 0.046), and feeding the pets with raw meat (AOR = 11.01, 95% CI: 5.21-19.43, P = 0.023) had an increased risk of acquiring toxocariasis. The study showed that demographic characteristics such as age, gender, place of residence, education, and pet's habitats were not significantly associated with toxocariasis. Given the findings and the progressive impact of toxocariasis in public health and its high prevalence in developing countries, including Iran, measures should be taken to inform the public about zoonoses and eliminate their putative transmission.


Identifying and Targeting Prediction of the PI3K-AKT Signaling Pathway in Drug-Induced Thrombocytopenia in Infected Patients Receiving Linezolid Therapy: A Network Pharmacology-Based Analysis.
The pharmacological mechanisms underlying the adverse effects of linezolid on thrombocytopenia have not been conclusively determined. This network pharmacology study aimed at investigating the potential pharmacological mechanisms of linezolid-induced adverse reactions in thrombocytopenia. In this study, target genes for linezolid and thrombocytopenia were compared and analyzed. Overlapping thrombocytopenia-associated targets and predicted targets of linezolid were imported to establish protein-protein interaction networks. Gene Ontology and the Kyoto Encyclopedia of Genes and Genome pathway enrichment analyses were performed to determine the enriched biological terms and pathways. The mechanisms involved in linezolid-induced thrombocytopenia were established to be associated with various biological processes, including T cell activation, peptidyl serine modification, and peptidyl serine phosphorylation. The top five relevant protein targets were obtained, including ALB, AKT1, EGFR, IL6, and MTOR. Enrichment analysis showed that the targets of linezolid were positively correlated with T cell activation responses. The mechanism of action of linezolid was positively correlated with the PI3K-AKT signaling pathway and negatively correlated with the Ras signaling pathway. We identified the important protein targets and signaling pathways involved in linezolid-induced thrombocytopenia in anti-infection therapy, providing new information for subsequent studies on the pathogenesis of drug-induced thrombocytopenia and potential therapeutic strategies for rational use of linezolid in clinical settings.


Intersex, Hermaphroditism, and Gonadal Plasticity in Vertebrates: Evolution of the Müllerian Duct and Amh/Amhr2 Signaling.
In vertebrates, sex organs are generally specialized to perform a male or female reproductive role. Acquisition of the Müllerian duct, which gives rise to the oviduct, together with emergence of the Amh/Amhr2 system favored evolution of viviparity in jawed vertebrates. Species with high sex-specific reproductive adaptations have less potential to sex reverse, making intersex a nonfunctional condition. Teleosts, the only vertebrate group in which hermaphroditism evolved as a natural reproductive strategy, lost the Müllerian duct during evolution. They developed for gamete release complete independence from the urinary system, creating optimal anatomic and developmental preconditions for physiological sex change. The common and probably ancestral role of Amh is related to survival and proliferation of germ cells in early and adult gonads of both sexes rather than induction of Müllerian duct regression. The relationship between germ cell maintenance and sex differentiation is most evident in species in which Amh became the master male sex-determining gene.


Formation of GABAergic synapses in the cerebellum.
In the adult central nervous system (CNS), gamma-amino butyric acid (GABA) is a predominant inhibitory neurotransmitter, and is involved in the expression of various higher brain functions. In the cerebellum, formation of GABAergic synapses is crucial for cerebellar functions. However, it is not fully understood how GABAergic synapses and networks are formed. We are morphologically investigating the developmental changes in GABAergic signaling and the mechanisms underlying the assembly of GABAergic synapses using the cerebellum, which provides an ideal system for the investigation of brain development. The anatomy and development of GABAergic synapses and networks in the cerebellar cortex are reviewed, the key factors for the formation of GABAergic synapses are addressed, and the mechanisms underlying the formation of cerebellar GABAergic networks are discussed.


The mucosal and systemic immune responses elicited by a chitosan-adjuvanted intranasal influenza H5N1 vaccine.
Development of influenza vaccines that induce mucosal immunity has been highlighted by the World Health Organisation as a priority (Vaccine 2005;23:1529). Dose-sparing strategies and an efficient mass-vaccination regime will be paramount to reduce the morbidity and mortality of a future H5N1 pandemic. This study has investigated the immune response and the dose-sparing potential of a chitosan-adjuvanted intranasal H5N1 (RG-14) subunit (SU) vaccine in a mouse model. Groups of mice were intranasally immunised once or twice with a chitosan (5 mg/ml)-adjuvanted SU vaccine [7·5, 15 or 30 μg haemagglutinin (HA)] or with a non-adjuvanted SU vaccine (30 μg HA). For comparison, another group of mice were intranasally immunised with a whole H5N1 (RG-14) virus (WV) vaccine (15 μg HA), and the control group consisted of unimmunised mice. The chitosan-adjuvanted SU vaccine induced an immune response superior to that of the non-adjuvanted SU vaccine. Compared with the non-adjuvanted SU group, the chitosan-adjuvanted SU vaccine elicited higher numbers of influenza-specific antibody-secreting cells (ASCs), higher concentrations of local and systemic antibodies and correspondingly an improved haemagglutination inhibition (HI) and single radial haemolysis (SRH) response against both the homologous vaccine strain and drifted H5 strains. We measured a mixed T-helper 1/T-helper 2 cytokine response in the chitosan-adjuvanted SU groups, and these groups had an increased percentage of virus-specific CD4(+) T cells producing two Thelper 1 (Th1) cytokines simultaneously compared with the non-adjuvanted SU group. Overall, the WV vaccine induced higher antibody concentrations in sera and an HI and SRH response similar to that of the chitosan-adjuvanted SU vaccine. Furthermore, the WV vaccine formulation showed a stronger bias towards a T-helper 1 profile than the SU vaccine and elicited the highest frequencies of CD4(+) Th1 cells simultaneously secreting three different cytokines (INFγ(+) , IL2(+) and INFα(+) ). As expected, two immunisations gave a better immune response than one in all groups. The control group had very low or not detectable results in the performed immunoassays. The cross-clade serum reactivity, improved B- and T-cell responses and dose-sparing potential of chitosan show that a chitosan-adjuvanted intranasal influenza vaccine is a promising candidate vaccine for further preclinical development.


Serum Copper, Zinc and Copper/Zinc Ratio and their Relationship to Age and Growth Status in Yemeni Adolescent Girls.
As no previous study has evaluated copper and zinc status in adolescent Yemeni girls, the purpose of this study was to measure their serum levels of zinc and copper and to examine the relationship between the serum levels of these two trace minerals with age, and anthropometric parameters. The study was conducted in April 2007 in Alwehda district in the municipality of Sana'a, Yemen. One hundred and fourteen adolescent girls were selected using systematic stratified sampling from a representative school which was randomly selected. Anthropometric indices were measured and blood samples were collected for biochemical analysis. The mean ±SD for copper, zinc, and copper/zinc ratio for the entire cohort were 17.47±3.31 μmol/L, 12.24±1.04 μmol/L, and 1.44±0.31, respectively. The prevalence of hypocuprimea was 4.4% and hypercuprimea was 2.6%. The levels of zinc were marginal in 96.5% of the girls and the prevalence of hypozincimea was 3.5%. The levels of copper were significantly higher (p = 0.007) and the levels of zinc were significantly lower (p = 0.003) in the 10-12 yrs girls than in other age groups. Height showed significant negative correlation with the levels of copper (p = 0.01) and significant positive correlation with the levels of zinc (p = 0.008). The results revealed that the Yemeni girls had marginal serum zinc levels, and 10-12 yrs girls had significantly lower zinc levels than other age groups. This provides a warning of consequent negative health effects since the physiological requirements for zinc are high in adolescence.


A cohort study of gestational diabetes mellitus and complimentary qualitative research: background, aims and design.
Women with gestational diabetes mellitus (GDM) and their offsprings are at increased risk of future type 2 diabetes and metabolic abnormalities. Early diagnosis and proper management of GDM, as well as, postpartum follow-up and preventive care is expected to reduce this risk. However, no large scale prospective studies have been done particularly from the developing world on this aspect. The objective of this study is to identify and follow a cohort of pregnant women with and without GDM and their offspring to identify determinants and risk factors for GDM, for various pregnancy outcomes, as well as, for the development of future diabetes and metabolic abnormalities. This is a prospective cohort study involving pregnant women attending prenatal clinics from urban, semi-urban and rural areas in the greater Chennai region in South India. Around 9850 pregnant women will be screened for GDM. Socio-economic status, demographic data, obstetric history, delivery and birth outcomes, perinatal and postnatal complications, neonatal morbidity, maternal postpartum and offsprings follow-up data will be collected. Those diagnosed with GDM will initially be advised routine care. Those unable to reach glycaemic control with diet alone will be advised to take insulin. Postpartum screening for glucose abnormalities will be performed at months 3 and 6 and then every year for 10 years. The offsprings will be followed up every year for anthropometric measurements and growth velocity, as well as, plasma glucose, insulin and lipid profile. In addition, qualitative research will be carried out to identify barriers and facilitators for early GDM screening, treatment compliance and postpartum follow-up and testing, as well as, for continued adherence to lifestyle modifications. The study will demonstrate whether measures to improve diagnosis and care of GDM mothers followed by preventive postpartum care are possible in the routine care setting. It will also map out the barriers and facilitators for such initiatives and provide new evidence on the determinants and risk factors for both GDM development and occurrence of adverse pregnancy outcomes and development of future diabetes and metabolic abnormalities in the GDM mother and her offspring.


A case of pervasive refusal syndrome: a diagnostic conundrum.
A case is presented of an 11-year-old girl with pervasive refusal syndrome (PRS) who ultimately recovered acutely and completely after an 18-month paediatric hospitalisation. There was an apparent absence of previously proposed important aetiological factors in PRS, such as family pathology and markedly traumatic or abusive experiences, and her recovery was sudden and complete. The authors consider the differential diagnoses of PRS paying particular attention to the possibility of a conversion disorder or catatonia, given the absence of PRS in the North American literature. Consideration of catatonia is important as it has a diagnostic test and responds rapidly to appropriate treatment, in contrast to conventional treatment for PRS and conversion disorder.


Action mechanism of retinoid-synergistic dibenzodiazepines.
4-[5H-2,3-(2,5-Dimethyl-2,5-hexano)-5-methyldibenzo[b,e][1,4 ]diazepin-11-yl]benzoic acid (HX600), as well as its oxa- (HX620) and thia- (HX630) analogs, enhanced the activity of retinoic acid and a receptor alpha (RAR alpha)-selective agonist Am80 in HL-60 cell differentiation assays. HX600 synergizes with Am80 by binding to, and transactivating through, the RXR subunit of the RXR-RAR heterodimer. HX600 exhibited RXR pan-agonist activity in transient transfections with a DR1-based reporter gene and synergized with RA-bound RAR alpha and RAR beta in inducing transcription from a DR5-based reporter. In addition, all three compounds at high concentrations acted as RAR pan-antagonists in stably transfected RAR "reporter cells." These efficient synergists bind only weakly with RXRs in vitro, suggesting that they are RXR-RAR heterodimer-selective activators. These HX retinoids exhibited dual functionality, since they affected signalling through both retinoid receptor families (RARs and RXRs).


Emotional Expression on Social Media Support Forums for Substance Cessation: Observational Study of Text-Based Reddit Posts.
Substance use disorder is characterized by distinct cognitive processes involved in emotion regulation as well as unique emotional experiences related to the relapsing cycle of drug use and recovery. Web-based communities and the posts they generate represent an unprecedented resource for studying subjective emotional experiences, capturing population types and sizes not typically available in the laboratory. Here, we mined text data from Reddit, a social media website that hosts discussions from pseudonymous users on specific topic forums, including forums for individuals who are trying to abstain from using drugs, to explore the putative specificity of the emotional experience of substance cessation. An important motivation for this study was to investigate transdiagnostic clues that could ultimately be used for mental health outreach. Specifically, we aimed to characterize the emotions associated with cessation of 3 major substances and compare them to emotional experiences reported in nonsubstance cessation posts, including on forums related to psychiatric conditions of high comorbidity with addiction. Raw text from 2 million posts made, respectively, in the fall of 2020 (discovery data set) and fall of 2019 (replication data set) were obtained from 394 forums hosted by Reddit through the application programming interface. We quantified emotion word frequencies in 3 substance cessation forums for alcohol, nicotine, and cannabis topic categories and performed comparisons with general forums. Emotion word frequencies were classified into distinct categories and represented as a multidimensional emotion vector for each forum. We further quantified the degree of emotional resemblance between different forums by computing cosine similarity on these vectorized representations. For substance cessation posts with self-reported time since last use, we explored changes in the use of emotion words as a function of abstinence duration. Compared to posts from general forums, substance cessation posts showed more expressions of anxiety, disgust, pride, and gratitude words. "Anxiety" emotion words were attenuated for abstinence durations >100 days compared to shorter durations (t12=3.08, 2-tailed; P=.001). The cosine similarity analysis identified an emotion profile preferentially expressed in the cessation posts across substances, with lesser but still prominent similarities to posts about social anxiety and attention-deficit/hyperactivity disorder. These results were replicated in the 2019 (pre-COVID-19) data and were distinct from control analyses using nonemotion words. We identified a unique subjective experience phenotype of emotions associated with the cessation of 3 major substances, replicable across 2 time periods, with changes as a function of abstinence duration. Although to a lesser extent, this phenotype also quantifiably resembled the emotion phenomenology of other relevant subjective experiences (social anxiety and attention-deficit/hyperactivity disorder). Taken together, these transdiagnostic results suggest a novel approach for the future identification of at-risk populations, allowing for the development and deployment of specific and timely interventions.


Transdermal Delivery of Metformin Hydrochloride from a Semisolid Vehicle.
Metformin hydrochloride is a traditional, FDA-approved drug used as a first-line drug of choice to treat type 2 diabetes. Research has shown metformin hydrochloride effective in injuries, including age-related maladies. The purpose of this ex vivo study was to evaluate the use of a commercial transdermal vehicle as a semisolid, liposomal vanishing cream (Pentravan) to deliver metformin hydrochloride through the human skin. The experiments were conducted as percutaneous absorption assay in Franz Diffusion Cells, coupled with freshly excised human skin and analyzed by high-performance liquid chromatography. Both methods were based on validated methods of both the United States Pharmacopeial Convention, Inc. and the International Conference on Harmonization. A 46.7% permeation percentage was found, with a drug flux of 3.91 µg cm-2 h-1 and a lag time of 0.51 h, following pseudo first-order absorption kinetics. These results showed that transdermal metformin hydrochloride can be an option for patients searching for diverse clinical effects.


Laser irradiation precipitation from nonlinear optical KH2PO4 crystal.
Structural stability of KH2PO4 (KDP) crystal under laser irradiation is a great challenge to nonlinear optical devices. Herein, the dependency of structural stability on the propagated laser wavelength was established. Separated precipitations with different morphologies, including irregular fusion, elongated prism, and quasi-equiaxial particles were irradiated from the KDP crystal surface by a laser with different wavelengths, including 0.103, 355, and 785 nm. All the precipitations induced by laser irradiation were identified to be the same KDP phase as its parent phase examined by electron diffraction. Noticeably, the stacked periodicity degree at (001) planes of precipitations becomes irregular somehow. It is believed that our research findings might have new implications and inspirations in constructing KDP devices with better stability.


Indium-mediated tandem radical addition-cyclization-trap reactions in aqueous media.
[reaction: see text] Tandem carbon-carbon bond-forming reactions were studied by using indium as a single-electron-transfer radical initiator. The radical addition-cyclization-trap reaction of a substrate having a vinyl sulfonamide group and an olefin moiety proceeded smoothly in aqueous media. The radical addition-cyclization reaction of hydrazone gave the functionalized cyclic products.


Levels of knowledge regarding malaria causes, symptoms, and prevention measures among Malawian women of reproductive age.
Malawi is a malaria-endemic country and approximately 6 million cases are reported annually. Improving knowledge of malaria causes and symptoms, and the overall perception towards malaria and its preventive measures is vital for malaria control. The current study investigated the levels of knowledge of the causes, symptoms and prevention of malaria among Malawian women. Data from the 2017 wave of the Malawi Malaria Indicator Survey (MMIS) were analysed. In total, 3422 women of reproductive age (15-49 years) were sampled and analysed. The levels of women's knowledge about: (1) causes of malaria; (2) symptoms of malaria; and, (3) preventive measures were assessed. The tertiles of the composite score were used as the cut-offs to categorize the levels of knowledge as 'low', 'medium' and 'high'. Multinomial logistic regression models were constructed to assess the independent factors while taking into account the complex survey design. Approximately 50% of all respondents had high levels of knowledge of causes, symptoms and preventive measures. The high level of knowledge was 45% for rural women and 55% for urban dwellers. After adjusting for the a wide range of factors, women of age group 15-19 years adjusted odds ratio ((aOR): 2.58; 95% Confidence Interval (CI) 1.69-3.92), women with no formal education (aOR: 3.73; 95% CI 2.20-6.33), women whose household had no television (aOR: 1.50; 95% CI 1.02-2.22), women who had not seen/heard malaria message (aOR: 1.53; 95% CI 1.20-1.95), women of Yao tribe (aOR: 1.95; 95% CI 1.10-3.46), and women from rural areas had low levels of knowledge about the causes of malaria, symptoms of malaria and preventive measures. Additionally, the results also showed that women aged 15-19 years (beta [β] = - 0.73, standard error [SE] = 0.12); P < .0001, women with no formal education (β = - 1.17, SE = 0.15); P < .0001, women whose household had no radio (β = - 0.15, SE = 0.0816); P = 0.0715 and women who had not seen or heard malaria message (β = - 0.41, SE = 0.07); P < .0001 were likely to have a lower knowledge score. The levels of malaria knowledge were reported to be unsatisfactory among adult women, underscoring the need to scale up efforts on malaria education. Beside insecticide-treated bed nets (ITNs) and prompt diagnosis, malaria can be best managed in Malawi by increasing knowledge of malaria causes, and symptoms especially for younger women, women with no formal education, women whose households have no media, women from Yao tribes, and rural dwellers.


Antitumor activity of polysaccharides from Serratia marcescens.
A lipopolysaccharide (serratigen) and a polysaccharide (serratimannan) were isolated from Serratia marcescens, red strain No. 51. They were different from any other polysaccharides previously reported. The antitumor activity of these polysaccharides was determined. Serratimannan showed 63% tumor inhibition and serratigen 38%, at a dose of 150 mg/kg, against solid tumor of sarcoma-180 using ICR mice. The fraction obtained by removal of proteins from the crude extract by the Sevag method showed a high antitumor activity against solid tumor of sarcoma-180 using Swiss albino mice, but did not show so high an activity using ICR mice. In total packed cell volume method, these polysaccharides exhibited a high rate of antitumor activity against ascites tumor of sarcoma-180.


Growth factor-assisted chemotherapy--the Manchester experience.
Stimulation of red cell production by erythropoietin and of granulocyte production by granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage-CSF (GM-CSF) has been demonstrated in several clinical studies. The first study to show that a human CSF could be used to shorten the period of neutropenia and reduce the risk of serious infection following intensive combination chemotherapy was carried out in Manchester using G-CSF. The period of neutropenia was significantly shortenened (by a median of 80%) and the neutrophil count levels were restored and above normal by 14 days after chemotherapy. In view of these results a further study was undertaken to examine the possibility of using intensive two weekly chemotherapy under cover of G-CSF. Treatment with Doxorubicin at doses of 75, 100, 125 and 150 mg/m2 was followed by infusion of G-CSF for 11 days. The neutrophil counts returned to normal within 12-14 days, allowing the delivery of up to three cycles of high dose chemotherapy at 14 day intervals. These studies demonstrated that intensive chemotherapy with dose-limiting myelodepression can be given with increased frequency under cover of G-CSF. Our studies using GM-CSF have also shown that administration by continuous i.v. infusion can reduce the period of life-threatening neutropenia following high dose Melphalan (120 mg/m2) without resort to autologous bone marrow transplantation (ABMT). In this study the period of granulocytopenia following Melphalan (less than 500 g x 10(9)/m2) was less than 15 days. This compares favourably with other series using high dose Melphalan followed by ABMT without CSF, where the duration of severe neutropenia was prolonged beyond three weeks. Although it appears that G-CSF and GM-CSF should be given either by continuous i.v. infusion or s.c. injection at doses between 3-10 micrograms/kg/day to obtain maximum biological effect, a great deal more work is required to determine optimum schedules and investigate the possibility of using more than one bioregulator.


Effect of soy isoflavones on implantation losses in Wistar rat: implication of progesterone receptors, vascular endothelial growth factor and estradiol receptors alpha.
Implantation is a crucial period determining the success of a full pregnancy. Endocrine disruptors such as phytoestrogens (PEs) were thought to adversely influence embryonic implantations. However, the mechanism by which they upset implantation was not fully elucidated. The effect of administering soy isoflavones on the implantation of Wistar rats was studied through the detection of progesterone receptors (PR), vascular endothelial growth factor (VEGF), and estradiol receptor alpha (ER-α) protein expression at gestation day 6 (GD6). Eighteen cyclic female Wistar rats were distributed into two groups, group A: control (n=9) were fed with a casein based diet, and group B (n=9) were fed with a casein diet and gavaged 50 mg/kg/day soy isoflavones' extract 40% starting from gestation day zero (GD0) to GD6. Feed intake, body weight (BW), body gain, and uterine weights were recorded. At the end of GD6 the number of corpora lutae (CLs) and implantation rates were recorded. Histopathology and immunohistochemistry (IHC) for PR, VEGF, and ER-α protein expression in implanted uteri were performed. Soy isoflavones significantly reduced feed intake, weight gain, uterine weights CL numbers, and implantation rates of the treated pregnant dams. The endometrium of the soy treated dams showed less proliferation than that of the control. Immunostaining percentage of PR and VEGF proteins significantly reduced in soy treated dams compared to the control. However, the mean expression percentage of ER-α exhibited significant elevation in the soy treated dams in comparison to the control group. Implantation losses caused by soy isoflavones seemed to be due to the down regulation of PR that failed to down regulate ER-α action and decreased VEGF production.


STAT3 Inhibitory Activity of Structurally Simplified Withaferin A Analogues.
Signal transducer and activator of transcription 3 (STAT3) is a component of the JAK/STAT pathway. Therapeutic inhibition of STAT3 has been of high interest, as its aberrant activation has been linked to cancer, inflammation, and other human diseases. The withanolide family natural product withaferin A (1) inhibits STAT3 activation. We designed, synthesized, and evaluated simplified withanolide analogues SLW1 (3) and SLW2 (4), and found that SLW1 retained the STAT3 inhibitory activity of withaferin A.


Serum urate levels between ages 10 and 14: changes in sex trends.
Urate levels were assayed in sera of 292 subjects between 10 and 14 years of age identified through a probability sample of a natural population. The sex trends in serum urate concentrations characteristic of childhood were seen to continue into early adolescence, with girls maintaining slightly higher means. Between 10 and 14 years there was first an overlap of male and female values followed by a reversal of trends, with much higher means in boys. Serum urate concentrations peaked in girls at age 11 and gradually stabilized at lower levels. Boys, on the other hand, showed little age variation in serum urate at 10 and 11 years but by age 12 showed sharp upward trends which continued throughout adolescence. Since age and body weight are known to be important covariates of serum urate, boys were matched to girls of the same age and body weight. Significant sex differences in urate levels persisted (after matching) only for 14-year-old adolescents and thus at this age could not be ascribed to weight differentials. The study highlights a peripubertal phenomenon whose mechanism might be endocrine related.


Preparation of human metabolites of propranolol using laboratory-evolved bacterial cytochromes P450.
Testing the toxicities and biological activities of the human metabolites of drugs is important for development of safe and effective pharmaceuticals. Producing these metabolites using human cytochrome P450s is difficult, however, because the human enzymes are costly, poorly stable, and slow. We have used directed evolution to generate variants of P450 BM3 from Bacillus megaterium that function via the "peroxide shunt" pathway, using hydrogen peroxide in place of the reductase domain, oxygen and NADPH. Here, we report further evolution of the P450 BM3 heme domain peroxygenase to enhance production of the authentic human metabolites of propranolol by this biocatalytic route. This system offers a versatile, cost-effective, and scaleable route to the synthesis of drug metabolites.


Rapid detection and characterization of minor reactive metabolites using stable-isotope trapping in combination with tandem mass spectrometry.
Stable-isotope trapping combined with mass spectrometry (MS) neutral loss scanning has recently been developed as a high-throughput method for the in vitro screening of major reactive metabolites. In fact, detection and identification of minor reactive metabolites are equally important since the minor metabolites, even though at low levels, may be highly reactive and also play an important role in drug-induced adverse reactions. In this study, 2-acetylthiophene, clozapine, troglitazone and 7-methylindole were selected as model compounds to further validate the advantages of this method for rapid detection and structural characterization of minor glutathione (GSH) adducts derived from reactive metabolites. The utility of the current method was clearly demonstrated by successful identification of novel reactive metabolites at low levels and also minor ones either masked by non-specific responses or co-eluted with other conjugates. In comparison with existing methods, this method is sensitive, efficient, and suitable for rapid screening and more complete profiling of reactive metabolites.


ABCG2 Gene and ABCG2 Protein Expression in Colorectal Cancer-In Silico and Wet Analysis.
ABCG2 (ATP-binding cassette superfamily G member 2) is a cell membrane pump encoded by the ABCG2 gene. ABCG2 can protect cells against compounds initiating and/or intensifying neoplasia and is considered a marker of stem cells responsible for cancer growth, drug resistance and recurrence. Expression of the ABCG2 gene or its protein has been shown to be a negative prognostic factor in various malignancies. However, its prognostic significance in colorectal cancer remains unclear. Using publicly available data, ABCG2 was shown to be underexpressed in colon and rectum adenocarcinomas, with lower expression compared to both the adjacent nonmalignant lung tissues and non-tumour lung tissues of healthy individuals. This downregulation could result from the methylation level of some sites of the ABCG2 gene. This was connected with microsatellite instability, weight and age among patients with colon adenocarcinoma, and with tumour localization, population type and age of patients for rectum adenocarcinoma. No association was found between ABCG2 expression level and survival of colorectal cancer patients. In wet analysis of colorectal cancer samples, neither ABCG2 gene expression, analysed by RT-PCR, nor ABCG2 protein level, assessed by immunohistochemistry, was associated with any clinicopathological factors or overall survival. An ABCG2-centered protein-protein interaction network build by STRING showed proteins were found to be involved in leukotriene, organic anion and xenobiotic transport, endodermal cell fate specification, and histone methylation and ubiquitination. Hence, ABCG2 underexpression could be an indicator of the activity of certain signalling pathways or protein interactors essential for colorectal carcinogenesis.


Acute effects of repeated bouts of aerobic exercise on arterial stiffness after glucose ingestion.
The aim of this study was to investigate the acute repeated bouts of aerobic exercise decrease leg arterial stiffness. However, the influence of repeated bouts of aerobic exercise on arterial stiffness after glucose ingestion is unknown. The present study investigates the acute effects of repeated bouts of aerobic exercise on arterial stiffness after the 75-g oral glucose tolerance test (OGTT). Ten healthy young men (age, 23.2 ± 0.9 years) performed repeated bouts of aerobic exercise trial (RE, 65% peak oxygen uptake; two 15 min bouts of cycling performed 20 min apart) and control trial (CON, seated and resting in a quiet room) at 80 min before the 75-g OGTT on separate days in a randomized, controlled crossover fashion. Carotid-femoral (aortic) and femoral-ankle (leg) pulse wave velocity, carotid augmentation index, brachial and ankle blood pressure, heart rate and blood glucose and insulin levels were measured before (baseline) and 30, 60 and 120 min after the 75-g OGTT. Leg pulse wave velocity, ankle systolic blood pressure and blood glucose levels increased from baseline after the 75-g OGTT in the CON trial, but not in the RE trial. The present findings indicate that acute repeated bouts of aerobic exercise before glucose ingestion suppress increases in leg arterial stiffness following glucose ingestion. Abbreviations: RE trial repeated bouts of aerobic exercise trial; CON trial control trial; BG blood glucose; VO2peak peak oxygen uptake; PWV Pulse wave velocity; AIx carotid augmentation index; BP blood pressure; HR heart rate; CVs coefficients of variation; RPE Ratings of perceived exertion; SE standard error.


CaVbeta subunit-mediated up-regulation of CaV2.2 currents triggered by D2 dopamine receptor activation.
Voltage-dependent Ca(2+) channels (VDCCs) are subject to modulation by a number of pathways, including membrane-delimited inhibition by heterotrimeric G-proteins and modulation through phosphorylation by diverse kinases. Here we report that in the Xenopus oocyte expression system Ca(V)2.2 channels undergo a sustained, linear and irreversible run-up lasting up to 30 min, which is potentiated during G-protein-mediated inhibition by activation of co-expressed G-protein coupled receptors (GPCRs). This up-regulation is not a result of receptor desensitization, but is associated with a hyperpolarization of the voltage for activation and depends on the presence of accessory subunits such that beta subunits promote, and alpha2delta subunits oppose the current increase. We have investigated the involvement of G-proteins and found that over-expression of Galpha(o) subunits or Galpha-transducin reduced the amount of agonist-mediated up-regulation. However, we have found no evidence for the involvement of any second messenger pathways in the increase of current run-up in the presence of a GPCR agonist. Taken together, our data suggest that the effect reported herein involves an enhancement of the GTPase activity of endogenous Galpha subunits, which is triggered by GPCR activation and mediated by accessory Ca(V)beta subunits. It may involve an increased association of Ca(V)beta subunits with alpha1 subunits in the plasma membrane or trafficking of channels to the plasma membrane.


Sodium-dependent movement of covalently bound FMN residue(s) in Na(+)-translocating NADH:quinone oxidoreductase.
Na(+)-translocating NADH:quinone oxidoreductase (Na(+)-NQR) is a component of respiratory electron-transport chain of various bacteria generating redox-driven transmembrane electrochemical Na(+) potential. We found that the change in Na(+) concentration in the reaction medium has no effect on the thermodynamic properties of prosthetic groups of Na(+)-NQR from Vibrio harveyi, as was revealed by the anaerobic equilibrium redox titration of the enzyme's EPR spectra. On the other hand, the change in Na(+) concentration strongly alters the EPR spectral properties of the radical pair formed by the two anionic semiquinones of FMN residues bound to the NqrB and NqrC subunits (FMN(NqrB) and FMN(NqrC)). Using data obtained by pulse X- and Q-band EPR as well as by pulse ENDOR and ELDOR spectroscopy, the interspin distance between FMN(NqrB) and FMN(NqrC) was found to be 15.3 Å in the absence and 20.4 Å in the presence of Na(+), respectively. Thus, the distance between the covalently bound FMN residues can vary by about 5 Å upon changes in Na(+) concentration. Using these results, we propose a scheme of the sodium potential generation by Na(+)-NQR based on the redox- and sodium-dependent conformational changes in the enzyme.


rKLO8, a novel Leishmania donovani - derived recombinant immunodominant protein for sensitive detection of visceral leishmaniasis in Sudan.
For effective control of visceral leishmaniasis (VL) in East Africa, new rapid diagnostic tests are required to replace current tests with low sensitivity. The aim of this study is to improve diagnosis of VL in East Africa by testing a new antigen from an autochthonous L. donovani strain in Sudan. We cloned, expressed and purified a novel recombinant protein antigen of L. donovani from Sudan, designated rKLO8, that contains putative conserved domains with significant similarity to the immunodominant kinesin proteins of Leishmania. rKLO8 exhibited 93% and 88% amino acid identity with cloned kinesin proteins of L. infantum (synonymous L. chagasi) (K39) and L. donovani (KE16), respectively. We evaluated the diagnostic efficiency of the recombinant protein in ELISA for specific detection of VL patients from Sudan. Data were compared with a rK39 ELISA and two commercial kits, the rK39 strip test and the direct agglutination test (DAT). Of 106 parasitologically confirmed VL sera, 104 (98.1%) were tested positive by rKLO8 as compared to 102 (96.2%) by rK39. Importantly, the patients' sera showed increased reactivity with rKLO8 than rK39. Specificity was 96.1% and 94.8% for rKLO8- and rK39 ELISAs, respectively. DAT showed 100% specificity and 94.3% sensitivity while rK39 strip test performed with 81.1% sensitivity and 98.7% specificity. The increased reactivity of Sudanese VL sera with the rKLO8 makes this antigen a potential candidate for diagnosis of visceral leishmaniasis in Sudan. However, the suitability at the field level will depend on its performance in a rapid test format.


Insights into the mechanism of action of benzoyl peroxide as a tumor promoter.
A comparison of the mechanism of action of benzoyl peroxide, a tumor promoter was studied in three different cell lines i.e. NIH 3T3, HDCS and A431. Benzoyl peroxide was found to mediate its effect by inducing poly ADP-ribosylation in all the three cell types studied but to different extents, with histone H1 serving as a common acceptor for poly ADP-ribose. It also stimulated the activities of the antioxidant enzymes CuZn superoxide dismutase and catalase in NIH 3T3 and HDCS cells, but not in A431. Alterations in the expression of c-jun and c-fos were observed in NIH 3T3 and A431 cells. Benzoyl Peroxide appeared to mediate its effect via genetic and epigenetic mechanisms.


Quasiparticles of spatially anisotropic triangular antiferromagnets in a magnetic field.
The spectral properties of the spin-1/2 Heisenberg antiferromagnet on an anisotropic triangular lattice in a magnetic field are investigated using a weak-interchain-coupling approach combined with exact solutions of a chain. Dominant modes induced by interchain interactions in a magnetic field behave as quasiparticles which show distinctive features such as anomalous incommensurate ordering and high-energy modes. In terms of them, various unusual features observed in the anisotropic triangular antiferromagnet Cs2CuCl4 in a magnetic field are quantitatively explained in a unified manner.


CADM1 suppresses c-Src activation by binding with Cbp on membrane lipid rafts and intervenes colon carcinogenesis.
Cell adhesion molecules act as tumor suppressors primarily by cell attachment activity, but additional mechanisms modifying signal transduction are suggested in some cases. Cell adhesion molecule 1 (CADM1), a membrane-spanning immunoglobulin superfamily, mediates intercellular adhesion by trans-homophilic interaction and acts as a tumor suppressor. Here, we investigated CADM1-associated proteins comprehensively using proteomic analysis of immune-precipitates of CADM1 by mass spectrometry and identified a transmembrane adaptor protein, Csk-binding protein (Cbp), known to suppress Src-mediated transformation, as a binding partner of CADM1. CADM1 localizes to detergent-resistant membrane fractions and co-immunoprecipitated with Cbp and c-Src. Suppression of CADM1 expression using siRNA reduces the amount of co-immunoprecipitated c-Src with Cbp and activates c-Src in colon cancer cells expressing both CADM1 and Cbp. On the other hand, co-replacement of CADM1 and Cbp in colon cancer cells lacking CADM1 and Cbp expression suppresses c-Src activation, wound healing and tumorigenicity in nude mice. Furthermore, expression of Cbp and CADM1 was lost in 55% and 83% of human colon cancer, respectively, preferentially in tumors with larger size and/or lymph node metastasis. CADM1 would act as a colon tumor suppressor by intervening oncogenic c-Src signaling through binding with Cbp besides its authentic cell adhesion activity.


Expression of PUMA in Follicular Granulosa Cells Regulated by FoxO1 Activation During Oxidative Stress.
Many studies have demonstrated that oxidative stress-induced apoptosis is a main cause of follicular atresia. Reactive oxygen species (ROS)-induced granulosa cell (GC) apoptosis is regulated by a variety of signaling pathways involving numerous genes and transcription factors. In this study, we found expression of the p53-upregulated modulator of apoptosis (PUMA), a BH3-only Bcl-2 subfamily protein, in ovarian GCs during oxidative stress. By overexpression and knockdown of Forkhead box O1 (FoxO1), we found that FoxO1 regulates PUMA at the protein level. Moreover, as c-Jun N-terminal kinase (JNK) has been shown to activate FoxO1 by promoting its nuclear import, we used a JNK inhibitor to reduce FoxO1 activation and detected decreased PUMA messenger RNA expression and protein levels during oxidative stress. In addition, in vivo oxidative stress-induced upregulation of PUMA was found following injection of 3 nitropropionic acid in mice. In conclusion, oxidative stress increases PUMA expression regulated by FoxO1 in follicular GCs.


Role of Sex Hormone Levels and Psychological Stress in the Pathogenesis of Autoimmune Diseases.
The aim of this review article is to assess the connection between psychological stress and sex hormones and their effect on the development of autoimmune diseases. Psychological stress describes what people feel when they are under mental, physical, or emotional pressure. We searched for online articles using MEDLINE®, Embase, Cochrane Library and Google Scholar. Our research yielded a total of 165 articles out of which 30 articles were considered for further perusal. The articles were reviewed from February 2016 to February 2017. Case reports and patients suffering from hematolymphoid malignancies and active infections were excluded from the review. Estrogen and testosterone are potential physiological regulatory factors for the peripheral development of CD4+CD25+ T regulatory cells. Stress at any age leads to the depletion of estrogen and testosterone stores in the body, leading to the loss of expansion of T regulatory cells, making the immature B cells evade the negative selection at the germinal center, or in other words, leading to the loss of central tolerance, a triggering event in autoimmune diseases like systemic lupus erythematosus. Autoimmune diseases in women are most likely due to changes in estrogen levels during mental, physical, pre-menopausal, post-menopausal, and pregnancy-induced stress. We conclude that modulating estrogen in females (pre-menopausal and post-menopausal) and testosterone in males can be used to treat stress-related immune imbalance resulting in autoimmune diseases in both sexes.


Spatial control of proton pump H,K-ATPase docking at the apical membrane by phosphorylation-coupled ezrin-syntaxin 3 interaction.
The digestive function of the stomach depends on acidification of the gastric lumen. Acid secretion into the lumen is triggered by activation of a cAMP-dependent protein kinase (PKA) cascade, which ultimately results in the insertion of gastric H,K-ATPases into the apical plasma membranes of parietal cells. A coupling protein is ezrin whose phosphorylation at Ser-66 by PKA is required for parietal cell activation. However, little is known regarding the molecular mechanism(s) by which ezrin operates in gastric acid secretion. Here we show that phosphorylation of Ser-66 induces a conformational change of ezrin that enables its association with syntaxin 3 (Stx3) and provides a spatial cue for H,K-ATPase trafficking. This conformation-dependent association is specific for Stx3, and the binding interface is mapped to the N-terminal region. Biochemical analyses show that inhibition of ezrin phosphorylation at Ser-66 prevents ezrin-Stx3 association and insertion of H,K-ATPase into the apical plasma membrane of parietal cells. Using atomic force microscopic analyses, our study revealed that phosphorylation of Ser-66 induces unfolding of ezrin molecule to allow Stx3 binding to its N terminus. Given the essential role of Stx3 in polarized secretion, our study presents the first evidence in which phosphorylation-induced conformational rearrangement of the ezrin molecule provides a spatial cue for polarized membrane trafficking in epithelial cells.


Oligohydramnios, renal insufficiency, and ileal perforation in preterm infants after intrauterine exposure to indomethacin.
Three preterm infants exposed antenatally to indomethacin developed a characteristic syndrome consisting of edema and hydrops with a bleeding disorder at birth, oliguric renal failure during the first 3 postnatal days, and acute pneumoperitoneum resulting from localized ileal perforation(s) at the end of the first week of life. Despite the value of indomethacin for arresting preterm labor, the physician must take into account the potential hazards of drug toxicity.


Management of hip fracture in the older people: rationale and design of the Italian consensus on the orthogeriatric co-management.
Hip fracture (HF) is a burdening health problem in older people. The orthogeriatric approach has been shown to favour functional recovery and reduce mortality, but its implementation in clinical practice cannot rely upon shared management protocols and greatly varies among different healthcare systems. Here, we present the rationale and design of the Italian consensus document on the management of HF in older people. A panel of multidisciplinary experts from ten Italian scientific societies involved in the care of HF and including geriatricians, orthopaedics, anaesthesiologists, physiatrists and general practitioners, will join to establish the content validity of a list of statements. A Delphi consensus methodology will be applied to obtain the opinions of the panel and to provide the final recommendations. The document will include indications on the following relevant topics: (1) optimal care path of older subjects with HF; (2) management of comorbidities and pre-operative alteration of physiological parameters; (3) management of selected categories of patients at expected increased risk of adverse outcomes; (4) continuity of care out of hospital; (5) screening and correction of risk factors for HF in older subjects; (6) information and divulgation of shared management strategies. The objective of the consensus will be to inform clinicians, patients, researchers, and health policy makers about the best management strategies for HF in older people and their inherent limitations, thus facilitating communication between stakeholders and promoting the most cost/effective models of care.


Developmentally non-redundant SET domain proteins SUVH2 and SUVH9 are required for transcriptional gene silencing in Arabidopsis thaliana.
In plants, RNA-directed DNA methylation (RdDM) and related transcriptional gene silencing (TGS) involve members of the suppressor of variegation 3-9-homologous (SUVH) group of putative histone methyltransferases. Utilizing a reverse genetic approach in Arabidopsis thaliana, we demonstrate that two closely related SUVH members, SUVH2 and SUVH9, act partially non-redundant in RdDM. DNA methylation, transcript accumulation and association with histone modifications were analyzed at the endogenous RdDM target AtSN1 (a SINE-like retroelement) in suvh2 and suvh9 single as well as suvh2 suvh9 double mutants. SUVH2 was found to be required for full DNA methylation at AtSN1 in early seed development and was also higher expressed in seeds than at later developmental stages. SUVH9 had its impact on RdDM later during vegetative development of the plant and was also higher expressed during that stage than at earlier developmental stages. The strongest reduction of RdDM at AtSN1 was found in suvh2 suvh9 double mutant plants. Histone 3-lysine 9-dimethylation (H3K9me2) associated with AtSN1 was reduced only in the simultaneous absence of functional SUVH2 and SUVH9. Thus, SUVH2 and SUVH9 functions in RdDM and TGS are overlapping in spite of some developmental specialization. Pol V specific transcripts were reduced in suvh2 suvh9 plants. This might indicate a role of these SUVH proteins in Pol V complex recruitment.


Fluctuating reaction rates and their application to problems of gene expression.
A reduced description is presented for noisy chemical reactions in small systems, such as cells. We show that, even when the number of molecules of a chemical species is small, its elimination from the description is possible provided that its characteristic time scale is short. The resulting effective chemical reaction has a reaction rate which fluctuates in time. The strength of the fluctuations depends on the time scale of the eliminated species as well as its variance. We derive the master equation of the reduced system, which includes additional terms of a diffusive kind, yielding a contribution towards fluctuations from the eliminated species. The stochastic kinetic equation for the reduced system is also derived. Finally, these results are applied to some problems of gene expression.