Phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as therapeutic targets in breast cancer.
Breast cancer is the most commonly diagnosed cancer among women in Turkey and worldwide. It is considered a heterogeneous disease and has different subtypes. Moreover, breast cancer has different molecular characteristics, behaviors, and responses to treatment. Advances in the understanding of the molecular mechanisms implicated in breast cancer progression have led to the identification of many potential therapeutic gene targets, such as Breast Cancer 1/2, phosphatidylinositol 3-kinase catalytic subunit alpha, and tumor protein 53. The aim of this review is to summarize the roles of phosphatidylinositol 3-kinase regulatory subunit 1 (alpha) (alias p85α) and phosphatase and tensin homolog in breast cancer progression and the molecular mechanisms involved. Phosphatase and tensin homolog is a tumor suppressor gene and protein. Phosphatase and tensin homolog antagonizes the phosphatidylinositol 3-kinase/AKT signaling pathway that plays a key role in cell growth, differentiation, and survival. Loss of phosphatase and tensin homolog expression, detected in about 20%-30% of cases, is known to be one of the most common tumor changes leading to phosphatidylinositol 3-kinase pathway activation in breast cancer. Instead, the regulatory subunit p85α is a significant component of the phosphatidylinositol 3-kinase pathway, and it has been proposed that a reduction in p85α protein would lead to decreased negative regulation of phosphatidylinositol 3-kinase and hyperactivation of the phosphatidylinositol 3-kinase pathway. Phosphatidylinositol 3-kinase regulatory subunit 1 protein has also been reported to be a positive regulator of phosphatase and tensin homolog via the stabilization of this protein. A functional genetic alteration of phosphatidylinositol 3-kinase regulatory subunit 1 that results in reduced p85α protein expression and increased insulin receptor substrate 1 binding would lead to enhanced phosphatidylinositol 3-kinase signaling and hence cancer development. Phosphatidylinositol 3-kinase regulatory subunit 1 underexpression was observed in 61.8% of breast cancer samples. Therefore, expression/alternations of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog genes have crucial roles for breast cancer progression. This review will summarize the biological roles of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog in breast cancer, with an emphasis on recent findings and the potential of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as a therapeutic target for breast cancer therapy.


Limited Value of Bladder Wash Cytology During Follow-Up of Patients With Non-muscle Invasive Bladder Cancer.
Aims We aimed to assess the performance of bladder wash cytology (BWC) in daily clinical practice in a pure follow-up cohort of patients previously diagnosed with non-muscle invasive bladder cancer (NMIBC). Materials and methods We analyzed 2064 BWCs derived from 314 patients followed for NMIBC (2003-2016). Follow-up investigations were performed using cystoscopy (CS) in combination with BWC. Patients with suspicious CS and/or positive BWC underwent bladder biopsy or transurethral resection. BWC was considered positive if malignant or suspicious cells were reported. Sensitivity (Sn) and specificity (Sp) were calculated for the entire cohort and separately for low-grade (LG) and high-grade (HG) tumors, and carcinoma in situ (CIS) subgroups. Results A total of 95 recurrences were detected, of which only three were detected by BWC alone. Overall, Sn and Sp of BWC were 17.9% and 99.5%, respectively. For LG disease, these numbers were 14.0% and 100%, and for HG disease, these were 22.2% and 99.1%, respectively. For patients with CIS at initial diagnosis, Sn and Sp were 11.0% and 71.4%, respectively. For isolated primary CIS, Sn was 50.0%, and Sp was 98.2%. Conclusion Routine use of BWC in the follow-up for NMIBC is of limited value even in HG tumors. In the presence of isolated primary CIS, adjunct BWC might be justified.


Protein fluctuations as the possible origin of the thermal activation of rod photoreceptors in the dark.
Efficient retinal photoisomerization, signal transduction, and amplification contribute to single-photon electrical responses in vertebrates visual cells. However, spontaneous discrete electrical signals arising in the dark, with identical intensity and time profiles as those generated by genuine single photons (dark events), limit the potential capability of the rod visual system to discern single photons from thermal noise. It is accepted that the light and the thermal activation of the rod photoreceptor rhodopsin (Rho) triggers the light and the dark events, respectively. However the activation barrier for the dark events (80-110 kJ/mol) appears to be only half of the barrier for light-dependent activation of Rho (> or =180 kJ/mol). On the basis of these observations, it has been postulated that both processes should follow different pathways, but the molecular mechanism for the thermal activation process still remains an open question and subject of debate. Here, performing infrared difference spectroscopy measurements, we found that the -OH group of Thr118 from bovine Rho exhibits a slow but measurable hydrogen/deuterium exchange (HDX) under native conditions. Given the location of Thr118 in the X-ray structures, isolated from the aqueous phase and in steric contact with the buried retinal chromophore, we assume that a protein structural fluctuation must drive the retinal binding pocket (RBP) transiently open. We characterized the kinetics (rate and activation enthalpy) and thermodynamics (equilibrium constant and enthalpy) of this fluctuation from the global analysis of the HDX of Thr118-OH as a function of the temperature and pH. In parallel, using HPLC chromatography, we determined the kinetics of the thermal isomerization of the protonated 11-cis retinal in solution, as a model for retinal thermal isomerization in an open RBP. Finally, we propose a quantitative two-step model in which the dark activation of Rho is triggered by thermal isomerization of the retinal in a transiently opened RBP, which accurately reproduced both the experimental activation barrier and the rate of the dark events. We conclude that the absolute sensitivity threshold of our visual system is limited by structural fluctuations of the chromophore binding pocket rather than in the chromophore itself.


[Changes in therapeutic attitude based on transesophageal echocardiography in cardiac surgery].
Transesophageal echocardiography is a monitoring system that is changing the practice of cardiovascular anesthesia and surgery by providing real time images of cardiovascular anatomy and pathophysiology. Our hospital's anesthesiology and postoperative intensive care departments, in particular the cardiac anesthesia team, initiated a joint project in June 1993 with the echocardiography laboratory team to incorporate this surgical monitoring system. Here we report the wealth of information we obtained and describe the possibility of modifying a therapeutic approach based on the images visualized, even when conventional monitoring gives contradictory information. Two illustrative case reports are included.


Toxic Ingestion of Acetaminophen and Acetylsalicylic Acid in a Parturient at 33 Weeks Gestation: A Case Report.
The anesthetic management of toxic ingestion during pregnancy requires concomitant concerns for both mother and fetus. We describe the management of a parturient at 33 weeks of gestation after a suicide attempt by ingestion of acetaminophen (APAP) and acetylsalicylic acid (ASA). Timing of toxin ingestion must be determined, prompt antidote administration prioritized, and hepatotoxicity-induced hematologic impairment anticipated. Fetal exposure to toxins must also be minimized. The use of point-of-care rotational thromboelastometry in conjunction with standard coagulation testing in such cases facilitates consideration of neuraxial anesthesia and determination of risk for postpartum hemorrhage.


"Sick-but-not-dead": multiple paths to catecholamine deficiency in Lewy body diseases.
Profound depletion of the catecholamines dopamine (DA) and norepinephrine in the brain, heart, or both characterizes Lewy body diseases such as Parkinson disease, dementia with Lewy bodies, and pure autonomic failure. Although one might presume that catecholamine deficiency in these disorders results directly and solely from loss of catecholaminergic neurons, there is increasing evidence that functional abnormalities in extant residual neurons contribute to the neurotransmitter deficiencies-the "sick-but-not-dead" phenomenon. This brief review highlights two such functional abnormalities-decreased vesicular sequestration of cytoplasmic catecholamines and decreased catecholamine biosynthesis. Another abnormality, decreased activity of aldehyde dehydrogenase, may have pathogenetic significance and contribute indirectly to the loss of catecholamine stores via interactions between the autotoxic catecholaldehyde 3,4-dihydroxyphenylacetaldehyde and the protein alpha-synuclein, which is a major component of Lewy bodies. Theoretically, chronically repeated stress responses could accelerate these abnormalities, via increased exocytosis and neuronal reuptake, which indirectly shifts tissue catecholamines from vesicular stores into the cytoplasm, and via increased tyrosine hydroxylation, which augments intra-cytoplasmic DA production. The discovery of specific paths mediating the sick-but-not-dead phenomenon offers novel targets for multi-pronged therapeutic approaches.


Towards Scale and Position Invariant Task Classification using Normalised Visual Scanpaths in Clinical Fetal Ultrasound.
We present a method for classifying tasks in fetal ultrasound scans using the eye-tracking data of sonographers. The visual attention of a sonographer captured by eye-tracking data over time is defined by a scanpath. In routine fetal ultrasound, the captured standard imaging planes are visually inconsistent due to fetal position, movements, and sonographer scanning experience. To address this challenge, we propose a scale and position invariant task classification method using normalised visual scanpaths. We describe a normalisation method that uses bounding boxes to provide the gaze with a reference to the position and scale of the imaging plane and use the normalised scanpath sequences to train machine learning models for discriminating between ultrasound tasks. We compare the proposed method to existing work considering raw eyetracking data. The best performing model achieves the F1-score of 84% and outperforms existing models.


Gait variability and symmetry in world-class senior and junior race walkers.
The aim of this study was to analyse gait variability and symmetry in race walkers. Eighteen senior and 17 junior athletes race walked on an instrumented treadmill (for 10 km and 5 km, respectively) at speeds equivalent to 103% of season's best time for 20 km and 10 km, respectively. Spatio-temporal and ground reaction force (GRF) data were recorded at 2.5 km, and at 4.5, 6.5 and 8.5 km for a subsection of athletes. Gait variability was measured using median absolute deviation (MAD) whereas inter-leg symmetry was measured using the symmetry angle. Both groups showed low variability for step length (<0.9%), step frequency (<1.1%), contact time (≤1.2%) and vertical peak force values (<5%), and neither variability nor symmetry changed with distance walked. Junior athletes were more variable for both step length (P = 0.004) and loading force (P = 0.003); no differences for gait symmetry were found. Whereas there was little mean asymmetry overall, individual analyses identified asymmetry in several athletes (symmetry angle ≥ 1.2%). Importantly, asymmetrical step lengths were found in 12 athletes and could result from underlying imbalances. Coaches are advised to observe athletes on an individual basis to monitor for both variability and asymmetry.


Inhibitory effects of Stewartia koreana on osteoclast differentiation and bone resorption.
Osteoclasts are responsible for bone lysis in several bone diseases such as osteoporosis and rheumatoid arthritis. Natural products from plants have been invaluable source in discovery of compounds for new therapies. In this study, we screened plant products for potential application to therapy for bone loss using a primary osteoclastogenesis culture system and found that extract of Stewartia koreana (SKE) had a strong inhibitory effect on osteoclast formation. To gain molecular insights, we examined the effect of SKE on signaling pathways and transcription factors stimulated by the osteoclast differentiation factor RANKL. SKE suppressed the induction of c-Fos and NFATc1 by RANKL. However, SKE did not inhibit NF-kappaB activation by RANKL. Among the MAPKs stimulated by RANKL, SKE significantly reduced the activation of ERK and p38. Therefore, the anti-osteoclastogenic effect of SKE is likely to be elicited by interference with RANKL signaling to ERK and p38, which mediate the induction of c-Fos and subsequently that of NFATc1. Consistent with the in vitro effect on osteoclast differentiation, SKE showed a great inhibitory effect on in vivo bone loss in LPS-challenged mice. Taken together, we demonstrated that SKE has inhibitory effects on osteoclast differentiation in vitro and confirmed its in vivo efficacy in prevention of inflammatory bone loss.


Estrogen receptor 1 gene polymorphisms in premenopausal women: interaction between genotype and smoking on lipid levels.
Estrogen has multiple effects on lipid and lipoprotein metabolism. We investigated the association between the four common single nucleotide polymorphisms in the estrogen receptor 1 (ESR1) gene locus, -1989T>G, +261G>C, IVS1-397T>C and IVS1-351A>G, and lipid and lipoprotein levels in southern Brazilians. The sample consisted in 150 men and 187 premenopausal women. The women were considered premenopausal if they had regular menstrual bleeding within the previous 3 months and were 18-50 years of age. Exclusion criteria were pregnancy, secondary hyperlipidemia due to renal, hepatic or thyroid disease, and diabetes. Smoking status was self-reported; subjects were classified as never smoked and current smokers. DNA was amplified by PCR and was subsequently digested with the appropriate restriction enzymes. Statistical analysis was carried out for men and women separately. In the study population, major allele frequencies were _1989*T (0.83), +261*G (0.96), IVS1-397*T (0.58), and IVS1-351*A (0.65). Multiple linear regression analyses indicated that an interaction between +261G>C polymorphism and smoking was a significant factor affecting high-density lipoprotein cholesterol (HDL-C) levels (P = 0.028) in women. Nonsmoking women with genotype G/C of +261G>C polymorphism had mean HDL-C levels higher than those with G/G genotype (1.40 +/- 0.33 vs 1.22 +/- 0.26 mmol/L; P = 0.033). No significant associations with lipid and lipoprotein levels in women and men were detected for other polymorphisms. In conclusion, the +261G>C polymorphism might influence lipoprotein and lipid levels in premenopausal women, but these effects seem to be modulated by smoking, whereas in men ESR1 polymorphisms were not associated with high lipoprotein levels.


Divergence of protein kinase A catalytic subunits in Cryptococcus neoformans and Cryptococcus gattii illustrates evolutionary reconfiguration of a signaling cascade.
Gene duplication and divergence via both the loss and gain of gene activities are powerful evolutionary forces underlying the origin of new biological functions. Here a comparative genetics approach was applied to examine the roles of protein kinase A (PKA) catalytic subunits in three closely related varieties or sibling species of the pathogenic fungus genus Cryptococcus. Previous studies revealed that two PKA catalytic subunits, Pka1 and Pka2, control virulence factor production and mating. However, only one of the two plays the predominant physiological role, and this function has been exchanged between Pka1 and Pka2 in strains of the Cryptococcus neoformans var. grubii serotype A lineage compared to divergent C. neoformans var. neoformans serotype D isolates. To understand the basis for this functional plasticity, here the activities of Pka1 and Pka2 were defined in the two varieties and the related sibling species Cryptococcus gattii by gene disruption and characterization, heterologous complementation, and analysis of serotype AD hybrid mutant strains. The findings provide evidence for a shared ancestral role of PKA in governing mating and virulence factor production and indicate that the exchange of catalytic subunit roles is attributable to loss of function. Our studies illustrate the plasticity of signaling networks enabling rapid rewiring during speciation of a clade of common human fungal pathogens.


Completed Suicide by Firearm in an Individual With the Agrammatic Variant of Primary Progressive Aphasia: Case Report.
The agrammatic or nonfluent variant of Primary Progressive Aphasia (nfvPPA) is a form of Frontotemporal Dementia (FTD) that is characterized by progressive language dysfunction, poor sentence construction, and low verbal fluency. Individuals with nfvPPA have intact insight into their decline, which may manifest as frustration and hopelessness, and show signs of impulsivity and disinhibition. Little is known about suicide risk in this patient population. Here we describe a case of an 84 year-old male with nfvPPA who, over the course of his care, experienced a decline in language and motoric functioning which coincided with increasing irritability and impulsivity. Despite this significant decline, he denied depressive symptoms or showed any suicidal tendencies, and he seemed to be looking forward to future events. His suicide, committed with a handgun during what appeared to be a rather innocuous trip to the garage, came as a significant shock to his spouse, family, and his clinical care team. To our knowledge, this is the first reported case of completed suicide in a patient with the nfvPPA subtype of FTD. Though this patient demonstrated demographic risk factors for suicide (advanced age, retired military veteran with easy access to firearms) there is a lack of data regarding how FTD may have contributed. Retained insight especially seems to be a risk factor for suicide across all forms of dementia. Impulsivity may be key when considering suicidality amongst FTD patients. Additionally, this case demonstrates the importance of addressing gun safety as there are few guidelines around gun ownership in this patient population.


Amitraz: a mimicker of organophosphate poisoning.
Amitraz is used as an ectoparasiticide for dogs and cattle. Human poisoning due to amitraz may be misdiagnosed as organophosphate/carbamate (OPC) toxicity, since amitraz poisoning shares several clinical features (miosis, bradycardia and hypotension) encountered with OPC poisoning. A 19-year-old man with an alleged history of suicidal ingestion of a pesticide presented with drowsiness and was found to have constricted pupils, hypotension and bradycardia. He was diagnosed as a case of OPC poisoning and was treated with atropine and pralidoxime prior to presentation to our centre. Absence of a hypersecretory state, and the presence of hyperglycaemia and hypothermia along with a normal serum cholinesterase level suggested an alternate possibility. Retrieval of the poison container confirmed the diagnosis of amitraz poisoning. The patient made a rapid recovery with supportive management. Clinician awareness is key to successful management of this poisoning, which carries a good prognosis.


Prevention and control of rabies in an age of global travel: a review of travel- and trade-associated rabies events--United States, 1986-2012.
Rabies prevention and control efforts have been successful in reducing or eliminating virus circulation regionally through vaccination of specific reservoir populations. A notable example of this success is the elimination of canine rabies virus variant from the United States and many other countries. However, increased international travel and trade can pose risks for rapid, long-distance movements of ill or infected persons or animals. Such travel and trade can result in human exposures to rabies virus during travel or transit and could contribute to the re-introduction of canine rabies variant or transmission of other viral variants among animal host populations. We present a review of travel- and trade-associated rabies events that highlight international public health obligations and collaborative opportunities for rabies prevention and control in an age of global travel. Rabies is a fatal disease that warrants proactive coordination among international public health and travel industry partners (such as travel agents, tour companies and airlines) to protect human lives and to prevent the movement of viral variants among host populations.


Integration of novel hybrid composite discharge electrode with semi-pilot novel cross-flow electrostatic precipitator.
Wet electrostatic precipitators (WESPs) are modern-era pollution control systems specifically designed to capture ultrafine particles as well as acid mist, highly resistive and sticky particles; however, this requires the use of expensive corrosion-resistant metal alloys. The work presented here is part of a continuing study at Ohio University aimed at reducing the cost of WESPs by using a novel combination of a polymer collector surfaces with a hybrid composite discharge electrode. In this study, a hybrid composite discharge electrode was tested, for the first time, inside a semi-pilot-scale experimental setup, with collection surfaces consists of a vertical array of strands. Particle laden gases were passed through this array of polymer ropes, which were kept wet by a small flow of water. The discharge electrodes were composite laminates of carbon fibers in a polymer matrix enclosing a metal mesh. The preliminary results showed that this new integrated system of composite discharge electrode and polymer collector surfaces can match or exceed the performance of a conventional metal alloy electrostatic precipitator (ESP) with metal discharge electrodes. There are additional advantages due to the system being compact, lightweight, and highly corrosion resistant. Implications: This study focused on integrating and assessing performance of a novel hybrid composite electrode (HCE) inside semi-pilot novel cross-flow electrostatic precipitator at conditions typically observed in coal-fired power plant exhausts. The results were collected for particulate collection efficiencies and were compared with a rigid metal electrode. The HCE outperformed metal electrode by showing higher particulate collection efficiency. This result showcases substantial potential for these two new technologies (HCE and cross-flow system) as a substitute for conventional metal based wet ESPs.


Porous calcium polyphosphate scaffolds for bone substitute applications in vivo studies.
Porous rods (6 mm in length and 4 mm in diameter) of calcium polyphosphate (CPP) made by gravity sintering of particles in the size ranges of 45-105, 105-150. and 150-250 microm and with initial volume percent porosity in the range of 35-45% were implanted in the distal femur of New Zealand white rabbits. In an initial experiment, four rabbits implanted with rods made from coarse particles (150-250 microm) were sacrificed at each of the following time points: 2 days, 2 weeks, 6 weeks and 12 weeks. In a subsequent experiment, 10 rabbits were implanted with rods made by sintering 45-105 microm particles and another 10 were made by using particles of 105-150 microm. These rabbits were sacrificed at 6 weeks (five rabbits) and 1 year (five rabbits). No adverse reaction was found histologically at any time point in either experiment. These experiments show that CPP macroporous rods can support bone ingrowth and that between 12 weeks and 1 year, the amount of bones formed is equivalent to the natural bone volume found at similar sites. The degradation of the CPP material is inversely proportional to the original particle size and is rapid initially (within the first 6 weeks) and slows down thereafter. In conclusion, this material seems to promote rapid bone ingrowth and can be tailored to degrade at a given rate in vivo to some degree through appropriate selection of the starting particle size.


Reliability and validity of the Persian version of patient assessment of constipation- quality of life (PAC-QOL) questionnaire.
The present study aimed to assess the reliability and validity of Persian version of patient assessment of constipation: quality of life (PAC-QOL) questionnaire in Iranian patients. Chronic constipation has significant effects on daily living, wellbeing and individuals' quality of life (QOL). Validated tools can help us to assessing QOL in affected ones and facilitating clinical management of them. The English version of Patient Assessment of Constipation: Quality of Life (PAC-QOL) was translated into the Persian language and was confirmed by back-translation. One hundred and forty patients with functional constipation, according Rome III criteria, completed the questionnaires .The questionnaires were analyzed using Cronbach's Alpha internal consistency score to determine the reliability. Twenty medical experts were then asked to evaluate the PAC-QOL and the results were used to calculate the Content Validity Ratio (CVR) and Content Validity Index (CVI). Due to obtained value for Cronbach`s α (0.975) and also for the subscale of physical discomfort (0.930), psychosocial discomfort (0.975) and worries and concerns (0.915), the internal consistency is established. According to medical experts' opinions, the value of CVR ranged from 0.5 to 0.8 and the value of CVI was 0.81. The Persian version of PAC-QOL questionnaire is shown to have acceptable reliability and validity to be used for psychometric evaluation in Iranian patients complaining of functional constipation.


TNF-Alpha in Peripheral Neuropathy Patients with Impaired Glucose Regulation.
Impaired glucose regulation (IGR) is the prestate of diabetes; about 1/3 of IGR patients will develop to diabetes finally. In this study, we investigated the serum tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) levels in peripheral neuropathy impaired patients with impaired glucose regulation (IGR). A total of 70 IGR patients received the conventional nerve conduction test, including 30 patients with peripheral neuropathy (PN) and 40 patients without peripheral neuropathy (NPN). The other 40 healthy individuals were recruited as controls. The serum TNF-α and IL-6 in IGR patients were higher than in control group, and serum TNF-α and IL-6 levels in IGR-PN group were higher than in IGR-NPN group (27.7 ± 17.8 versus 13.1 ± 6.7 pg/mL and 18.1 ± 17.7 versus 6.4 ± 3.7 pg/mL, resp., both p < 0.05). Multifactors logistic regression analysis showed that TNF-α (OR = 0.893; p = 0.009) was an independent factor affecting whether IGR could combine with peripheral neuropathy. TNF-α and IL-6 could aggregate peripheral neuropathy in impaired glucose regulation patients; TNF-α might be independent risk factor for peripheral neuropathy in glucose regulation impaired patients.


[Contribution of medical technologists in team medical care of diabetics].
For the effective treatment of diabetic mellitus (DM), patients are encouraged to self-manage their disease according to the doctor's instructions and advice from certified diabetes educators (CDE) and other comedical staff. Therefore, the cooperation of medical staff consisting of a doctor, CDE, nurse, pharmacist, dietitian, and medical technologist is important for DM education. Medical technologists licensed for CDE (MT-CDE) have been participating in the DM education team in Kobe University Hospital since 2000. MT-CDE are in charge of classes for medical tests, guidance for self-monitoring of blood glucose and teaching how to read the fluctuation graph of the blood glucose level in the education program for hospitalized DM patients. MT-CDEs teach at the bedside how to read the results of medical tests during the first few days of hospitalization using pamphlets for medical tests. The pamphlets are made comprehensible for patients by using graphics and photographs as much as possible. It is important to create a friendly atmosphere and answer frank questions from patients, since they often feel stress when having medical tests at the early stage of hospitalization. This process of questions and answers promotes their understanding of medical tests, and seems to reduce their anxiety about having tests. We repeatedly evaluate their level of understanding during hospitalization. By showing them the fluctuation graph of the glucose level, patients can easily understand the status of their DM. When prescriptions are written on the graph, their therapeutic effects are more comprehensible for the patients. The items written on the graph are chosen to meet the level of understanding of each patient to promote their motivation. In summary, the introduction of MT-CDE has been successful in the education program for DM patients in our hospital. We plan to utilize the skills and knowledge of MT-CDE more in our program so that our DM education program will help patients cope with life with DM.


Ascending and descending propriospinal pathways between lumbar and cervical segments in the rat: evidence for a substantial ascending excitatory pathway.
Precise mechanisms are required to coordinate the locomotor activity of fore- and hind-limbs in quadrupeds and similar mechanisms persist to coordinate movement of arms and legs in humans. Propriospinal neurons (PSNs) are major components of the networks that coordinate these mechanisms. The b subunit of cholera toxin (CTb) was injected unilaterally into either L1 or L3 segments in order to label ascending and descending propriospinal pathways. Labelled cells were examined with light or confocal microscopy. Cells projecting to lumbar segments were evenly distributed, bilaterally throughout all cervical segments. However many more cells were labelled from L1 injections than L3 injections. Roughly 15% of cells in both sides of the C2 segment was found to be immunoreactive for calretinin and a small number (4%) was immunoreactive for calbindin. Axons projecting from L1 to cervical segments formed predominant ipsilateral projections to the cervical intermediate grey matter and ventral horn. Very large numbers of terminals were concentrated within the ventrolateral motor (VLM) nuclei of C7-8 segments but there was sparse innervation of the contralateral nucleus. The vast majority (85%) of these axon terminals in the ipsilateral VML was immunoreactive for the vesicular glutamate transporter 2 (VGLUT2) and the remaining 15% was immunoreactive for the vesicular GABA transporter (VGAT); many of these contained GABA and/or glycine. Inhibitory and excitatory terminals were also found in the contralateral VLM. Most of the terminals in the VLM made contacts with motoneurons. The major finding of this study is the existence of a substantial excitatory propriospinal pathway that projects specifically to the VLM. Motoneurons in the VLM supply muscles of the axilla therefore this pathway is likely to have a profound influence on the activity of the shoulder joint. This pathway may synchronise lumbar and cervical pattern generators and hence the coordination of locomotor activity in the fore- and hind limbs.


Dissecting the heterogeneity of rheumatoid arthritis through linkage analysis of quantitative traits.
To dissect the heterogeneity of rheumatoid arthritis (RA) through linkage analysis of quantitative traits, specifically, IgM rheumatoid factor (IgM-RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibody titers. Subjects, 1,002 RA patients from 491 multiplex families recruited by the North American RA Consortium, were typed for 379 microsatellite markers. Anti-CCP titers were determined based on a second-generation enzyme-linked immunosorbent assay, and IgM-RF levels were quantified by immunonephelometry. We used the Merlin statistical package to perform nonparametric quantitative trait linkage analysis. For each of the quantitative traits, evidence of linkage, with logarithm of odds (LOD) scores of >1.0, was found in 9 regions. For both traits, the strongest evidence of linkage was for marker D6S1629 on chromosome 6p (LOD 14.02 for anti-CCP and LOD 12.09 for RF). Six other regions with LOD scores of >1.0 overlapped between the 2 traits, on chromosomes 1p21.1, 5q15, 8p23.1, 16p12.1, 16q23.1, and 18q21.31. Evidence of linkage to anti-CCP titer but not to RF titer was found in 2 regions (chromosomes 9p21.3 and 10q21.1), and evidence of linkage to RF titer but not to anti-CCP titer was found in 2 regions (chromosomes 5p15.2 and 1q42.3). Several covariates were significantly associated with 1 or both traits, and linkage analysis exploring the covariate effects revealed striking effects of sex in modulating linkage signals for several chromosomal regions. For example, sex had a striking impact on the linkage results for both quantitative traits on chromosome 6p (P = 0.0007 for anti-CCP titer and P = 0.0012 for RF titer), suggesting a sex-HLA region interaction. Analysis of quantitative components of RA is a promising approach for dissecting the genetic heterogeneity of this complex disorder. These results highlight the potential importance of sex or other covariates that may modulate some of the genetic effects that influence the risk of specific disease manifestations.


Draft Genome of the Rice Coral Montipora capitata Obtained from Linked-Read Sequencing.
The rice coral, Montipora capitata, is widely distributed throughout the Indo-Pacific and comprises one of the most important reef-building species in the Hawaiian Islands. Here, we describe a de novo assembly of its genome based on a linked-read sequencing approach developed by 10x Genomics. The final draft assembly consisted of 27,870 scaffolds with a N50 size of 186 kb and contained a fairly complete set (81%) of metazoan benchmarking (BUSCO) genes. Based on haploid assembly size (615 Mb) and read k-mer profiles, we estimated the genome size to fall between 600 and 700 Mb, although the high fraction of repetitive sequence introduced considerable uncertainty. Repeat analysis indicated that 42% of the assembly consisted of interspersed, mostly unclassified repeats, and almost 3% tandem repeats. We also identified 36,691 protein-coding genes with a median coding sequence length of 807 bp, together spanning 7% of the assembly. The high repeat content and heterozygosity of the genome proved a challenging scenario for assembly, requiring additional steps to merge haplotypes and resulting in a higher than expected fragmentation at the scaffold level. Despite these challenges, the assembly turned out to be comparable in most quality measures to that of other available coral genomes while being considerably more cost-effective, especially with respect to long-read sequencing methods. Provided high-molecular-weight DNA is available, linked-read technology may thus serve as a valuable alternative capable of providing quality genome assemblies of nonmodel organisms.


Inhibitors of DNA Glycosylases as Prospective Drugs.
DNA glycosylases are enzymes that initiate the base excision repair pathway, a major biochemical process that protects the genomes of all living organisms from intrinsically and environmentally inflicted damage. Recently, base excision repair inhibition proved to be a viable strategy for the therapy of tumors that have lost alternative repair pathways, such as BRCA-deficient cancers sensitive to poly(ADP-ribose)polymerase inhibition. However, drugs targeting DNA glycosylases are still in development and so far have not advanced to clinical trials. In this review, we cover the attempts to validate DNA glycosylases as suitable targets for inhibition in the pharmacological treatment of cancer, neurodegenerative diseases, chronic inflammation, bacterial and viral infections. We discuss the glycosylase inhibitors described so far and survey the advances in the assays for DNA glycosylase reactions that may be used to screen pharmacological libraries for new active compounds.


Role of fibrinogen concentrates for treatment of critical perioperative hemorrhage.
Acquired hypofibrinogenemia is a frequent cause of maintained bleeding in perioperative high-risk settings. Loss, consumption and dilution under resuscitation fluid therapy are the principal causes for fibrinogen depletion. Severe hypofibrinogenemia is frequently associated with an early bleeding complication that cannot be reliably avoided with high-ratio plasma transfusion strategies. Real-time monitoring with viscoelastic hemostatic assays is a useful tool for timely diagnosis and treatment of detected coagulopathies. Replenishment of fibrinogen in uncontrolled bleeding events is currently recommended by most published guidelines, suggesting treatment thresholds to maintain a minimum of 1.5 g/L plasma fibrinogen concentration for nonobstetrical hemorrhage. Fibrinogen concentrates, originally licensed for treatment of bleeding episodes in patients with congenital hypo-, dys- or afibrinogenemia disorders, are used in many clinical situations as supplementary therapy for the treatment of acquired hypofibrinogenemia. This review seeks to provide an overview of the most relevant topics associated to fibrinogen replacement therapy for critical perioperative hemorrhage highlighting currently available evidence on the risk/benefit profile of purified fibrinogen concentrates for this extended clinical indication.


[Biochemical studies of the assessment of transplant function following clinical heart transplantation--initial experiences].
Average and specific individual courses of the following parameters are reported in this paper, with reference being made to eight of eleven clinical heart transplantations so far performed at the authors' department: lactate, pyruvate, myoglobin, ASAT, ALAT, GGT, CK, CK-MB, LDH, LDH-1, and glycogen phosphorylase. Glycogen phosphorylase was found to deviate most strongly from normal, with the enzyme exhibiting two initial maxima. The enzyme activity in the serum vanished not later than twelve days from transplantation. The curve of myoglobin was largely parallel to that of phosphorylase. Phosphorylase seemed to be of particular suitability for assessment of ischaemic damage in the wake of transplantation. The individual courses seemed to suggest that none of the investigated parameters exhibited sufficiently sensitive correlations with pathomorphological signs of rejection.


Early steps of metabolism evolution inferred by cladistic analysis of amino acid catabolic pathways.
Among abiotic molecules available in primitive environments, free amino acids are good candidates as the first source of energy and molecules for early protocells. Amino acid catabolic pathways are likely to be one of the very first metabolic pathways of life. Among them, which ones were the first to emerge? A cladistic analysis of catabolic pathways of the sixteen aliphatic amino acids and two portions of the Krebs cycle is performed using four criteria of homology. The cladogram shows that the earliest pathways to emerge are not portions of the Krebs cycle but catabolisms of aspartate, asparagine, glutamate, glutamine, proline, arginine. Earliest enzymatic catabolic functions were deaminations and transaminations. Later on appeared enzymatic decarboxylations. The consensus tree allows to propose four time spans for catabolism development and corroborates the views of Cordón in 1990 about the evolution of catabolism.


Action observation and speech production: study on children and adults.
The present study aimed to determine whether observation of upper limb actions selectively influences speech production. We compared the effects on children with those on adults, hypothesizing that action observation is used by children for speech learning. Children and adults observed an actor either grasping a cherry or an apple, or bringing the same fruits to his mouth. They pronounced the syllable/ba/ at the end of the action. In a control experiment, children and adults executed the two bringing-to-the-mouth actions, still pronouncing/ba/. As previously found ([Euro. J. Neurosci., 17 (2003) 179]; [Euro. J. Neurosci., 19 (2004) 192]), the observed kinematics of the action, which were different according to the fruit size, influenced lip shaping kinematics and voice formants. In addition, the effect was selective for the action since the observations of actions such as grasping and bringing-to-the-mouth affected formant 1 and formant 2 in the voice spectra, respectively. The effects on speech were greater in the children than in the adults. By contrast, the effects on lip shaping did not differ between the two groups. Effects similar to those found for action observation were found for action execution in spite of a different arm kinematics between children and adults. The results of the present study are discussed according to the hypothesis that action observation induces in the viewer action recognition and activation of the successive mouth act (probably grasping-with-the-mouth when observing grasping-with-the-hand and chewing when observing bringing-to-the-mouth). This subsequently seems to affect characteristics peculiar to the emitted vowel. This mechanism might have been used by humans to transfer a primitive arm gesture communication system from the arm to the mouth and may be further used by children for speech learning.


Primary care management of type 2 diabetes: a comparison of the efficacy and safety of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP4is) exert their effects via the incretin system, which augments glucose-dependent insulin secretion in response to nutrient intake (the 'incretin effect'). Both classes are well-established pharmacologic options for the management of glycemic control in individuals with type 2 diabetes (T2D) after failure of first-line metformin; however, they have inherent differences in their mechanisms of action that are reflected in their clinical safety and efficacy profiles. GLP-1RAs have high glycemic efficacy and are associated with weight loss and, in some cases, cardioprotective effects, with a side-effect profile of predominantly transient gastrointestinal adverse events. Most GLP-1RAs are administered as subcutaneous injection, although an oral formulation of one GLP-1RA, semaglutide, has recently become available. DPP4is provide moderate glycemic control, are weight-neutral, and do not offer any cardiovascular benefits, but are generally well tolerated. DPP4is are all administered orally. This narrative review aims to provide guidance for a primary care audience on the similarities and differences between GLP-1RA and DPP4i therapies, with a focus on their mechanism of action, clinical safety, efficacy, and real-world effectiveness. The role of incretin-based therapies in the T2D treatment paradigm, including key considerations for guiding treatment decisions, will also be discussed.


Time Courses of Cortical Glucose Metabolism and Microglial Activity Across the Life Span of Wild-Type Mice: A PET Study.
Contrary to findings in the human brain, 18F-FDG PET shows cerebral hypermetabolism of aged wild-type (WT) mice relative to younger animals, supposedly due to microglial activation. Therefore, we used dual-tracer small-animal PET to examine directly the link between neuroinflammation and hypermetabolism in aged mice. Methods: WT mice (5-20 mo) were investigated in a cross-sectional design using 18F-FDG (n = 43) and translocator protein (TSPO) (18F-GE180; n = 58) small-animal PET, with volume-of-interest and voxelwise analyses. Biochemical analysis of plasma cytokine levels and immunohistochemical confirmation of microglial activity were also performed. Results: Age-dependent cortical hypermetabolism in WT mice relative to young animals aged 5 mo peaked at 14.5 mo (+16%, P < 0.001) and declined to baseline at 20 mo. Similarly, cortical TSPO binding increased to a maximum at 14.5 mo (+15%, P < 0.001) and remained high to 20 mo, resulting in an overall correlation between 18F-FDG uptake and TSPO binding (R = 0.69, P < 0.005). Biochemical and immunohistochemical analyses confirmed the TSPO small-animal PET findings. Conclusion: Age-dependent neuroinflammation is associated with the controversial observation of cerebral hypermetabolism in aging WT mice.


Inhibition of basal cell proliferation during storage of detached cultured epidermal keratinocyte sheets.
Grafting of human cultured keratinocytes is a promising possibility for the treatment of large burned skin areas. However, during the preparation of cultures for grafting, a necessary step of detachment from culture substratum is performed by incubation with Dispase. In the present paper, we report studies performed to determine whether prolonged storage after detachment would have a detrimental effect on keratinocyte proliferation. Our results show that the number of bromodeoxyuridine-incorporating cells located in the basal layer of the culture gradually diminishes during storage of detached cultured epidermal keratinocyte sheets. Furthermore, the rate of [3H]thymidine incorporation in such detached cultures is also progressively reduced. These observations indicate that the detachment and storage of cultured epidermal keratinocyte sheets for grafting impedes their cell proliferation capacity, as revealed by DNA-synthesis measurements.


 Cultural adaptation of the Rheumatoid Arthritis Quality of Life (RAQoL) for Portugal.
Rheumatoid Arthritis (RA) is a chronic inflammatory disease that has a major impact on patients´ quality of life. The Rheumatoid Arthritis Quality of Life (RAQoL) questionnaire is a patient-reported outcome measure, specific to RA. The aim of this study was to translate and perform the cross-cultural adaptation of the RAQoL into Portuguese. The dual panel methodology was used to translate the UK RAQoL into Portuguese. This involved conducting a bilingual panel (providing the initial translation into Portuguese) followed by a lay panel (where items are assessed for comprehension and acceptability). Cognitive debriefing interviews were conducted with Portuguese RA patients to determine the face and content validity of the translated scale. The translation panels produced a Portuguese version of the RAQoL that was easily understood and considered natural by native speakers. Twelve RA patients participated in the cognitive debriefing interviews. Patients considered the translated questionnaire to be clear, relevant and appropriate. The Portuguese version of the RAQoL was found to be comprehensible and demonstrated excellent face and content validity. Research examining the psychometric properties of this Portuguese version of the RAQoL is underway.


Genetic Fate Mapping Defines the Vascular Potential of Endocardial Cells in the Adult Heart.
Endocardium is the major source of coronary endothelial cells (ECs) in the fetal and neonatal hearts. It remains unclear whether endocardium in the adult stage is also the main origin of neovascularization after cardiac injury. To define the vascular potential of adult endocardium in homeostasis and after cardiac injuries by fate-mapping studies. We generate an inducible adult endocardial Cre line (Npr3 [natriuretic peptide receptor C]-CreER) and show that Npr3-CreER efficiently and specifically labels endocardial cells but not coronary blood vessels in the adult heart. The adult endocardial cells do not contribute to any vascular ECs during cardiac homeostasis. To examine the formation of blood vessels from endocardium after injury, we generate 4 cardiac injury models with Npr3-CreER mice: myocardial infarction, myocardial ischemia-reperfusion, cryoinjury, and transverse aortic constriction. Lineage tracing experiments show that adult endocardium minimally contributes to coronary ECs after myocardial infarction. In the myocardial ischemia-reperfusion, cryoinjury, or transverse aortic constriction models, adult endocardial cells do not give rise to any vascular ECs, and they remain on the inner surface of myocardium that connects with lumen circulation. In the myocardial infarction model, very few endocardial cells are trapped in the infarct zone of myocardium shortly after ligation of coronary artery, indicating the involvement of endocardial entrapment during blood vessels formation. When these adult endocardial cells are relocated and trapped in the infarcted myocardium by transplantation or myocardial constriction model, very few endocardial cells survive and gain vascular EC properties, and their contribution to neovascularization in the injured myocardium remains minimal. Unlike its fetal or neonatal counterpart, adult endocardium naturally generates minimal, if any, coronary arteries or vascular ECs during cardiac homeostasis or after injuries.


Characterization of chromosome stability in diploid, polyploid and hybrid yeast cells.
Chromosome instability is a key component of cancer progression and many heritable diseases. Understanding why some chromosomes are more unstable than others could provide insight into understanding genome integrity. Here we systematically investigate the spontaneous chromosome loss for all sixteen chromosomes in Saccharomyces cerevisiae in order to elucidate the mechanisms underlying chromosome instability. We observed that the stability of different chromosomes varied more than 100-fold. Consistent with previous studies on artificial chromosomes, chromosome loss frequency was negatively correlated to chromosome length in S. cerevisiae diploids, triploids and S. cerevisiae-S. bayanus hybrids. Chromosome III, an equivalent of sex chromosomes in budding yeast, was found to be the most unstable chromosome among all cases examined. Moreover, similar instability was observed in chromosome III of S. bayanus, a species that diverged from S. cerevisiae about 20 million years ago, suggesting that the instability is caused by a conserved mechanism. Chromosome III was found to have a highly relaxed spindle checkpoint response in the genome. Using a plasmid stability assay, we found that differences in the centromeric sequence may explain certain aspects of chromosome instability. Our results reveal that even under normal conditions, individual chromosomes in a genome are subject to different levels of pressure in chromosome loss (or gain).


Immune reactions and long-term therapy with human leukocyte interferon.
Twenty patients with osteosarcoma were treated with exogenous human leukocyte interferon for periods ranging from 6 to 18 months. Eleven of them remained free from detectable tumour growth during this treatment. Blood samples from all patients were tested for antibodies against interferon and against impurities in the interferon preparations. No patient developed detectable levels of neutralizing antibodies against interferon. All patients formed antibodies against contaminants in the concentrated crude interferon and the partially purified interferon preparation which had been used for treatment.


Objective Pharyngeal Phenotyping in Obstructive Sleep Apnea With High-Resolution Manometry.
Drug-induced sleep endoscopy (DISE) is a commonly used diagnostic tool for surgical procedural selection in obstructive sleep apnea (OSA), but it is expensive, subjective, and requires sedation. Here we present an initial investigation of high-resolution pharyngeal manometry (HRM) for upper airway phenotyping in OSA, developing a software system that reliably predicts pharyngeal sites of collapse based solely on manometric recordings. Prospective cross-sectional study. An academic sleep medicine and surgery practice. Forty participants underwent simultaneous HRM and DISE. A machine learning algorithm was constructed to estimate pharyngeal level-specific severity of collapse, as determined by an expert DISE reviewer. The primary outcome metrics for each level were model accuracy and F1-score, which balances model precision against recall. During model training, the average F1-score across all categories was 0.86, with an average weighted accuracy of 0.91. Using a holdout test set of 9 participants, a K-nearest neighbor model trained on 31 participants attained an average F1-score of 0.96 and an average accuracy of 0.97. The F1-score for prediction of complete concentric palatal collapse was 0.86. Our findings suggest that HRM may enable objective and dynamic mapping of the pharynx, opening new pathways toward reliable and reproducible assessment of this complex anatomy in sleep.


Racial differences in trends and predictors of infant sleep positioning in South Carolina, 1996-2007.
This paper examines racial differences in trends and predictors of prone and lateral infant sleep positioning among South Carolina mothers and infants. Pregnancy Risk Assessment Monitoring System data were used to analyze linear trends in prone, lateral, and supine infant sleep positioning among 14,648 mother-infant pairs from 1996 to 2007. Logistic regression models were used to examine the predictors of prone and lateral positioning among 9,015 mother-infant pairs from 2000 to 2007. From 1996 to 2007, white infants experienced a reduction in both prone and lateral positioning and an increase in supine positioning (28.2-66.7%), while black infants had smaller decreases in prone and lateral positioning and a smaller increase in supine positioning (22.6-47.1%) than white infants. Compared to births in 2000-2005, births after the explicit recommendation that infants not be placed in the lateral sleep position (2006-2007) were associated with decreased odds of lateral positioning among white infants (odds ratio [OR]: 0.66; 95% confidence interval [CI]: 0.51, 0.87) but not among black infants. The significant predictors of white infants being placed in the prone position were different from the predictors for black infants. Additionally, with regard to lateral sleep positioning, more significant predictors were observed among white infants than black infants. These findings suggest that efforts are warranted to increase the prevalence of supine sleep positioning, especially among black infants. Race-specific programs may efficiently reduce non-supine sleep positioning to help narrow racial gaps in sudden infant death syndrome.


Long-term potentiation involves increases in the probability of neurotransmitter release.
There is great interest in understanding the mechanisms of expression underlying long-term potentiation (LTP). They are agreed to involve an increase in synaptic efficacy, which is described by three multiplicative parameters: p, the probability of neurotransmitter release; n, the number of active release sites; and q, the postsynaptic unit response to transmitter release. We report three new lines of evidence suggesting that increases in p contribute to LTP expression. (i) When the contributions to LTP by p, n, and q are maximized, and p alone is decreased, another high-frequency stimulation elicits additional LTP. The additional potentiation is only associated with decreases in paired-pulse facilitation (PPF) suggesting an increase in p. (ii) There is an inverse relationship between baseline p [corrected] and the magnitude of LTP elicited, consistent with p [corrected] having more or less room to increase when p is smaller or greater. (iii) It has been shown that there is an inverse relationship between the magnitude of LTP induced and the associated changes in PPF. Now I find that decreasing p before inducing LTP moves the set-point for measuring those changes in PPF from before to after p is decreased, which would only occur if p contributes to LTP. Three lines of evidence, then, suggest that increases in p contribute to LTP expression, which is consistent with a presynaptic contribution to LTP. These experiments do not address potential postsynaptic contributions.


A Systematic Review and Meta-analysis of Randomized Controlled Trials of Stabilizing Exercises for Lumbopelvic Region Impact in Postpartum Women With Low Back and Pelvic Pain.
BackgroundCountless women experience lumbopelvic pain (LBPP) after pregnancy. Physical activity is revealed as a beneficial procedure to alleviate LBPP, yet it appears that individual investigations report mixed conclusions about its effectiveness. Objective: This systematic review and meta-analysis examined the impact of stabilizing exercises on pain intensity, disability, and quality of life (QoL) in postpartum women. Data sources: A systematic search was conducted in PubMed, MEDLINE, Google Scholar, Scopus, and reference lists of included studies up to September, 2021. Study selection: Eleven studies comprising 623 participants were included and analyzed using a random-effects model. Results: Data displayed that stabilizing exercises significantly reduced pain (standard mean difference; SMD: -0.76, 95% confidence interval (CI): -1.26 to -0.27, p = .002), and disability (SMD: -1.19, 95% CI: -1.7 to -0.68, p < .001). However, our study found no significant change in QoL following stabilizing exercises (MD: 4.42, 95% CI: -5.73, 14.57, p = .39). Conclusion: Our systematic review and meta-analysis demonstrated that stabilizing interventions had some benefits in postpartum women. While there is some evidence to display the efficacy of stabilizing exercises for relieving LBPP, additional longer-term and high-quality studies are required to confirm the current findings.


Absolute helical arrangement of sulfonamide in the crystal.
[reaction: see text] 1,2-Bis(N-benzenesulfonyl-N-methylamino)benzene (2), which has no fixed asymmetric element, was crystallized from ethyl acetate as chiral crystals belonging to space group P4(1)2(1)2 (No. 92) or P4(3)2(1)2 (No. 96). The array of molecules built by the CH-pi interaction along the c-axis forms an enantiomeric helical superstructure in each individual crystal. The absolute configurations of the chiral crystals of 2 were determined by X-ray crystal structure analysis using the Flack parameter method. The solid-state CD spectra of the chiral crystals in KBr were mirror images. The equilibrium between the two enantiomers in solution is fast during crystallization at ambient temperature, and the energy barrier (DeltaG()) is estimated to be 11.7 +/- 0.3 kcal/mol (233 K).


Rapid diagnostic tests for typhoid and paratyphoid (enteric) fever.
Differentiating both typhoid (Salmonella Typhi) and paratyphoid (Salmonella Paratyphi A) infection from other causes of fever in endemic areas is a diagnostic challenge. Although commercial point-of-care rapid diagnostic tests (RDTs) for enteric fever are available as alternatives to the current reference standard test of blood or bone marrow culture, or to the widely used Widal Test, their diagnostic accuracy is unclear. If accurate, they could potentially replace blood culture as the World Health Organization (WHO)-recommended main diagnostic test for enteric fever. To assess the diagnostic accuracy of commercially available rapid diagnostic tests (RDTs) and prototypes for detecting Salmonella Typhi or Paratyphi A infection in symptomatic persons living in endemic areas. We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, IndMED, African Index Medicus, LILACS, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) up to 4 March 2016. We manually searched WHO reports, and papers from international conferences on Salmonella infections. We also contacted test manufacturers to identify studies. We included diagnostic accuracy studies of enteric fever RDTs in patients with fever or with symptoms suggestive of enteric fever living in endemic areas. We classified the reference standard used as either Grade 1 (result from a blood culture and a bone marrow culture) or Grade 2 (result from blood culture and blood polymerase chain reaction, or from blood culture alone). Two review authors independently extracted the test result data. We used a modified QUADAS-2 extraction form to assess methodological quality. We performed a meta-analysis when there were sufficient studies for the test and heterogeneity was reasonable. Thirty-seven studies met the inclusion criteria and included a total of 5080 participants (range 50 to 1732). Enteric fever prevalence rates in the study populations ranged from 1% to 75% (median prevalence 24%, interquartile range (IQR) 11% to 46%). The included studies evaluated 16 different RDTs, and 16 studies compared two or more different RDTs. Only three studies used the Grade 1 reference standard, and only 11 studies recruited unselected febrile patients. Most included studies were from Asia, with five studies from sub-Saharan Africa. All of the RDTs were designed to detect S.Typhi infection only.Most studies evaluated three RDTs and their variants: TUBEX in 14 studies; Typhidot (Typhidot, Typhidot-M, and TyphiRapid-Tr02) in 22 studies; and the Test-It Typhoid immunochromatographic lateral flow assay, and its earlier prototypes (dipstick, latex agglutination) developed by the Royal Tropical Institute, Amsterdam (KIT) in nine studies. Meta-analyses showed an average sensitivity of 78% (95% confidence interval (CI) 71% to 85%) and specificity of 87% (95% CI 82% to 91%) for TUBEX; and an average sensitivity of 69% (95% CI 59% to 78%) and specificity of 90% (95% CI 78% to 93%) for all Test-It Typhoid and prototype tests (KIT). Across all forms of the Typhidot test, the average sensitivity was 84% (95% CI 73% to 91%) and specificity was 79% (95% CI 70% to 87%). When we based the analysis on the 13 studies of the Typhidot test that either reported indeterminate test results or where the test format means there are no indeterminate results, the average sensitivity was 78% (95% CI 65% to 87%) and specificity was 77% (95% CI 66% to 86%). We did not identify any difference in either sensitivity or specificity between TUBEX, Typhidot, and Test-it Typhoid tests when based on comparison to the 13 Typhidot studies where indeterminate results are either reported or not applicable. If TUBEX and Test-it Typhoid are compared to all Typhidot studies, the sensitivity of Typhidot was higher than Test-it Typhoid (15% (95% CI 2% to 28%), but other comparisons did not show a difference at the 95% level of CIs.In a hypothetical cohort of 1000 patients presenting with fever where 30% (300 patients) have enteric fever, on average Typhidot tests reporting indeterminate results or where tests do not produce indeterminate results will miss the diagnosis in 66 patients with enteric fever, TUBEX will miss 66, and Test-It Typhoid and prototype (KIT) tests will miss 93. In the 700 people without enteric fever, the number of people incorrectly diagnosed with enteric fever would be 161 with Typhidot tests, 91 with TUBEX, and 70 with Test-It Typhoid and prototype (KIT) tests. The CIs around these estimates were wide, with no difference in false positive results shown between tests.The quality of the data for each study was evaluated using a standardized checklist called QUADAS-2. Overall, the certainty of the evidence in the studies that evaluated enteric fever RDTs was low. In 37 studies that evaluated the diagnostic accuracy of RDTs for enteric fever, few studies were at a low risk of bias. The three main RDT tests and variants had moderate diagnostic accuracy. There was no evidence of a difference between the average sensitivity and specificity of the three main RDT tests. More robust evaluations of alternative RDTs for enteric fever are needed.


Esophageal function testing: Billing and coding update.
Esophageal function testing is being increasingly utilized in diagnosis and management of esophageal disorders. There have been several recent technological advances in the field to allow practitioners the ability to more accurately assess and treat such conditions, but there has been a relative lack of education in the literature regarding the associated Common Procedural Terminology (CPT) codes and methods of reimbursement. This review, commissioned and supported by the American Neurogastroenterology and Motility Society Council, aims to summarize each of the CPT codes for esophageal function testing and show the trends of associated reimbursement, as well as recommend coding methods in a practical context. We also aim to encourage many of these codes to be reviewed on a gastrointestinal (GI) societal level, by providing evidence of both discrepancies in coding definitions and inadequate reimbursement in this new era of esophageal function testing.


Changes in distribution of cardiac output by surface-induced deep hypothermia in dogs.
The effects of surface-induced deep hypothermia on organ blood flow and on the distribution of cardiac output were investigated in the anesthetized dog. Organ flows were determined by the radioactive microsphere technique. Phenoxybenzamine (POB) was administered prior to hypothermia to minimize vasoconstriction and hence facilitate cooling. Measurements were made before POB, on stabilization after POB, and during hypothermia. Cardiac output was reduced by POB as was blood flow to the pancreas, small intestine, and skeletal muscle. Hypothermia, following POB, produced a further fall in Q and during this maneuver blood flow fell in all organs and vascular beds studied. The relative distribution of Q during hypothermia was essentially the same as in the control except the brain, kidneys, and pancreas received a smaller fraction of the total output. The relatively normal distribution of a reduced cardiac output during hypothermia was in marked contrast to distribution of comparable low cardiac output induced by hemorrhage. In the latter condition, the fraction of the cardiac output perfusing the brain, kidneys, adrenals, and hepatic artery was increased.


Caring for older people with an intellectual disability: a systematic review.
This review critically evaluates the available research literature on aging among people with an intellectual disability. 42 papers meeting the review inclusion criteria are presented under three themes: studies with a service user perspective (13), studies of carers of older people with ID (14) and studies of service provision for older people with ID (15). User view specific findings relate to concerns about accommodation; experiences of services; and perceptions of aging; with a common underlying finding from all user focused themes that of unmet need. Carer specific findings relate to fear of the future; experiences of older carers; and planning for the future. Services themes reflect the debate over specialist or generalist services as people age; accommodation; retirement from day services; and staff training. Overall this review reveals a lack of robust research evidence concerning the lives of older people with ID and a need for more research that directly engages with older people with ID and their carers.


Repellent and Lethal Activities of Extracts From Fruits of Chinaberry (Melia azedarach L., Meliaceae) Against Triatoma infestans.
Triatoma infestans is the principal vector of Trypanosoma cruzi, parasite responsible of Chagas's Disease transmission in Argentina. Pyrethroids have become common pesticides for the control of T. infestans but increasing resistance encourages the search of new alternatives and the use of natural products for biological control arises as a new strategy. Melia azedarach L. is originated from the Himalaya's region and several compounds are part of its rich phytochemistry. Folk medicine of the plant is due to its repellent and insecticidal activities. Aims of this work were to evaluate the repellent activity of methanolic and acetonic extracts from fruits of M. azedarach by means of the area preference method of fifth and first nymph stages as well as to test the acute lethal effect of the more repellent extract by means of direct application on cuticle on both stages. For repellence, qualitative filter papers were divided into two halves, one treated with methanolic (ME) or acetonic (AC) extract and the other without treatment. Controls were impregnated half with methanol or acetone and half without the solvents. One nymph was located in each Petri or well and repellence percentage was determined. For the lethal effect, fasted and fed to repletion 5th stage nymphs were topically administered with different concentrations of AC and deaths were registered after 24, 48, 72, 96, and 120 h. Phytochemical analysis of extracts was performed as well. AC demonstrated high repellent activity (100%, both stages), whereas ME extract activity was slight (10-21%). AC extract was selected for lethal assays due to early repellent activity. Fed to repletion nymphs were more sensitive to the lethal activity of the extract when compared to fasted nymphs (LD50: 11.5 vs. 23.1 μg/insect, respectively). Phytochemistry assays of extracts showed a higher concentration of flavonoids, alkaloids and triterpenes for AC. Considering these results, next assays will include the test of Melia azedarach extract on T. infestans that are resistant to pyrethroids for a possible synergism between AC and the pesticides.


Long-term trends in adult mortality for U.S. Blacks and Whites: an examination of period- and cohort-based changes.
Black-white differences in U.S. adult mortality have narrowed over the past five decades, but whether this narrowing unfolded on a period or cohort basis is unclear. The distinction has important implications for understanding the socioeconomic, public health, lifestyle, and medical mechanisms responsible for this narrowing. We use data from 1959 to 2009 and age-period-cohort (APC) models to examine period- and cohort-based changes in adult mortality for U.S. blacks and whites. We do so for all-cause mortality among persons aged 15-74 as well as for several underlying causes of death more pertinent for specific age groups. We find clear patterns of cohort-based reductions in mortality for both black men and women and white men and women. Recent cohort-based reductions in heart disease, stroke, lung cancer, female breast cancer, and other cancer mortality have been substantial and, save for breast cancer, have been especially pronounced for blacks. Period-based changes have also occurred and are especially pronounced for some causes of death. Period-based reductions in blacks' and whites' heart disease and stroke mortality are particularly impressive, as are recent period-based reductions in young men's and women's mortality from infectious diseases and homicide. These recent period changes are more pronounced among blacks. The substantial cohort-based trends in chronic disease mortality and recent period-based reductions for some causes of death suggest a continuing slow closure of the black-white mortality gap. However, we also uncover troubling signs of recent cohort-based increases in heart disease mortality for both blacks and whites.


Ultrastructural study across the leprosy spectrum.
We have carried out a systematic ultrastructural study of the bacilli, the cell-mediated response in the host, and the dermal microvasculature in lepromatous (LL), borderline lepromatous (BL), and borderline tuberculoid (BT) types of active leprosy (eight cases). In the types of least resistance (LL and BL), macrophages with large cytoplasmic processes were observed; in addition, numerous peripheral vacuoles were found in BL. Mast cells were abundant and vascular alterations constant. BT macrophages showed more regular outlines and multivacuolated cytoplasms with plentiful rough endoplasmic reticulum. Giant cells were scarce. Bacilli, both isolated and in globi, were contained within the vacuoles and appeared constantly in macrophages and endothelial and Schwann cells in LL and BL. Conversely, in BT they were found singly, infrequently in the endothelial cells, and not at all in Schwann cells. Forms in the process of destruction or degradation were more common than intact forms, in which the symmetric outline of the membrane could be seen clearly.


Zymosan-stimulated production of phosphatidic acid by macrophages: relationship to release of superoxide anion and inhibition by agents that increase intracellular cyclic AMP.
Murine peritoneal macrophages (m phi) respond to unopsonized zymosan with the production of superoxide anion (O2-). We investigated the involvement of phospholipid turnover in the transduction mechanism for this phenomenon. Zymosan-stimulated m phi produced increased amounts of phosphatidic acid (PA); the increase was first detected at 1.5 min and continued for 10 min of incubation. Production of O2- was not detected until between 2 to 4 min after stimulation, and continued to increase through 60 min. Inhibition experiments suggested that these two processes were linked. Theophylline (theo)/dibutyrylcyclic AMP (dbcAMP) and theo/prostaglandin E2 (PGE2) inhibited O2- production at every time point (79% and 80% inhibition, respectively, at 4 min). Corresponding inhibition of PA production was also achieved at every time point (85% by theo/dbcAMP; 67% by theo/PGE2 at 4 min). These results are compatible with a role for phospholipid remodeling in the transduction process associated with the respiratory burst. Results suggest that the phospholipid species could be phosphatidylcholine (PC) as well as phosphatidylinositol (PI).


Trifluoromethyloxadiazoles: inhibitors of histone deacetylases for control of Asian soybean rust.
Trifluoromethyloxadiazoles (TFMOs) are selective inhibitors of class II histone deacetylases (HDACs). To date, class II HDACs have not been addressed as target enzymes by commercial fungicides. Antifungal testing of a broad variety of TFMOs against several important plant pathogens showed activity against only rusts, and especially Phakopsora pachyrhizi, the cause of Asian soybean rust. A structure-activity relationship was established, leading to highly active fungicides that inhibit fungal class II and HOS3-type HDACs of Aspergillus nidulans. Studies of the enzyme-inhibitor binding mode using protein structural information based on the crystal structure of human HDAC4 argue that TFMOs inhibit these enzymes only after undergoing hydration. Fungal class II HDACs are potential target enzymes for the control of at least some biotrophic crop diseases, in particular Asian soybean rust. As with any novel mode-of-action, class II HDAC fungicides would offer the potential to control fungal isolates that show reduced sensitivity toward existing commercial fungicides.


E90 subunit vaccine protects mice from Zika virus infection and microcephaly.
Zika virus (ZIKV) became a global threat due to its unprecedented outbreak and its association with congenital malformations such as microcephaly in developing fetuses and neonates. There are currently no effective vaccines or drugs available for the prevention or treatment of ZIKV infection. Although multiple vaccine platforms have been established, their effectiveness in preventing congenital microcephaly has not been addressed. Herein, we tested a subunit vaccine containing the 450 amino acids at the N-terminus of the ZIKV envelope protein (E90) in mouse models for either in utero or neonatal ZIKV infection. In one model, embryos of vaccinated dams were challenged with a contemporary ZIKV strain at embryonic day 13.5. The other model infects neonatal mice from vaccinated dams by direct injection of ZIKV into the developing brains. The vaccine led to a substantial reduction of ZIKV-infected cells measured in the brains of fetal or suckling mice, and successfully prevented the onset of microcephaly compared to unvaccinated controls. Furthermore, E90 could protect mice from ZIKV infection even at 140 days post-immunization. This work directly demonstrates that immunization of pregnant mice protects the developing brains of offspring both in utero and in the neonatal period from subsequent ZIKV infection and microcephaly. It also supports the further development of the E90 subunit vaccine towards clinical trials.


Long-term Supplementation With n-6 and n-3 PUFAs Improves Moderate-to-Severe Keratoconjunctivitis Sicca: A Randomized Double-Blind Clinical Trial.
Supplementation with gamma-linolenic acid (GLA) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) has been found to decrease the production of disease-relevant inflammatory mediators that are implicated in the pathogenesis of chronic dry eye. This study evaluated the effect of a supplement containing both GLA and n-3 PUFAs on signs and symptoms of moderate-to-severe keratoconjunctivitis sicca in postmenopausal patients. This multicenter, double-masked placebo-controlled clinical trial enrolled 38 patients (both eyes) with tear dysfunction who were randomized to supplemental GLA + n-3 PUFAs or placebo for 6 months. Disease parameters, including Ocular Surface Disease Index, Schirmer test, tear breakup time, conjunctival fluorescein and lissamine green staining, and topographic corneal smoothness indexes (surface asymmetry index and surface regularity index), were assessed at baseline and at 4, 12, and 24 weeks. The intensity of dendritic cell CD11c integrin and HLA-DR expression was measured in conjunctival impression cytologies. The Ocular Surface Disease Index score improved with supplementation and was significantly lower than placebo (21 ± 4 vs. 34 ± 5) after 24 weeks (P = 0.05, n = 19 per group). The surface asymmetry index was significantly lower in supplement-treated subjects (0.37 ± 0.03, n = 15) than placebo (0.51 ± 0.03, n = 16) at 24 weeks (P = 0.005). Placebo treatment also significantly increased HLA-DR intensity by 36% ± 9% and CD11c by 34% ± 7% when compared with supplement treatment (n = 19 per group, P = 0.001, 24 weeks). Neither treatment had any effect on tear production, tear breakup time, or corneal or conjunctival staining. Supplemental GLA and n-3 PUFAs for 6 months improved ocular irritation symptoms, maintained corneal surface smoothness, and inhibited conjunctival dendritic cell maturation in patients with postmenopausal keratoconjunctivitis sicca.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00883649.


Predictive effects of good self-control and poor regulation on alcohol-related outcomes: do protective behavioral strategies mediate?
In the present study, we examined whether use of protective behavioral strategies mediated the relationship between self-control constructs and alcohol-related outcomes. According to the two-mode model of self-control, good self-control (planfulness; measured with Future Time Perspective, Problem Solving, and Self-Reinforcement) and poor regulation (impulsivity; measured with Present Time Perspective, Poor Delay of Gratification, Distractibility) are theorized to be relatively independent constructs rather than opposite ends of a single continuum. The analytic sample consisted of 278 college student drinkers (68% women) who responded to a battery of surveys at a single time point. Using a structural equation model based on the two-mode model of self-control, we found that good self-control predicted increased use of three types of protective behavioral strategies (Manner of Drinking, Limiting/Stopping Drinking, and Serious Harm Reduction). Poor regulation was unrelated to use of protective behavioral strategies, but had direct effects on alcohol use and alcohol problems. Further, protective behavioral strategies mediated the relationship between good self-control and alcohol use. The clinical implications of these findings are discussed.


Effect of ester on rhodium-catalyzed intermolecular [5+2] cycloaddition of 3-acyloxy-1,4-enynes and alkynes.
We systematically examined the effect of different esters on the rhodium-catalyzed intermolecular [5+2] cycloaddition of 3-acyloxy-1,4-enynes and alkynes with a concomitant 1,2-acyloxy migration. Significant rate acceleration was observed for benzoate substrates bearing an electron-donating substituent. The cycloaddition can now be conducted under much more practical conditions for most terminal alkynes.


Childhood diabetes.
There has been a quiet revolution in the care of children with diabetes over the last decade. The establishment of child-centred teams together with advances in management help the child achieve a normal lifestyle while avoiding both the long- and short-term complications of diabetes.


Association of hypertension status and cardiovascular risks with sympathovagal imbalance in first degree relatives of type 2 diabetics.
As reports show cardiovascular (CV) risks in first-degree relatives (FDR) of type 2 diabetics, and autonomic imbalance predisposing to CV risks, in the present study we have assessed the contribution of sympathovagal imbalance (SVI) to CV risks in these subjects. Body mass index (BMI), waist-to-hip ratio (WHR), basal heart rate (BHR), blood pressure (BP), rate pressure product (RPP), and spectral indices of heart rate variability (HRV) were reordered and analyzed in FDR of type 2 diabetics (study group, n = 293) and in subjects with no family history of diabetes (control group, n = 405). The ratio of low-frequency (LF) to high-frequency (HF) power of HRV (LF-HF), a sensitive marker of SVI, was significantly increased (P < 0.001) in the study group compared with the control group. The SVI in the study group was due to concomitant sympathetic activation (increased LF) and vagal inhibition (decreased HF). In the study group, the LF-HF ratio was significantly correlated with BMI, WHR, BHR, BP and RPP. Multiple regression analysis showed an independent contribution of LF-HF to hypertension status (P = 0.000), and bivariate logistic regression showed significant prediction (odds ratio 2.16, confidence interval 1.130-5.115) of LF-HF to increased RPP, the marker of CV risk, in the study group. Sympathovagal imbalance in the form of increased sympathetic and decreased parasympathetic activity is present in FDR of type 2 diabetics. Increased resting heart rate, elevated hypertension status, decreased HRV and increased RPP in these subjects make them vulnerable to CV risks. SVI in these subjects contributes to CV risks independent of the degree of adiposity.


Anaplastic thyroid carcinoma with humoral hypercalcemia of malignancy (HHM): an autopsy case report.
An 84-year-old woman was admitted to our hospital for the examination and treatment of painful right thyroid swelling on August 2, 2002. Thyroid ultrasonography showed a mass of about 6 cm in diameter at the right thyroid lobe. Aspiration biopsy cytology (ABC) of her mass showed a thyroid carcinoma. Her neck mass was cold on (123)I scintigraphy and hot on both early- and delayed- phase (201)Tl scintigraphy. Whole body (67)Ga scintigraphy scan showed a strong hot accumulation in the area from the right thyroid lobe to the right lateral lobe. Multiple lung tumors were observed from chest computed tomography (CT) scans. She was diagnosed as having an anaplastic thyroid carcinoma with metastatic lung tumors. As her thyroid carcinoma was inoperable, percutaneous injection therapy of lipiodol and ethanol (lip-PEIT) against the primary thyroid carcinoma was performed twice a week. However, the thyroid carcinoma gradually enlarged and oppressed her trachea. Two months after the initiation of lip-PEIT, parathyroid hormone-related protein (PTHrP)-dependent hypercalcemia was diagnosed because serum levels of calcium, phosphate and intact-PTHrP were 2.72 mmol/l (10.9 mg/dl), 0.71 mmol/l (2.2 mg/dl), 3.2 pmol/l, respectively. The hypercalcemia was reduced by the use of pamidronate. After one week she died of an airway obstruction caused by the developing thyroid carcinoma. Carcinoma cells with a mixed papillary and squamoid pattern were positively stained immunohistochemically by anti-PTHrP(1-34) antisera. Herein, we report a rare autopsy case of a PTHrP-producing thyroid carcinoma.


Dynamic formation of hybrid peptidic capsules by chiral self-sorting and self-assembly.
Owing to their versatility and biocompatibility, peptide-based self-assembled structures constitute valuable targets for complex functional designs. It is now shown that artificial capsules based on β-barrel binding motifs can be obtained by means of dynamic covalent chemistry (DCC) and self-assembly. Short peptides (up to tetrapeptides) are reversibly attached to resorcinarene scaffolds. Peptidic capsules are thus selectively formed in either a heterochiral or a homochiral way by simultaneous and spontaneous processes, involving chiral sorting, tautomerization, diastereoselective induction of inherent chirality, and chiral self-assembly. Self-assembly is shown to direct the regioselectivity of reversible chemical reactions. It is also responsible for shifting the tautomeric equilibrium for one of the homochiral capsules. Two different tautomers (keto-enamine hemisphere and enol-imine hemisphere) are observed in this capsule, allowing the structure to adapt for self-assembly.


Management of dysplastic nevi: a survey of fellows of the American Academy of Dermatology.
Opinions concerning the significance of dysplastic nevi and their management vary among dermatologists. The purpose of this study was to assess how fellows of the American Academy of Dermatology (AAD) perceive and manage dysplastic nevi. Questionnaires were sent to 1216 fellows of the AAD; 456 questionnaires were returned. Almost all respondents (98%) accept the dysplastic nevus, or atypical mole, as an entity. Seventy-five percent of respondents perform follow-up total cutaneous examinations on all their patients with dysplastic nevi, and another 22% on some of them; 86% usually intend to do total removals when they perform biopsies of dysplastic nevi; 75% use margins of 2 mm or less when removing dysplastic nevi; 49% order baseline total-cutaneous photographs of some or all of their patients with multiple dysplastic nevi, although only 12% do so routinely; 67% prefer to re-excise dysplastic nevi when margins are positive, some using histologic atypia as a criterion; 60% recommend an ophthalmologic examination for at least some of their patients with many dysplastic nevi, although only 3% do so routinely; 12% always recommend cutaneous examinations of blood relatives of their patients with dysplastic nevi and another 81% recommend such examinations for at least some of their patients with dysplastic nevi; 23% use dermoscopy; 99% recommend self-examination; almost 100% recommend sunscreen use and 93%, sun avoidance. Most respondents, in agreement with the literature, accept the concept that patients with dysplastic nevi are at increased risk for melanoma and that methods for prevention and early detection of melanomas are appropriate for these patients.


AltMV TGB1 Nucleolar Localization Requires Homologous Interaction and Correlates with Cell Wall Localization Associated with Cell-to-Cell Movement.
The Potexvirus Alternanthera mosaic virus (AltMV) has multifunctional triple gene block (TGB) proteins, among which our studies have focused on the properties of the TGB1 protein. The TGB1 of AltMV has functions including RNA binding, RNA silencing suppression, and cell-to-cell movement, and is known to form homologous interactions. The helicase domains of AltMV TGB1 were separately mutated to identify which regions are involved in homologous TGB1 interactions. The yeast two hybrid system and Bimolecular Fluorescence Complementation (BiFC) in planta were utilized to examine homologous interactions of the mutants. Helicase motif I of AltMV TGB1 was found to be critical to maintain homologous interactions. Mutations in the remaining helicase motifs did not inhibit TGB1 homologous interactions. In the absence of homologous interaction of TGB1, subcellular localization of helicase domain I mutants showed distinctively different patterns from that of WT TGB1. These results provide important information to study viral movement and replication of AltMV.


Defective repair of UV-induced DNA damage in cultured primary skin fibroblasts from Saudi thyroid cancer patients.
This study was conducted to examine the sensitivity of primary skin fibroblasts from Saudi thyroid cancer (TC) patients to ultraviolet (UV) irradiation. Cell survival was studied by a colony forming assay and DNA repair defects with a host cell reactivation (HCR) assay using UV-irradiated Herpes Simplex Virus (HSV). In addition, p53 gene expression was examined in the same TC cells exhibiting enhanced radiosensitivity. Skin fibroblasts from TC patients (n=4) showed significantly enhanced sensitivity to UV radiation. The average UV dose to reduce survival to 37% of the initial survival (D(37)) value (in Jm(-2)) for fibroblasts from TC patients was 4.6 (3.7-5.6) compared to 7.3 (6.3-8.3) for healthy individuals (n=3). UV-sensitive xeroderma pigmentosum (XP) cells, which were used as positive control, were found to be extremely sensitive with a D(37) value of 0.6 Jm(-2). In a host cell reactivation assay, UV-irradiated HSV was tested for its plaque-forming ability (PFA), by plating infected fibroblasts from TC patients (used as host cells) on African Green Monkey (Vero) kidney cells to form plaques. A significant reduction in the PFA of the UV-irradiated virus (about three fold) on TC cells compared to fibroblasts from the healthy subjects was seen, suggesting a DNA-repair deficiency in the primary fibroblasts of the TC patients. Furthermore, no significant accumulation in radiation-induced p53 expression was observed in cells from the TC patients. Our results, based on a relatively small group of subjects, indicate that Saudi TC patients primary fibroblasts (non-cancerous in nature) may be carriers of cancer-susceptible gene(s) arising from defective DNA repair/processing. These results warrant a larger study to investigate the role of UV-induced bulky DNA damage in thyroid cancer susceptibility.


Adults with diabetic peripheral neuropathy exhibit impairments in multitasking and other executive functions.
Diabetic peripheral neuropathy (DPN) contributes to functional impairment, and there is growing evidence that neuropsychological factors also influence physical function. We compared cognitive and executive function in adults with DPN with an age-matched comparison group, and examined the relationships between DPN, executive function, and physical function. Twenty subjects with DPN and 20 comparison subjects were assessed. Diabetic peripheral neuropathy was quantified via the Michigan Neuropathy Screening Instrument and nerve conduction velocity testing. Subjects were administered Beck's Depression Inventory, the Mini-Mental Status Examination, and the Timed Up and Go (TUG) test. Each participant also completed a battery of 7 executive function tasks, including the Cognitive Timed Up and Go (cTUG) test, in which a concurrent mental subtraction task was added to the standard TUG test. The DPN group demonstrated poorer letter fluency (34.2 ± 11.6 words vs 46.2 ± 12.2 words; P = 0.001), category fluency (47.0 ± 8.1 words vs 56.3 ± 8.5 words; P = 0.003), and Rey-Osterrieth scores (25.9 ± 4.3 points vs 31.7 ± 2.4 points; P < 0.001), and took longer to complete both the TUG (10.3 ± 2.8 seconds vs 5.9 ± 1.0 seconds; P < 0.001) and cTUG (13.0 ± 5.8 seconds vs 6.9 ± 1.6 seconds; P < 0.001). Poorer global cognitive performance and greater depression symptoms were significantly related to each other (r = -0.46; P = 0.04) and to slower TUG times (r = -0.53; P = 0.02; and r = 0.54; P = 0.02, respectively). Verbal, visuospatial, and multitasking measures of executive function may be impaired in adults with DPN. Future research should examine how these and other cognitive and psychological factors, such as depression, affect physical function in this population.


Pharmacological, Biochemical and Immunological Studies on Protective Effect of Mangiferin in 6-Hydroxydopamine (6-OHDA)-Induced Parkinson's Disease in Rats.
Parkinson's disease is a neurodegenerative disorder and is marked by inflammation and death of neurons in the striatum region of the midbrain. It has been reported that expression of NF-κB increases during Parkinson's disease, which promotes oxidative stress, stimulates release of proinflammatory cytokines, and induces expression of nitric oxide. Therefore, in this study, we have used mangiferin a specific NF-κB inhibitor. Mangiferin is a polyphenolic compound traditionally used for its antioxidant and anti-inflammatory properties. The study utilized male Wistar rats weighing 200-250 g (56 rats; n = 8/group). On day "0," stereotaxic surgery of rats was done to induce 6-hydroxydopamine lesioning in rats. Coordinates for substantia nigra were anteroposterior-2 mm, mediolateral-5 mm and dorsoventral-8.2 mm. After 14 days, those rats which show at least 210 contralateral rotations after administration of apomorphine (0.5 mg/kg S.C.) were selected for the study and were given treatment for 28 days. On day 28 of treatment, rats were subjected to behavioral studies to evaluate the effect of mangiferin and their brains were taken out after euthanasia to perform biochemical, molecular and immunological studies. Treatment with mangiferin significantly improves the key parameters of locomotor activity and oxidative stress and reduces the parameters of inflammatory stress. Also, the activity of caspases was reduced. Significant decrease in activity of both cyclooxygenase 1 and 2 was also observed. Maximum improvement in all parameters was observed in rats treated with grouping of mangiferin 45 µg/kg and levodopa 10 mg/kg. Treatment with levodopa alone has no significant effect on biochemical and molecular parameters though it significantly improves behavioral parameters. Current treatment of Parkinson's disease does not target progression of Parkinson's disease. Results of this study suggest that mangiferin has protective effect in hemi-Parkinsonian rats. Therefore, the combination therapy of mangiferin and levodopa can be helpful in management of Parkinson's disease.


Eight-year prospective follow-up of mentalization-based treatment versus structured clinical management for people with borderline personality disorder.
Participants (n = 134) treated in a randomized controlled trial with mentalization-based treatment (MBT) compared with structured clinical management were followed up for 8 years after starting treatment in terms of the initial primary outcome of the trial-namely, suicide attempts, self-harm, and hospitalization-as well as service use and functional outcomes. Patients in the study group were interviewed by research assistants who remained masked to the original group allocation. Interviews were scheduled annually. Of the original participants, 98 (73%) agreed to participate. Overall, the beneficial outcomes at the end of treatment were maintained in both groups. Over the follow-up period, the number of patients who continued to meet the primary recovery criteria was significantly higher in the MBT group (74% vs. 51%). Use of most other services was comparable. Participants treated with MBT showed better functional outcomes in terms of being more likely to be engaged in purposeful activity and reporting less use of professional support services and social care interventions. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Methodology for teaching theory in occupational therapy basic professional education.
This article proposes a methodology for teaching theoretical concepts to undergraduate occupational therapy students. The methodology is based upon a learning theory and three conceptual models of psychosocial dysfunction. It is suggested that such a method will help students to understand theoretical principles and to develop the ability to apply these principles to treatment. This method has been used successfully by the authors in classroom instruction.


The Ro52/SS-A autoantigen has elevated expression at the brain microvasculature.
An expression cloning technique was used to identify proteins selectively expressed at the blood-brain barrier that may mediate interactions between the brain microvasculature and IgG molecules. Ro52/SS-A is an IgG-binding protein and is an autoantigen implicated in Sjogren's syndrome and systemic lupus erythematosus. The present studies describe the expression cloning of this gene product from a bovine brain microvascular cDNA library. The Ro52 protein interacted with IgG molecules independent of specificity suggesting a potential role as a general antibody receptor. Northern blotting shows the Ro52/SS-A transcript is enriched in the microvascular compartment of brain. The selective expression of Ro52/SS-A in brain at the microvasculature may play a role in brain vascular involvement in autoimmune diseases.


The surgical management of obstruction and perforation of the left colon.
Patients requiring emergency surgical treatment of the left side of the colon have a poor prognosis. Age, advanced malignant disease and systemic sepsis are contributory factors to the high morbidity and mortality rates, but making surgical decisions is also important. Any surgeon is likely to encounter only a few such patients per year and this adds to the uncertainty regarding management. Although the traditional three-staged approach was based on safety, it has been demonstrated that immediate resection is feasible and beneficial in most patients. This should be accompanied by primary anastomosis in all instances except in the presence of generalized peritonitis or a large abscess cavity causing severe systemic sepsis. When such circumstances occur, resection with terminal colostomy is the safest policy. We conclude that multicenter randomized prospective clinical trials should be initiated to establish the optimum and most economic method of resection and primary anastomosis for emergency operation of the left side of the colon.