Factors affecting response, number of laser sessions and complications in nevus of Ota treated by Q-switched alexandrite laser: a retrospective study.
The aim of this study was to study and analyze the factors influencing the treatment response to Q-switched alexandrite laser in patients with nevus of Ota and the factors influencing the number of laser sessions. Forty-eight patients treated with Q-switched alexandrite between 2009 and 2013 for nevus of Ota were enrolled in this retrospective, single-center study. The subjects (13 male, 35 female) were divided into three groups according to the number of treatment sessions. Patients were then called back to the hospital for a follow-up interview and examination. Single and multiple variate analyses of various factors were performed. The 48 patients were predominantly female (35 female, 13 male, F:M ratio = 2.7:1), mean age 17.2±10.41. Twenty-five (52.1%) had lesion on the right side of the face, 22 (45.8%) on the left side, and one (2.1%) on both sides. The predominant color was brown (41.7%), followed by cyan (39.6%) and lividity (18.8%). Satisfactory result was observed in all patients, after 3 to 11 treatment sessions (mean 5.37±2); 19 of these (39.6%) needed three to four sessions (short treatment sessions), 22 (45.8%) needed five to seven sessions (intermediate treatment sessions), and 7 (14.6%) needed nine to eleven sessions (long treatment sessions). The clinical response and treatment sessions of the young-age group were significantly better than the adult group. Those with higher Tanino's classification needed more treatment sessions. Dark-colored lesions, which reflect deep melanosis of the lesion, needed more sessions than lighter-colored lesions. As for skin color, better response was obtained in light-skinned patients than in dark-skinned ones. Two patients showed transient hypopigmentation that lasted for less than six months, and recurrence has been seen in one child with dark-colored lesion. Q-switched alexandrite laser is an ideal minimally-invasive method for treating nevus of Ota. Fewer treatment sessions are needed for children and younger patients, whereas brown lesion, lower Tanino's classification and light skin patients.


An experimental investigation of the functional hypothesis and evolutionary advantage of stone-tipped spears.
Stone-tipped weapons were a significant innovation for Middle Pleistocene hominins. Hafted hunting technology represents the development of new cognitive and social learning mechanisms within the genus Homo, and may have provided a foraging advantage over simpler forms of hunting technology, such as a sharpened wooden spear. However, the nature of this foraging advantage has not been confirmed. Experimental studies and ethnographic reports provide conflicting results regarding the relative importance of the functional, economic, and social roles of hafted hunting technology. The controlled experiment reported here was designed to test the functional hypothesis for stone-tipped weapons using spears and ballistics gelatin. It differs from previous investigations of this type because it includes a quantitative analysis of wound track profiles and focuses specifically on hand-delivered spear technology. Our results do not support the hypothesis that tipped spears penetrate deeper than untipped spears. However, tipped spears create a significantly larger inner wound cavity that widens distally. This inner wound cavity is analogous to the permanent wound cavity in ballistics research, which is considered the key variable affecting the relative 'stopping power' or 'killing power' of a penetrating weapon. Tipped spears conferred a functional advantage to Middle Pleistocene hominins, potentially affecting the frequency and regularity of hunting success with important implications for human adaptation and life history.


A 10 year single centre experience of percutaneous and endoscopic extraction of bile duct stones with T tube in situ.
A non-randomised single centre study of 226 consecutive patients referred over 10 years with retained common bile duct stones and a T tube in situ or a cholecystostomy tube are reported. Percutaneous extraction was attempted in 204 and endoscopic extraction in 68 patients. Percutaneous clearance was achieved in 158 (77.5%) patients and endoscopic clearance in 52 (76.5%) patients. Six of 153 (3.9%) patients followed after percutaneous treatment suffered major complications (pancreatitis, cholangitis, or tract perforation). Three of 67 (44%) patients followed after endoscopic treatment suffered major complications (pancreatitis, cholangitis, or bleeding). When the initial method of treatment failed, the alternative was used, resulting in an overall success rate of bile duct clearance of 94.3%. It is concluded that percutaneous and endoscopic methods of bile duct clearance in patients with a T tube in situ are equally effective, carrying similar complication rates. This study has helped to clarify the indications and efficacy of these alternative treatments.


Thyroid and other autoantibodies in British and Japanese women: an epidemiological study of breast cancer.
To define the role of asymptomatic autoimmune thyroiditis in the cause of breast cancer, the presence of circulating thyroid autoantibodies was studied in two populations, one with a high risk of breast cancer (British women) and one with a low risk (Japanese women). Ostensibly healthy women and patients with breast cancer from both countries were studied. There was no difference in the incidence of thyroid autoantibodies between women with breast cancer and healthy women in either race. The incidence of thyroid autoantibodies in healthy British women, however, was two to three times that in healthy Japanese women. The incidence of reticulin antibodies, was considerably higher in both groups of Japanese women. No remarkable differences in the incidence of antinuclear, smooth-muscle, antimitochondrial, gastric parietal cell, or liver-kidney microsomal antibodies were found between women with breast cancer and healthy women or between the two races. Only the incidence of antinuclear antibodies was marginally higher in Japanese patients with advanced cancer. These results indicate that asymptomatic autoimmune thyroid disease is more prevalent among British than among Japanese women, but they fail to provide direct evidence that autoimmune thyroid disease is associated with breast cancer. Prospective studies of women with autoimmune thyroiditis and studies of young women from low-risk and high-risk populations are needed.


Inherited prothrombotic risk factors in Turkish children with acute lymphoblastic leukemia: significance of concomitant genetic mutation.
Our study was designed to prospectively evaluate the role of the methylenetetrahydrofolate reductase (MTHFR) TT677 genotype, the prothrombin (PT) 620210A mutation, the factor V G1691A mutation in leukemic Turkish children treated according to modified BFM 95 study protocols with respect to the onset at thromboembolic events. Eighty-two consecutive leukemic children investigated had are established inherited prothrombotic risk factor: 29 children showed the MTHFR genotype (heterozygous, n = 22; homozygous, n = 7); 3 showed the heterozygous PT G20210A variant; 16 were carriers of the factor V mutation (heterozygous). In addition, combined prothrombotic defects were found in a further 11 patients the MTHFR mutation was combined with the F V mutation (n = 7), the PT G20210A variant (n = 2). In 7 (8.5%) of these 82 patients, venous thromboembolism occurred. In conclusion, the presence of inherited thrombophilia with Turkish children treated acute lymphoblastic leukemia may be useful for designing targeted primary prevention strategies.


Brief Behavioral Treatment for Insomnia vs. Cognitive Behavioral Therapy for Insomnia: Results of a Randomized Noninferiority Clinical Trial Among Veterans.
The goal of this study was to compare a brief behavioral treatment for insomnia (BBTI), which has fewer sessions (4), shorter duration (<30-45 minutes), and delivers treatment in-person plus phone calls to cognitive behavioral therapy for insomnia (CBTI), which has 5 in-person sessions. The hypothesis was BBTI would be noninferior to CBTI. The Reliable Change Index was used to establish a noninferiority margin (NIM) of 3.43, representing the maximum allowable difference between groups on the pre-post Insomnia Severity Index change (ΔISI). Sixty-three veterans with chronic insomnia were randomized to either BBTI or CBTI and veterans in both groups had significant reductions of their insomnia severity per the ISI and improved their sleep onset latency, total wake time, sleep efficiency, and sleep quality per sleep diaries. While CBTI had a larger pre-post ΔISI, this was not significantly different than ΔISI BBTI and was less than the NIM. However, the 95% confidence interval of the between group pre-post ΔISI extended beyond the NIM, and thus BBTI was inconclusively noninferior to CBTI. Limitations, such as small sample size and high rate of dropout, indicate further study is needed to compare brief, alternative yet complementary behavioral insomnia interventions to CBTI. Still, evidence-based brief and flexible treatment options will help to further enhance access to care for veterans with chronic insomnia, especially in non-mental-health settings like primary care.


Mortality from asthma: a new epidemic in New Zealand.
Trends in mortality attributed to asthma in the 5-34-year age group were examined in New Zealand, Australia, England and Wales, the United States, Canada, and West Germany for the years 1959-79. An epidemic of deaths from asthma occurred in the mid-1960s in New Zealand, Australia, and England and Wales but not in the other countries. In Australia and England and Wales the death rate quickly returned to pre-epidemic levels, but in New Zealand the decline in mortality was slow, and by 1974 the death rate was still almost double the pre-epidemic level. Of great concern was an abrupt increase in reported deaths from asthma in New Zealand after 1976 with the mortality rate during 1977-9 being greater than during the previous epidemic. In contrast, asthma mortality had remained relatively stable in the other populations.The new epidemic in New Zealand was investigated and appeared to be real. It could not be explained by changes in the classification of deaths from asthma, inaccuracies in death certification, or changes in diagnostic fashions. The most likely explanation appeared to be related to the management of asthma in New Zealand, and this is being investigated.


Hybrid PET/MRI enables high-spatial resolution, quantitative imaging of amyloid plaques in an Alzheimer's disease mouse model.
The emergence of PET probes for amyloid plaques and neurofibrillary tangles, hallmarks of Alzheimer disease (AD), enables monitoring of pathology in AD mouse models. However, small-animal PET imaging is limited by coarse spatial resolution. We have installed a custom-fabricated PET insert into our small-animal MRI instrument and used PET/MRI hybrid imaging to define regions of amyloid vulnerability in 5xFAD mice. We compared fluorine-18 [18F]-Florbetapir uptake in the 5xFAD brain by dedicated small-animal PET/MRI and PET/CT to validate the quantitative measurement of PET/MRI. Next, we used PET/MRI to define uptake in six brain regions. As expected, uptake was comparable to wild-type in the cerebellum and elevated in the cortex and hippocampus, regions implicated in AD. Interestingly, uptake was highest in the thalamus, a region often overlooked in AD studies. Development of small-animal PET/MRI enables tracking of brain region-specific pathology in mouse models, which may prove invaluable to understanding AD progression and therapeutic development.


Resource utilization with fluticasone propionate and salmeterol in a single inhaler compared with other controller therapies in children with asthma.
To determine resource utilization in controller naïve children diagnosed with asthma receiving initial therapy with fluticasone propionate (FP) and salmeterol (SAL) in a single inhaler (FSC), FP alone, montelukast (MON), inhaled corticosteroid (ICS) + SAL from separate inhalers, or ICS + MON. A retrospective, observational, 18-month (6-month pre-index and 12-month follow-up) database study using medical and pharmacy claims from a 5 million member managed care organization. Multivariate modeling was used to evaluate post-index resource utilization and asthma-related costs. Refill rates during the 12-month follow-up period were compared across cohorts. The study included controller-naïve children (n = 9192) aged 4-17 years with an asthma diagnosis. Children treated with FSC were significantly less likely to receive additional prescriptions for short-acting beta-agonists compared with all other cohorts (p <or= 0.007) and oral corticosteroids compared with the MON, ICS + SAL, and ICS + MON cohorts (p <or= 0.009). Children receiving FSC were also significantly less likely to add another controller therapy compared with children started on FP alone, MON, or ICS + SAL (p <or= 0.001) and to receive care in an emergency department or hospital compared with children receiving ICS + MON (p < 0.001). The number of prescriptions for FSC in the 12-month post-index period was greater (p < 0.05) than the number of ICS claims in the FP, ICS + SAL, and ICS + MON cohorts. Compared with FSC, the adjusted total asthma-related post-index costs were greater (p <or= 0.008) in the MON and ICS + MON cohorts. Although adherence was greater with MON compared with FSC, MON was associated with less favorable clinical outcomes and greater resource utilization and costs. FSC in children is associated with improved clinical outcomes and decreased resource utilization compared with other controller regimens.


Cloning, phylogenetic and expression analysis of two MyoDs in yellowtail kingfish (Seriola lalandi).
Yellowtail kingfish (Seriola lalandi) is a pelagic piscivore distributed circumglobally. Owing to its great market value, the growth mechanism of S. lalandi, including muscle development and growth, is a hot research topic. The myoblast determination protein (MyoD) gene has been shown to play an important role in formation of myoblasts and the function of somites in fish. The open reading frame (ORF) sequences of MyoD1 and MyoD2 in S. lalandi encoded 298 and 263 amino acids possessing three common characteristic domains, respectively, containing a myogenic basic domain, a bHLH domain, and a ser-rich region (helix III). S. lalandi MyoDs shared the highest identity with the MyoDs of S. dumerili. MyoDs are highly expressed in white muscle (P < 0.05) in S. lalandi. The expression level of MyoD1 mRNA was higher than that of MyoD2 mRNA during embryonic and early developmental stages, indicating that the two MyoD isoforms may have different roles in muscle formation. Moreover, the mRNA expression of MyoDs in the brain, pituitary, liver and muscle of endocrine growth axis were analyzed in the various sizes and ages stages. The expression levels of MyoDs in the different sizes and ages of S. lalandi showed that expression of both these genes was particularly high in 400-g fish and 2-year-old fish (P < 0.05). Moreover, the increases in the mRNA expression and plasma levels of growth hormone (GH) and insulin-like growth factor (IGF-I) were accompanied by an increase in mRNA expression of MyoDs, indicating the roles of GH and IGF-I in muscle development and growth of S. lalandi. Overall, the expression profiles of genes associated with muscle development are the first step taken towards deciphering fast growth mechanism in this important Seriola fish.


Allelic expression of deleterious protein-coding variants across human tissues.
Personal exome and genome sequencing provides access to loss-of-function and rare deleterious alleles whose interpretation is expected to provide insight into individual disease burden. However, for each allele, accurate interpretation of its effect will depend on both its penetrance and the trait's expressivity. In this regard, an important factor that can modify the effect of a pathogenic coding allele is its level of expression; a factor which itself characteristically changes across tissues. To better inform the degree to which pathogenic alleles can be modified by expression level across multiple tissues, we have conducted exome, RNA and deep, targeted allele-specific expression (ASE) sequencing in ten tissues obtained from a single individual. By combining such data, we report the impact of rare and common loss-of-function variants on allelic expression exposing stronger allelic bias for rare stop-gain variants and informing the extent to which rare deleterious coding alleles are consistently expressed across tissues. This study demonstrates the potential importance of transcriptome data to the interpretation of pathogenic protein-coding variants.


Ethical management guidelines for the shanghai disease-based biobank network.
The Ethical Management Guidelines for the Shanghai Disease-Based Biobank Network are intended to safeguard the interests of all the participants, to standardize the construction, management, and resource sharing of the Shanghai Disease-based Biobank Network, to promote the development of medical research, and to improve public health and well-being. The guidelines contain seven chapters: General Principles; Informed Consent; Use of Bio-samples from Persons without the Capacity to Consent; Privacy and Confidentiality; Applications of Use of Biological Samples and Data; Intellectual Property and Resource Sharing; and Conflict of Interest.


Impact of the prolymphangiogenic crosstalk in the tumor microenvironment on lymphatic cancer metastasis.
Lymphangiogenesis is a very early step in lymphatic metastasis. It is regulated and promoted not only by the tumor cells themselves, but also by cells of the tumor microenvironment, including cancer associated fibroblasts, mesenchymal stem cells, dendritic cells, or macrophages. Even the extracellular matrix as well as cytokines and growth factors are involved in the process of lymphangiogenesis and metastasis. The cellular and noncellular components influence each other and can be influenced by the tumor cells. The knowledge about mechanisms behind lymphangiogenesis in the tumor microenvironmental crosstalk is growing and offers starting points for new therapeutic approaches.


[Isolation of antibiotic-producing Actinomycetes from soil samples exposed to UV light].
The use of nonroutine means in isolation of microorganisms from natural substrates extended the possibilities of detecting new cultures which often appear to be producers of previously unknown antibiotics. A new procedure for isolating actinomyces of definite groups was developed. It implies preliminary exposure of soil suspensions to UV light. With the use of the procedure, 2539 strains of actinomycetes belonging to different genera were isolated. There was a marked decrease after the irradiation in isolation of cultures belonging to Streptomyces, a genus most widely distributed in nature and studied in detail while isolation of cultures belonging to other genera, promising as sources of novel antibiotics, increased. Micromonospora, Amycolatopsis and Nocardia proved to be the most stable to the effect of UV light. With the use of the procedure it is possible to increase 2-3-fold isolation of cultures belonging to Micromonospora, a genus known as a producer of many antibiotics including those used clinically.


Transpulmonary Expression of Exosomal microRNAs in Idiopathic and Congenital Heart Disease-Related Pulmonary Arterial Hypertension.
Pulmonary artery hypertension (PAH) is a fatal disease characterized by a complex pathogenesis. Exosomes containing microRNAs (miRs) have emerged as a novel biomarker. Transpulmonary exosomal miRs offer valuable insights into pulmonary circulation microenvironments. Hereby, we aimed to explore the potentials of transpulmonary exosomal miRs as differentiating factors between idiopathic PAH and congenital heart disease (CHD)-related PAH. During right heart catheterization, we collected exosomes at pulmonary arteries in 25 patients diagnosed with idiopathic PAH and 20 patients with CHD-related PAH. Next-generation sequencing identified several candidate exosomal miRs. Using quantitative polymerase chain reaction, we validated the expressions of these miRs and revealed significantly elevated expressions of miR-21, miR-139-5p, miR-155-5p, let-7f-5p, miR-328-3p, miR-330-3p, and miR-103a-3p in patients with CHD-related PAH, in contrast to patients with idiopathic PAH. Among these miRs, miR-21 exhibited the highest expression in patients with CHD-related PAH. These findings were further corroborated in an external cohort comprising 10 patients with idiopathic PAH and 8 patients with CHD-related PAH. Using an in vitro flow model simulating the shear stress experienced by pulmonary endothelial cells, we observed a significant upregulation of miR-21. Suppressing miR-21 rescued the shear stress-induced downregulation of the RAS/phosphatidylinositol 3-kinase/protein kinase B pathway, leading to a mitigation of apoptosis. Our study identified a pronounced expression of transpulmonary exosomal miR-21, particularly in patients with CHD-related PAH, through next-generation sequencing analysis. Further investigation is warranted to elucidate the regulatory mechanisms involving miR-21 in the pathophysiology of PAH.


Intercellular communication through gap junctions: a potential role in pharmacomechanical coupling and syncytial tissue contraction in vascular smooth muscle isolated from the human corpus cavernosum.
Kinetic and steady-state protocols were used to examine the effects of disruption of intercellular communication with heptanol, on contractile responses elicited by activation of the alpha 1-adrenergic receptor in human corporal vascular smooth muscle. For the steady-state studies, strips of corporal tissue from 19 patients were submaximally precontracted with phenylephrine (PE) and then relaxed by the cumulative addition of heptanol. Heptanol completely and reversibly relaxed all tissues studied in a concentration-dependent manner. The heptanol concentration response data were then computer fit to the general logistic equation to obtain pEC50 (negative logarithm of the concentration that elicits one-half of the maximal effect) and slope factor values, with Emax (maximal relaxation) set to 100%. The mean pEC50 and slope factor values, respectively, were 2.86 +/- 0.04 and 1.86 +/- 0.17. Furthermore, kinetic studies on corporal tissues from a subset of the patient population (11 patients) revealed that preincubation of tissues with 2 mM heptanol caused a significant decrease in both the rate and magnitude of PE-induced contractions in all tissues studied, without affecting the rate constant for onset of contraction (k(obs)). The present results on intact tissue extend our previous observations on cultured corporal cells, and support the supposition that intercellular communication through gap junctions may play an important role in the initiation, maintenance and modulation of alpha 1-adrenergic contractions in human vascular smooth muscle.


Impact of Oxidative Stress and Protein S-Glutathionylation in Aortic Valve Sclerosis Patients with Overt Atherosclerosis.
Aortic valve sclerosis (AVSc) is characterized by non-uniform thickening of the leaflets without hemodynamic changes. Endothelial dysfunction, also caused by dysregulation of glutathione homeostasis expressed as ratio between its reduced (GSH) and its oxidised form (GSSG), could represent one of the pathogenic triggers of AVSc. We prospectively enrolled 58 patients with overt atherosclerosis and requiring coronary artery bypass grafting (CABG). The incidence of AVSc in the studied population was 50%. The two groups (No-AVSc and AVSc) had similar clinical characteristics. Pre-operatively, AVSc group showed significantly lower GSH/GSSG ratio than No-AVSc group (p = 0.02). Asymmetric dimethylarginine (ADMA) concentration was significantly higher in AVSc patients compared to No-AVSc patients (p < 0.0001). Explanted sclerotic aortic valves presented a significantly increased protein glutathionylation (Pr-SSG) than No-AVSc ones (p = 0.01). In vitro, inhibition of glutathione reductase caused β-actin glutathionylation, activation of histone 2AX, upregulation of α2 smooth muscle actin (ACTA2), downregulation of platelet and endothelial cell adhesion molecule 1 (PECAM1) and cadherin 5 (CDH5). In this study, we showed for the first time that the dysregulation of glutathione homeostasis is associated with AVSc. We found that Pr-SSG is increased in AVSc leaflets and it could lead to EndMT via DNA damage. Further studies are warranted to elucidate the causal role of Pr-SSG in aortic valve degeneration.


CRISPR/Cas as a Genome-Editing Technique in Fruit Tree Breeding.
CRISPR (short for "Clustered Regularly Interspaced Short Palindromic Repeats") is a technology that research scientists use to selectively modify the DNA of living organisms. CRISPR was adapted for use in the laboratory from the naturally occurring genome-editing systems found in bacteria. In this work, we reviewed the methods used to introduce CRISPR/Cas-mediated genome editing into fruit species, as well as the impacts of the application of this technology to activate and knock out target genes in different fruit tree species, including on tree development, yield, fruit quality, and tolerance to biotic and abiotic stresses. The application of this gene-editing technology could allow the development of new generations of fruit crops with improved traits by targeting different genetic segments or even could facilitate the introduction of traits into elite cultivars without changing other traits. However, currently, the scarcity of efficient regeneration and transformation protocols in some species, the fact that many of those procedures are genotype-dependent, and the convenience of segregating the transgenic parts of the CRISPR system represent the main handicaps limiting the potential of genetic editing techniques for fruit trees. Finally, the latest news on the legislation and regulations about the use of plants modified using CRISPR/Cas systems has been also discussed.


Temperature efficiency for dormancy release in apricot varies when applied at different amounts of chill accumulation.
Our aim was to assess the possible differential effect of increasing temperatures due to global warming on dormancy progression in apricot. The effect of a range of chilling temperatures on vegetative and reproductive bud dormancy progression in excised shoots was examined during two seasons. Temperature treatments were applied in different dormant stages to evaluate the possible interaction of date × temperature for dormancy release in apricot. During sampling, chill accumulated in the field ranged from 0 to 49 chill portions (CPs), corresponding to 0-100% of the chilling requirement (CR) of the apricot selection Z505-2. Forcing conditions were applied after a 60-day chill treatment on each sampling date, and rate to budbreak (1/mean time to bud break: MTB(-1) ) was established in vegetative (terminal and lateral) and reproductive buds to determine depth of dormancy. Results showed that the stage of dormancy has a strong influence on the effect of different temperatures on dormancy progression in apricot. For the first time, a non-linear effect of different chilling temperatures during the dormancy cycle in apricot was obtained, especially in the superior range of temperatures traditionally considered to release dormancy. Thus, introduction of this differential effect could help to improve the models to estimate dormancy release in the context of climate change.


Robotics for neuroendovascular intervention: Background and primer.
The simultaneous growth of robotic-assisted surgery and telemedicine in recent years has only been accelerated by the recent coronavirus disease 2019 pandemic. Robotic assistance for neurovascular intervention has garnered significant interest due to opportunities for tele-stroke models of care for remote underserved areas. Lessons learned from medical robots in interventional cardiology and neurosurgery have contributed to incremental but vital advances in medical robotics despite important limitations. In this article, we discuss robot types and their clinical justification and ethics, as well as a general overview on available robots in thoracic/abdominal surgery, neurosurgery, and cardiac electrophysiology. We conclude with current clinical research in neuroendovascular intervention and a perspective on future directions.


Spleen/liver ratio in RES-scintigraphy. A comparison between posterior registration and emission computed tomography.
The relative uptake of the spleen compared with the liver in RES-scintigraphy is of diagnostic significance. The spleen/liver (S/L) ratio from a posterior registration is most often used. The high S/L ratios found in earlier reports could well be explained by splenomegaly. Posterior registration as well as emission computed tomography was performed in 29 patients. In cases with splenomegaly the S/L ratio derived from the posterior registration was about the same as from emission computed tomography. In cases without splenomegaly the S/L ratios found by emission computed tomography were significantly higher and more correct than the values recorded from a posterior registration.


Environmental risk factors in endemic pemphigus foliaceus (fogo selvagem).
An ongoing sero-epidemiological study of the Terena reservation of Limao Verde, known to have a high prevalence and incidence of FS, has revealed important information about this autoimmune disease. During surveillance of this population of approximately 1,200, which began in 1994, we documented 43 FS cases and studied the transition from the normal state to the disease state in several of these individuals. Furthermore, we established that FS patients as well as a large number of normal individuals on the reservation possess anti-dsg1 autoantibodies. The following interesting observations were made: (1) the ectodomain of dsg1 contains epitopes recognized by both autoantibodies and T cells from FS patients; (2) pathogenic anti-dsg1 autoantibodies in FS belong to the IgG4 subclass; (3) nonpathogenic anti-dsg1 autoantibodies of the IgG1 subclass were detected in normal individuals from Limao Verde and in patients in the preclinical stage of the disease; (4) anti-dsg1 autoantibodies from normal individuals and patients in the preclinical stage of FS recognize the EC5 domain of dsg1, whereas pathogenic anti-dsg1 autoantibodies bind the EC1/EC2 domains; (5) houses of FS patients are rustic, with thatched roofs and walls and dirt floors; (6) there was a high frequency of hematophagous insects (bedbugs and kissing bugs) in the houses of FS patients; (7) previous studies revealed that the predominant black fly on this reservation belongs to the species Simunlium nigrimanum. These findings suggest that the environmental antigen(s) triggering the autoimmune response in FS may be linked to exposure to hematophagous insects.


Sox2 is not required for melanomagenesis, melanoma growth and melanoma metastasis in vivo.
Melanoma is a dangerous form of skin cancer derived from the malignant transformation of melanocytes. The transcription factor SOX2 is not expressed in melanocytes, however, it has been shown to be differentially expressed between benign nevi and malignant melanomas and to be essential for melanoma stem cell maintenance and expansion in vitro and in xenograft models. By using a mouse model in which BRafV600E mutation cooperates with Pten loss to induce the development of metastatic melanoma, we investigated if Sox2 is required during the process of melanomagenesis, melanoma growth and metastasis and in the acquisition of resistance to BRAF inhibitors (BRAFi) treatments. We found that deletion of Sox2 specifically in Pten null and BRafV600E-expressing melanocytes did not prevent tumor formation and did not modify the temporal kinetics of melanoma occurrence compared to Sox2 wt mice. In addition, tumor growth was similar between Sox2 wt and Sox2 deleted (del) melanomas. By querying publicly available databases, we did not find statistically significant differences in SOX2 expression levels between benign nevi and melanomas, and analysis on two melanoma patient cohorts confirmed that Sox2 levels did not significantly change between primary and metastatic melanomas. Melanoma cell lines derived from both Sox2 genotypes showed a similar sensitivity to vemurafenib treatment and the same ability to develop vemurafenib resistance in long-term cultures. Development of vemurafenib resistance was not dependent on SOX2 expression also in human melanoma cell lines in vitro. Our findings exclude an oncogenic function for Sox2 during melanoma development and do not support a role for this transcription factor in the acquisition of resistance to BRAFi treatments.


Warfarin-induced tissue necrosis: a case study.
Warfarin-induced tissue necrosis is a rare and serious side effect associated with warfarin treatment. A case study of a patient with warfarin-induced tissue necrosis taken from clinical practice illustrates the importance of timely diagnosis and treatment to avoid the devastating consequences of this adverse drug reaction. Nurse prescribers must be alert to and aware of potential adverse drug reactions that may be caused by any prescribing decision, and should be able to take appropriate action when such an event occurs.


The therapeutic management of gut barrier leaking: the emerging role for mucosal barrier protectors.
Gut barrier is a functional unit organized as a multi-layer system and its multiple functions are crucial for maintaining gut homeostasis. Numerous scientific evidences showed a significant association between gut barrier leaking and gastro-intestinal/extra-intestinal diseases. In this review we focus on the relationship between gut barrier leaking and human health. At the same time we speculate on the possible new role of gut barrier protectors in enhancing and restoring gut barrier physiology with the final goal of promoting gut health. The alteration of the equilibrium in gut barrier leads to the passage of the luminal contents to the underlying tissues and thus into the bloodstream, resulting in the activation of the immune response and in the induction of gut inflammation. This permeability alteration is the basis for the pathogenesis of many diseases, including infectious enterocolitis, inflammatory bowel diseases, irritable bowel syndrome, small intestinal bacterial overgrowth, celiac disease, hepatic fibrosis, food intolerances and also atopic manifestations. Many drugs or compounds used in the treatment of gastrointestinal disease are able to alter the permeability of the intestinal barrier. Recent data highlighted and introduced the possibility of using gelatin tannate, a mucosal barrier protector, for an innovative approach in the management of intestinal diseases, allowing an original therapeutic orientation with the aim of enhancing mucus barrier activity and restoring gut barrier. These results suggest how the mucus layer recovering, beside the gut microbiota modulation, exerted by gut barrier protectors could be a useful weapon to re-establish the physiological intestinal homeostasis after an acute and chronic injury.


Development of the spontaneous activity transients and ongoing cortical activity in human preterm babies.
Recent experimental studies have shown that developing cortex in several animals species, including humans, exhibits spontaneous intermittent activity that is believed to be crucial for the proper wiring of early brain networks. The present study examined the developmental changes in these spontaneous activity transients (SAT) and in other ongoing cortical activities in human preterm babies. Full-band electroencephalography (FbEEG) recordings were obtained from 16 babies at conceptional ages between 32.8 and 40 wk. We examined the SATs and the intervening ongoing cortical activities (inter-SAT; iSAT) with average waveforms, their variance and power, as well as with wavelet-based time-frequency analyses. Our results show, that the low frequency power and the variance of the average waveform of SAT decrease during development. There was a simultaneous increase in the activity at higher frequencies, with most pronounced increase at theta-alpha range (4-9 Hz). In addition to the overall increase, the activity at higher frequencies showed an increased grouping into bursts that are nested in the low frequency (0.5-1 Hz) waves. Analysis of the iSAT epochs showed a developmental increase in power at lower frequencies in quiet sleep. There was an increase in a wide range of higher frequencies (4-16 Hz), whereas the ratio of beta (16-30 Hz) and theta-alpha (4-9 Hz) range activity declined, indicating a preferential increase at theta-alpha range activity. Notably, SAT and iSAT activities remained distinct throughout the development in all measures used in our study. The present results are consistent with the idea that SAT and the other ongoing cortical activities are distinct functional entities. Recognition of these two basic mechanisms in the cortical activity in preterm human babies opens new rational approaches for an evaluation and monitoring of early human brain function.


Automation of slide coverslipping for large tissue sections.
Coverslipping is the process of placing a cover glass or coverslip over a glass slide mounted with a stained tissue specimen without forming air bubbles, which can negatively impact the microscopic examination. While manual coverslipping is still widely used, automated systems have made the process easier and more consistent. Commercially available automated cover-slippers are limited to handling only slides that are 1" x 3", suitable for processing smaller tissue specimens. However, for larger tissue specimens sectioned from organs like the brain, liver, etc., slides can reach sizes up to 6" x 8", exceeding the capabilities of these systems. We present SLIDE PROTEKT, a fully automated large format coverslipping system designed to efficiently coverslip large format slides. This system has multiple zones for slide and coverslip transportation, dispensing of mounting medium, and precise placement of the coverslip without air bubbles. The ability of the system to output quality coverslipped slides was validated by processing 50 large-format brain tissue slides. The results were found to be comparable to manual coverslipping. The system achieved a coverslip placement accuracy of 80% with a mean positional offset that was within a tolerance of ±3 millimeters. Additionally, 75% of the slides had no air bubbles, while the remaining slides had air bubbles that were less than 120 micrometers in size. These results demonstrate the potential impact of SLIDE PROTEKT in the field of histology.


Delivery of a GDNF gene into the substantia nigra after a progressive 6-OHDA lesion maintains functional nigrostriatal connections.
The effects of delivering GDNF via an adenoviral vector (AdGDNF) 1 week after lesioning dopaminergic neurons in the rat substantia nigra (SN) with 6-hydroxydopamine (6-OHDA) were examined. Rats were unilaterally lesioned by injection of 6-OHDA into the striatum, resulting in progressive degeneration of dopaminergic neurons in the SN. One week later, when substantial damage had already occurred, AdGDNF or a control vector harboring beta-galactosidase (AdLacZ) was injected into either the striatum or SN (3.2 x 10(7) PFU/microl in 2 microl). Rats were examined behaviorally with the amphetamine-induced rotation test and for forelimb use for weight-bearing movements. On day 30 postlesion, the extent of nigrostriatal tract degeneration was determined by injecting a retrograde tracer (FluoroGold) bilaterally into the lesioned striatum. Five days later, rats were sacrificed within 2 h of amphetamine injection to examine amphetamine-induced Fos expression in the striatum, a measure of dopaminergic-dependent function in target neurons. AdGDNF injection in the SN rescued dopaminergic neurons in the SN and increased the number of dopaminergic neurons that maintained a connection to the striatum, compared to rats injected with AdLacZ. Further support that these spared SN cells maintained functional connections to the striatum was evidenced by increased Fos expression in striatal target neurons and a decrease in amphetamine-induced rotation. In contrast to the effects observed in rats injected with AdGDNF in the SN, rats injected with AdGDNF in the striatum did not exhibit significant ameliorative effects. This study demonstrates that experimentally increasing levels of GDNF biosynthesis near the dopaminergic neuronal soma is effective in protecting the survival of these neurons and their function even when therapy is begun after 6-OHDA-induced degeneration has commenced. Thus, GDNF gene therapy may ameliorate the consequences of Parkinson's disease through rescuing compromised dopaminergic neurons.


Association of Bone Morphogenetic Protein (BMP)/Smad Signaling Pathway with Fracture Healing and Osteogenic Ability in Senile Osteoporotic Fracture in Humans and Rats.
BACKGROUND To investigate the effect of the BMP/Smad signaling pathway on fracture healing and osteogenic ability in senile osteoporotic fracture on humans and rats. MATERIAL AND METHODS Sixty-two patients and well-matched normal controls were enrolled for clinical observation. A rat model of senile osteoporotic fracture was established. Serum BMP2 and Smad4 levels, as well as alkaline phosphatase (ALP) activity, were detected by ELISA. Fracture healing was observed by X-ray radiography and bone formation was analyzed by micro-CT. RESULTS Serum BMP2 and Smad4 levels in patients with senile osteoporotic fracture were significantly lower than those in normal controls (all P<0.01). BMP2 was highly positively correlated with Smad4 in patients with senile osteoporotic fracture (r=0.738). Compared with patients with low serum BMP2 and Smad4 levels, visual analog scale scores decreased, bone mineral density (BMD) increased, and duration of fracture healing was shortened in patients with high levels (all P<0.05). Compared with the Model group, serum BMP2 and Smad4 levels increased, fracture healing was improved, BMD, trabecular bone volume (TBV), tissue volume (TV), bone volume fraction (BV/TV), mean trabecular thickness (Tb. Th), and mean number of trabecular bone (Tb. N) were increased, and ALP activity increased in the BMP2 overexpression group (all P<0.05), while each index in the NC group showed no statistical difference relative to rats in the Model group (all P>0.05). CONCLUSIONS BMP2 overexpression can promote fracture healing and osteogenic ability in senile osteoporotic fractures through activating the BMP/Smad signaling pathway.


Relation between brain interstitial and systemic glucose concentrations after subarachnoid hemorrhage.
The aim in the present investigation was to study the relation between brain interstitial and systemic blood glucose concentrations during the acute phase after subarachnoid hemorrhage (SAH). The authors also evaluated the effects of insulin administration on local brain energy metabolism. Nineteen patients with spontaneous SAH were prospectively monitored with intracerebral microdialysis (MD). The relation between plasma glucose and MD-measured interstitial brain glucose concentrations as well as the temporal pattern of MD glucose, lactate, pyruvate, glutamate, and glycerol was studied for 7 days after SAH. Using a target plasma glucose concentration of 5-10 mmol/L, the effect of insulin injection was also evaluated. The mean (± SD) correlation coefficient between plasma glucose and MD glucose was 0.27 ± 0.27 (p = 0.0005), with a high degree of individual variation. Microdialysis glucose, the MD/plasma glucose ratio, and MD glutamate concentrations decreased in parallel with a gradual increase in MD pyruvate and MD lactate concentrations. There were no significant changes in the MD L/P ratio or MD glycerol levels. Insulin administration induced a decrease in MD glucose and MD pyruvate. After SAH, there was a positive correlation between plasma and MD glucose concentrations with a high degree of individual variation. A gradual decline in MD glucose and the MD/plasma glucose ratio and an increase in MD pyruvate and MD lactate concentrations during the 1st week after SAH suggest a transition to a hyperglycolytic state with increased cerebral glucose consumption. The administration of insulin was related to a lowering of MD glucose and MD pyruvate, often to low levels even though plasma glucose values remained above 6 mmol/L. After SAH, the administration of insulin could impede the glucose supply of the brain.


Is there still a role for peripheral parenteral nutrition?
Peripheral parenteral nutrition (PPN) is often viewed as the stepchild of parenteral nutrition (PN) infused via a central venous catheter. Anecdotal reports suggest that there has been increased interest in PPN in the United States and even more so in Europe because of improvements in catheter design and infusion technology, both of which have the potential to decrease complications such as infusion phlebitis. PPN, like PN via a central venous catheter, contains dextrose, amino acids, electrolytes, vitamins, and minerals, but in more limited capacity. One of the perceived benefits of PPN is the relative ease in establishing peripheral access, which may prevent delays in establishing nutrition support. PPN is intended for short-term use or supplementation. In most instances, it is used to maintain a previously well-nourished, nonhypermetabolic patient or to serve as a bridge to centrally administered infusions or enteral feedings until more suitable nutrition can be provided. In some cases, inappropriate use may result in infusion phlebitis or inadequate nutrient intake. Conflicting recommendations from various organizations further complicate and confuse prescribers. The intent of this review is to discuss PPN and the challenges its use presents to the practitioner.


[Effect of terrilytin on antifungal antibiotic activity].
The antifungal activity of terrilitine, an enzymatic preparation of microbial origin and its effect on the activity of antifungal polyenic antibiotics and griseofulvine were studied in vitro. It was found with the method of serial dilutions in Sabourand's liquid medium that terrilitine was active against C. albicans and certain dermatophytes. In combination with amphotericin B, amphoglucamine, mycoheptine, levorin, nystatin or griseofulvin it increased the activity of these antibiotics 2-16 times.


Interaction of the Brain-Selective Sulfotransferase SULT4A1 with Other Cytosolic Sulfotransferases: Effects on Protein Expression and Function.
Sulfotransferase (SULT) 4A1 is a brain-selective sulfotransferase-like protein that has recently been shown to be essential for normal neuronal development in mice. In the present study, SULT4A1 was found to colocalize with SULT1A1/3 in human brain neurons. Using immunoprecipitation, SULT4A1 was shown to interact with both SULT1A1 and SULT1A3 when expressed in human cells. Mutation of the conserved dimerization motif located in the C terminus of the sulfotransferases prevented this interaction. Both ectopically expressed and endogenous SULT4A1 decreased SULT1A1/3 protein levels in neuronal cells, and this was also prevented by mutation of the dimerization motif. During differentiation of neuronal SH-SY5Y cells, there was a loss in SULT1A1/3 protein but an increase in SULT4A1 protein. This resulted in an increase in the toxicity of dopamine, a substrate for SULT1A3. Inhibition of SULT4A1 using small interference RNA abrogated the loss in SULT1A1/3 and reversed dopamine toxicity. These results show a reciprocal relationship between SULT4A1 and the other sulfotransferases, suggesting that it may act as a chaperone to control the expression of SULT1A1/3 in neuronal cells. SIGNIFICANCE STATEMENT: The catalytically inactive sulfotransferase (SULT) 4A1 may regulate the function of other SULTs by interacting with them via a conserved dimerization motif. In neuron-like cells, SULT4A1 is able to modulate dopamine toxicity by interacting with SULT1A3, potentially decreasing the metabolism of dopamine.


[Plaut-Vincent's acute necrotizing ulcerative fusospirillum tonsillitis associated to infectious mononucleosis].
We report the case of a 14 years old girl patient with recurrent tonsillitis who had been diagnosed and admitted previously with Plaut-Vincent's angina. Six weeks after leaving the hospital she was assited in Emergencies by an infectious mononucleosis associated to unilateral tonsillar necrotizing ulceration from which a sample was taken to microbiological exam finding the fusospirochaetal complex Borrelia vincenti and Fusobacterium necrophorum. A literature review at the respect of such association and its treatment is performed.


A case of a solid renal mass together with a cystic pancreatic lesion in a 50-year-old patient.
Pancreatic cysts may be incidentally detected in asymptomatic patients evaluated for other clinical manifestations. Microcystic adenomas are particularly rare among pancreatic cyst neoplasms. They are benign lesions and can present as solitary pancreatic tumors or as a radiological manifestation combined with other cystic and tumoral lesions affecting different organs. A 50-year-old man presented with hematuria. A computed tomography scan of the abdomen showed a 9-centimeter renal mass in the left kidney consistent with a renal-cell carcinoma as well as a cystic lesion the head of the pancreas. The histopathological study of the cystic mass, following a computed tomography guided biopsy, showed a microcystic adenoma. Therefore, further studies were performed so as to assess the relationship between both lesions and determine the final diagnosis. Microcystic adenomas are exceedingly rare tumors among pancreatic cysts. The combination of a solid renal mass and a pancreatic cystic lesion should lead to a broad differential diagnosis. Pancreatic magnetic resonance imaging has been proven to be particularly useful in evaluating cystic masses. The presence of walls and internal septations in the pancreatic mass with gadolinium enhancement should raise the possibility of an underlying Von Hippel-Lindau syndrome.


Role of interleukin 17 in inflammation, atherosclerosis, and vascular function in apolipoprotein e-deficient mice.
Interleukin 17A (IL17A) is involved in many inflammatory processes, but its role in atherosclerosis remains controversial. We examined the role of IL17A in mouse and human atherosclerosis. Atherosclerosis was induced in apolipoprotein E (ApoE)(-/-) and IL17A/ApoE(-/-) mice using high-fat feeding, angiotensin II infusion, or partial carotid ligation. In ApoE(-/-) mice, 3 months of high-fat diet induced interferon-γ production by splenic lymphocytes, and this was abrogated in IL17A/ApoE(-/-) mice. IL17A/ApoE(-/-) mice had reduced aortic superoxide production, increased aortic nitric oxide levels, decreased aortic leukocyte and dendritic cell infiltration, and reduced weight gain after a high-fat diet compared with ApoE(-/-) mice. Despite these favorable effects, IL17A deficiency did not affect aortic plaque burden after a high-fat diet or angiotensin II infusion. In a partial carotid ligation model, IL17A deficiency did not affect percentage of stenosis but reduced outward remodeling. In this model, neutralization of the related isoform, IL17F, in IL17A/ApoE(-/-) mice did not alter atherosclerosis. Finally, there was no correlation between IL17A levels and carotid intima-media thickness in humans. IL17 contributes to vascular and systemic inflammation in experimental atherosclerosis but does not alter plaque burden. The changes in plaque composition caused by IL17 might modulate plaque stability.


The electrocardiographic response of females to centrifuge +Gz stress.
Women continue to expand their participation in all areas of aviation, including flying high performance fighter aircraft. Acceleration (+Gz) stress is unique to fighter aviation, therefore it is important to thoroughly understand the electrocardiographic (ECG) response to +Gz stress since it reflects a portion of the cardiovascular +Gz tolerance. A comparison of the ECG response to centrifuge +Gz stress between 685 men and 94 women was made from data existing within a centrifuge data repository. The frequency of occurrence of specific types of atrial, ventricular, and the other most frequently observed ECG changes to +Gz stress were compared for females and males. Females had less atrial ectopy; essentially equivalent premature ventricular contractions (PVC's), multiformed PVC's, paired PVC's; less frequent ventricular and supraventricular tachycardia; and more frequent PVC's in a bigeminal pattern and QRS on T PVC's. Sinus arrhythmia, sinus bradycardia, and increased T-waves post +Gz stress were more frequent in males, with ectopic atrial rhythm and atrioventricular dissociation essentially equivalent in males and females. Although few women have participated in either simulated aerial combat maneuver type centrifuge profiles or centrifuge high-G training, they have shown similar ECG changes including conduction and rhythm disturbances infrequently seen in males, such as +Gz-induced right bundle branch block and high-G bradycardia. Based on the currently available ECG response data, women have no demonstrated unique susceptibility to +Gz-induced ECG changes. Therefore, no contraindication exists to initiating additional acceleration research to fully evaluate women's tolerance to the more stressful, higher levels of +Gz stress.


[Schizophrenia after forty and its relation with estrogens].
There has been a lot of interest in the many aspects of women's mental health especially after Kraepelin's description of gender differences in 1896 and the implication of gonad hormones in explaining these differences. Studies on the effects of hormonal changes in mental health have mainly been focused on the various phases of the menstrual cycle, pregnancy and postpartum period; however, there is little research regarding menopause. During this period women are at risk of developing a new schizophrenic illness the so-called 'second peak'. Research has shown that estrogen acts as a protective factor due to its anti-dopaminergic properties, thus providing an explanation for the risk increase of a new psychotic disorder during menopause. This review article highlights the importance of a clear understanding of this phase of life in patients suffering from or who present a risk of developing schizophrenia.


The predictors of access to health services for people with disabilities: A cross sectional study in Iranian context.
Background: In developing countries, people with disabilities (PWD) are more likely to have unequitable access to health care services than their counterparts without disabilities. Access to health care is a multidimensional concept and PWD experience various barriers to use health care. This quantitative study explored the predictors and determents of access to health care for PWD in an Iranian context. Methods: Data were collected from a cross sectional study conducted in Tehran in 2017. A total of 403 adults with physical and/or intellectual disabilities were selected using census method. The data on PWD were collected from 14 rehabilitation centers affiliated to Welfare Organization and Red Crescent Organization. The self-report World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) was used to collect data on disability status. T test, ANOVA, and multiple linear regressions were used to determine factors influencing access to health care for PWD. Significance level was set at 5%. Also, SPSS software version 20.0 was used for data analysis. Results: The mean of access to health care among people with intellectual disabilities (mean: 61.77, 95% confidence interval (CI):59.20, 64.35) was significantly lower than their counterparts with physical disabilities (Mean: 67.97, 95% CI: 65.26, 70.69). The results of multiple linear regression analysis showed that in the affordability dimension, type of disability, marital status, and supplemental health insurance could predict access to health services for PWD. In availability dimension, only location predicted the outcome variable significantly. Also, location and type of disability were considered to be potential predictors of access to health services in acceptability dimension. Conclusion: The results indicate that various factors can limit access to health services for PWD. To achieve universal health coverage, vulnerable groups and their needs should be identified to increase equitable access to health care services. Also, the health care system should pay more attention to demographic differences when planning and providing affordable and acceptable health care for PWD. Finally, the role of the government as the heath stewardship is vital to promote health care access for PWD in Iran.


Cardiovascular disease prevention and treatment in patients with human immunodeficiency virus.
Highly active antiretroviral therapy has dramatically improved the quality of life and life expectancy of patients with human immunodeficiency virus. However, the prolonged use of HAART leads to severe metabolic adverse events. Both HIV infection and HAART can cause changes in lipid and glucose metabolism as well as elevation of blood pressure, promoting the development of atherosclerosis. Cardiovascular diseases have become a major cause of mortality among HIV-infected subjects who respond well to antiretroviral therapy. Nevertheless, a proper lifestyle and pharmacologic intervention can improve cardiovascular risk factors in the HIV-treated population and significantly reduce healthcare investments in the treatment of future cardiovascular complications in this population. In this review we summarize the current knowledge of CVD prevention and treatment in HIV patients.


[Experiences with the ELISA at the serodiagnosis of infections with viruses of the herpes-group (author's transl)].
A commercially available and standardized enzymeimmunoassay was applied at 737 patients in order to diagnose immunologically a recent or reactivated infection with Herpes simplex, Herpes zoster V. and/or Cytomegalovirus. During this course of investigation rises or falls of the titer of virus specific IgG between the range of 1 : 320, 1 : 1280 and greater than or equal to 1 : 5120 turned out to mark mainly recent infections with one of the three herpes viruses. Statistical evaluations of the tests performed proved the elevated sensitivity of the IgG-ELISA as compared with the complement binding reaction. The range of specificity of the two tests was similar. A significant titer of IgM (greater than or equal to 1 : 40) as a marker of a recent infection with one of the three herpes viruses could only be demonstrated at 13-19% of the cases of recent herpes viral infection. Controls of the sera with a significant virus specific IgM-titer in the ELISA by sucrose gradient centrifugation or with a reference-ELISA confirmed their virus specific mu-specificity in almost all of the cases (96%).


Efavirenz pharmacokinetics during the third trimester of pregnancy and postpartum.
The impact of pregnancy on efavirenz (EFV) pharmacokinetics is unknown. International Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is an on-going, prospective, nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving 600 mg EFV once daily as part of combination antiretroviral therapy. Intensive steady-state 24-hour blood sampling was performed during the third trimester and at 6-12 weeks postpartum. Maternal and umbilical cord blood samples were drawn at delivery. Pharmacokinetics targets were the estimated 10th percentile EFV area under the curve (AUC) in nonpregnant historical controls (40.0 mcg·hr(-1)·mL(-1)) and a trough concentration of 1 mcg/mL. Twenty-five women were enrolled during the third trimester: median (range) age was 29.3 (18.9-42.9) years, weight 69.0 (40-130) kg, and gestational age 32.9 (30.1-38.7) weeks. Median (range) EFV AUC(0-24), C(max), and C(24 hours) were 55.4 mcg·hr(-1)·mL(-1) (13.5-220.3), 5.4 mcg/mL (1.9-12.2), and 1.6 mcg/mL (0.23-8.13), respectively. EFV AUC and C(max) did not differ during pregnancy and postpartum but C(24 hours) was lower during the third trimester (1.6 vs. 2.1 mcg/mL, P = 0.01). During the third trimester, 5 of 25 (20%) women had an EFV AUC below the target and 3 of 25 (12%) had a trough concentration below 1 mcg/mL. EFV cord blood/maternal concentration ratio was 0.49 (0.37-0.74). All women had a HIV-1 RNA viral load less than 400 copies per milliliter at delivery and 19 (76%) had a viral load below 50 copies per milliliter. One child was perinatally HIV infected. Three women were exposed to EFV throughout the first 6 weeks of pregnancy. EFV was well tolerated, and among the 25 infants, no congenital anomalies or newborn complications were reported. Changes in EFV pharmacokinetics during pregnancy compared with postpartum are not sufficiently large enough to warrant a dose adjustment during pregnancy.


Clay aquitards as archives of holocene paleoclimate: delta18O and thermal profiling.
Paleoclimatic conditions in the Holocene were reconstructed from a detailed vertical profile of pore water delta(18)O and a series of downhole thermal profiles at a thick, hydrogeologically simple, aquitard research site in the Northern Great Plains of Saskatchewan. Reconstructions were obtained using the theory of one-dimensional diffusive transport and an empirical Bayesian inversion technique. Inversion of the delta(18)O profile shows that input signal consists of a sudden increase of +6 per thousand (corresponding to a temperature increase of about 18 degrees C) at about 12,000 years before present (BP), after which no measurable change in delta(18)O is apparent to present day. This research shows, at this location, that there is no evidence of large amplitude temperature shifts in the Holocene and supports the commonly used assumption in ground water studies of constant atmospheric delta(18)O values throughout the Holocene. Inversion of the temperature profiles suggests the ground surface temperature increased primarily in the last half of the 20th century, with a peak temperature (about 3 degrees C) circa 1990. For both profiles, the ability to resolve historical variability decays rapidly with time. For the temperature profiles, the decay in resolution precluded the development of reliable estimates of climatic conditions prior to about 1950 and, in the case of the delta(18)O profile, it prevented the precise definition of climate changes (e.g., Hypsithermal and Little Ice Age) in the Holocene.


Case Report: Cardiovascular Manifestations Due to Flea-Borne Typhus.
Flea-borne typhus is a vector-borne disease caused by Rickettsia typhi that occurs worldwide, except in Antarctica. In the United States, most cases are restricted to California, Hawaii, and Texas. The syndrome is characterized by nonspecific signs and symptoms: fever, headache, rash, arthralgia, cough, hepatosplenomegaly, diarrhea, and abdominal pain. Although flea-borne typhus can cause pulmonary, neurological, and renal complications, the cardiovascular system is rarely affected. We present a case of endocarditis resulting from flea-borne typhus diagnosed by blood microbial cell-free DNA testing that required valve replacement and antibiotic therapy for 6 months. In addition, we review 20 cases of presumed and confirmed cardiovascular manifestations resulting from flea-borne typhus in the literature.


Challenges of Organizing Mission Surgery in Resource Limited Environments.
Interest in global burden of disease that can be surgically treated is on the rise, and plastic surgeons, with a wide scope of practice, have the tools that make them integral in providing much of the needed surgical support in the world. Since the 1950 s, plastic surgeons have been closely involved in volunteer surgery, and it is through the success and growth of organizations such as Interplast and Operation Smile that we are able to take part in the current paradigm shift to local empowerment and self-sufficiency instead of service delivery alone. This kind of growth started with medical mission work that fostered international partnerships and that remain an important aspect of addressing the unmet surgical burden of disease. Building a mission comprised of an international team of volunteers that travels to a resource-limited environment and provides top-quality surgical care is not without challenges. The aim of this article is to discuss some of these challenges and how they might be overcome.


Enhanced autoimmune arthritis in IFN-gamma receptor-deficient mice is conditioned by mycobacteria in Freund's adjuvant and by increased expansion of Mac-1+ myeloid cells.
Induction of experimental autoimmune diseases often relies on immunization with the organ-specific autoantigens in CFA, which contains heat-killed mycobacteria. In several of these models, including collagen-induced arthritis, endogenous IFN-gamma acts as a disease-limiting factor in the pathogenesis of the disease. Here we show that in collagen-induced arthritis the protective effect of IFN-gamma depends on the presence of mycobacteria in the adjuvant. Omission of mycobacteria inverts the role of endogenous IFN-gamma to a disease-promoting factor. Thus, the mycobacterial component of CFA opens a pathway by which endogenous IFN-gamma exerts a protective effect that supersedes its otherwise disease-promoting effect. Extramedullary hemopoiesis and expansion of the Mac-1+ cell population accompanied the accelerated and more severe disease course in the IFN-gamma receptor knockout mice immunized with CFA. Treatment of such mice with Abs against the myelopoietic cytokines IL-6 or IL-12 inhibited both disease development and the expansion of the Mac-1+ population. We postulate that mycobacteria in CFA stimulate the expansion of the Mac-1+ cell population by a hemopoietic process that is restrained by endogenous IFN-gamma. These results have important implications for the validity of animal models of autoimmunity to study the pathogenesis and to evaluate cytokine-based therapy of autoimmune diseases.


The effects of the light:dark cycle and sympathetically-active drugs on pineal N-acetyltransferase activity and melatonin content in the Richardson's ground squirrel, Spermophilus richardsonii.
When adult Richardson's ground squirrels, born in the wild, are kept in the laboratory under light:dark cycles of 14:10 (lights out at 2000 h), pineal N-acetyltransferase (NAT) activity and melatonin levels begin to rise shortly after lights out; both reach peak levels by 4 h into the dark phase. The rise in pineal NAT activity is partially blocked by phentolamine, an alpha-receptor blocker, and totally blocked by propranolol, a beta-receptor blocker. Phentolamine had no inhibitory influence on the nocturnal rise in pineal melatonin while propranolol partially prevented the increase in melatonin. Isoproterenol, a beta-receptor agonist, seemed to stimulate both NAT activity and the melatonin content in the pineal gland of the Richardson's ground squirrel. In the final study adult squirrels were kept in either 10 h of darkness at night or they were exposed to light (intensity = 370-400 ftc) during the normal period of darkness. Groups of squirrels were killed at 2000, 2400, 0200, 0400 and 0800 h. Darkness was associated with a marked rise in both pineal NAT activity and melatonin content. However, even when the squirrels were kept in light during the normal dark period, the activity of the acetylating enzyme and melatonin levels rose greatly and reached peak values at 0400 h.


Why is it so difficult to use gemtuzumab ozogamicin?
In this issue of Blood, Petersdorf et al report negative results of the phase 3 study designed by the Southwest Oncology Group (SWOG), which tested the addition of gemtuzumab ozogamicin (GO) to a 317 regimen in a randomized fashion in adult patients newly diagnosed with acute myeloid leukemia (AML) who are younger than 60 years. Also in this issue of Blood, Rowe and Löwenberg discuss results of this study in the context of 4 other controlled studies (1 negative and 1 positive in a predefined subset of patients, and 2 positive) performed during the same period in Europe.


Genetic heterogeneity of uncharacterized childhood autoimmune diseases with lymphoproliferation.
Autoimmune diseases in children are rare and can be difficult to diagnose. Single causative genes have been identified for some pediatric autoimmune diseases. Such orphan diseases may not be diagnosed properly due to the variability of patients' phenotypes. Guidelines for the diagnostic process need to be developed. Fifteen patients with uncharacterized childhood autoimmune diseases with lymphoproliferation that had negative testing for autoimmune lymphoproliferative syndrome were subjected to whole-exome sequencing to identify genes associated with these conditions. Five causative genes, CTLA4, STAT3, TNFAIP3, IKZF1, and PSTPIP1, were identified. These genes should be considered as candidates for uncharacterized childhood autoimmune diseases with lymphoproliferation.


[Loco-regional thrombolysis in deep venous thrombosis].
Anticoagulation, by means of heparin and warfarin is, till now, the most common treatment in deep venous thrombosis. Although thrombolytic agents have been available for over 10 years, their use remains quite low, ranging from 15 to 20% of deep venous thromboses. This is due to the relatively high incidence of contraindications as well as to the fact that the potential advantages versus heparin are diminished by the increased bleeding risk and by the potential risk of pulmonary embolism (migration of partially lysed thrombi). Following the example of the "triple armed therapy" proposed by Rosenthal for the treatment of pulmonary embolism, we will evaluate if loco-regional thrombolysis, with the catheter wedged against the thrombus, associated with a temporary vena cava interruption by means of an intraluminal filter, can achieve a better lysis of the thrombus without pulmonary embolism. In our Unit 18 patients affected by proximal deep venous thrombosis were submitted to thrombolytic therapy, 6 to systemic treatment, 3 to local treatment and the last 9 to loco-regional thrombolysis, using recombinant tissue-type Plasminogen Activator. We obtained 10 complete lyses, 1 with systemic and 9 with loco-regional treatment. There were no major complications. Thus, we think that venous loco-regional thrombolysis with rt-PA at lower doses, associated with temporary caval interruption, can probably achieve a better lysis than systemic treatment without risk of pulmonary embolism and with a very low haemorrhagic risk, as in arterial loco-regional thrombolysis. Furthermore, loco-regional thrombolysis, by means of a faster thrombus dissolution, could better prevent post-phlebitic syndrome.


Studies on the isopropylbenzene 2,3-dioxygenase and the 3-isopropylcatechol 2,3-dioxygenase genes encoded by the linear plasmid of Rhodococcus erythropolis BD2.
The enzymes responsible for the degradation of isopropylbenzene (IPB) and co-oxidation of trichloroethene (TCE) by Rhodococcus erythropolis BD2 are encoded by the linear plasmid pBD2. Fragments containing IPB catabolic genes were cloned from pBD2 and the nucleotide sequence was determined. By means of database searches and expression of the cloned genes in recombinant strains, we identified five clustered genes, ipbA1A2A3A4C, which encode the three components of the IPB 2,3-dioxygenase system, reductaseIPB (ipbA4), ferredoxinIPB (ipbA3) and the two subunits of the terminal dioxygenase (ipbA1A2), as well as the 3-isopropylcatechol (IPC) 2,3-dioxygenase (ipbC). The protein sequences deduced from the ipbA1A2A3A4C gene cluster exhibited significant homology with the corresponding proteins of analogous degradative pathways in Gram-negative and Gram-positive bacteria, but the gene order differed from most of them. IPB 2,3-dioxygenase and 3-IPC 2,3-dioxygenase could both be expressed in Escherichia coli, but the IPB 2,3-dioxygenase activities were too low to be detected by polarographic and TCE degradative means. However, inhibitor studies with the R. erythropolis BD2 wild-type are in accordance with the involvement of the IPB 2,3-dioxygenase in TCE oxidation.


Qualitative study of patients' perceptions of the quality of care for depression in general practice.
Research into quality of care in primary mental health care has largely focused on the role of the general practitioner (GP) in the detection and management of patients' problems. To explore depressed patients' perceptions of the quality of care received from GPs. Qualitative study using semi-structured interviews. General practices in Greater Manchester. Purposive sampling and semi-structured interviewing of 27 patients who had received care from 10 GPs for depression. Quality of care in depression depends on good communication between the doctor and the patient, but patients who are depressed often have difficulty in discussing their problems with doctors. They are also unlikely to be active in seeking care; for example, in making follow-up appointments, especially when they are uncertain that depression is a legitimate reason for seeing the doctor. Patients sometimes accept care that does not meet professional standards, either because of low expectations of what the National Health Service (NHS) can provide, or because of low self-worth associated with their problem. The depressed person may feel that they do not deserve to take up the doctor's time, or that it is not possible for doctors to listen to them and understand how they feel. Doctors need to be active in providing care that meets professional standards. We advocate a model of care in which patients with depression are followed up systematically.


Serum-blocking factors versus specific cellular tolerance in long-term survival of rat heart allografts.
Long-term survival of Ag-B compatible rat heart allografts was obtained by short-term treatment of the recipients with antilymphocytic serum (ALS). Graft survival apparently was based on a specific change in the hosts rather than on persistent nonspecific effects of ALS. The hosts were not fully tolerant in that they were able to reject secondary skin allografts from the heart donor strain, although in a delayed fashion. The long-surviving heart allografts retained their immunogenicity as they were rejected when retransplanted to new hosts. The passive transfer of serum from long-term heart graft acceptors to new hosts receiving fresh allografts delayed rejection by several days. This effect was seen only with the serum from long-term acceptors suggesting that serum-blocking factors were involved in long-term survival of the heart allografts. However, the ability of adoptively transferred lymphoid cells to break tolerance to a heart allograft residing in a classically tolerant host was tested. In contrast to normal lymphoid cells, cells from the long-term acceptors were unable to break tolerance, suggesting that a specific cellular tolerance had been induced in this cell population. Moreover, a serum from the long-term acceptors failed to block the breakage of tolerance by normal lymphoid cells.


POPFNN-CRI(S): pseudo outer product based fuzzy neural network using the compositional rule of inference and singleton fuzzifier.
A pseudo-outer product based fuzzy neural network using the compositional rule of inference and singleton fuzzifier [POPFNN-CRI(S)] is proposed in this paper. The correspondence of each layer in the proposed POPFNN-CRI(S) to the compositional rule of inference using standard T-norm and fuzzy relation gives it a strong theoretical foundation. The proposed POPFNN-CRI(S) training consists of two phases; namely: the fuzzy membership derivation phase using the novel fuzzy Kohonen partition (FKP) and pseudo Kohonen partition (PFKP) algorithms, and the rule identification phase using the novel one-pass POP learning algorithm. The proposed two-phase learning process effectively constructs the membership functions and identifies the fuzzy rules. Extensive experimental results based on the classification performance of the POPFNN-CRI(S) using the Anderson's Iris data are presented for discussion. Results show that the POPFNN-CRI(S) has taken only 15 training iterations and misclassify only three out of all the 150 patterns in the Anderson's Iris data.


A Multilayer Perceptron Neural Network Model to Classify Hypertension in Adolescents Using Anthropometric Measurements: A Cross-Sectional Study in Sarawak, Malaysia.
This study outlines and developed a multilayer perceptron (MLP) neural network model for adolescent hypertension classification focusing on the use of simple anthropometric and sociodemographic data collected from a cross-sectional research study in Sarawak, Malaysia. Among the 2,461 data collected, 741 were hypertensive (30.1%) and 1720 were normal (69.9%). During the data gathering process, eleven anthropometric measurements and sociodemographic data were collected. The variable selection procedure in the methodology proposed selected five parameters: weight, weight-to-height ratio (WHtR), age, sex, and ethnicity, as the input of the network model. The developed MLP model with a single hidden layer of 50 hidden neurons managed to achieve a sensitivity of 0.41, specificity of 0.91, precision of 0.65, F-score of 0.50, accuracy of 0.76, and Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) of 0.75 using the imbalanced data set. Analyzing the performance metrics obtained from the training, validation and testing data sets show that the developed network model is well-generalized. Using Bayes' Theorem, an adolescent classified as hypertensive using this created model has a 66.2% likelihood of having hypertension in the Sarawak adolescent population, which has a hypertension prevalence of 30.1%. When the prevalence of hypertension in the Sarawak population was increased to 50%, the developed model could predict an adolescent having hypertension with an 82.0% chance, whereas when the prevalence of hypertension was reduced to 10%, the developed model could only predict true positive hypertension with a 33.6% chance. With the sensitivity of the model increasing to 65% and 90% while retaining a specificity of 91%, the true positivity of an adolescent being hypertension would be 75.7% and 81.2%, respectively, according to Bayes' Theorem. The findings show that simple anthropometric measurements paired with sociodemographic data are feasible to be used to classify hypertension in adolescents using the developed MLP model in Sarawak adolescent population with modest hypertension prevalence. However, a model with higher sensitivity and specificity is required for better positive hypertension predictive value when the prevalence is low. We conclude that the developed classification model could serve as a quick and easy preliminary warning tool for screening high-risk adolescents of developing hypertension.


The sympathetic nervous system and obstructive sleep apnea: implications for hypertension.
Patients with obstructive sleep apnea experience repetitive apneic events during sleep, with consequent hypoxia and hypercapnia. Hypoxia and hypercapnia, acting via the chemoreflexes, elicit increases in sympathetic nerve activity. The sympathetic responses to hypoxia and hypercapnia are potentiated during apnea, when the sympathetic inhibitory influence of the thoracic afferent nerves is eliminated. As a consequence of the sympathetic vasoconstrictor response to apneic events, patients with obstructive sleep apnea manifest marked increases in blood pressure during sleep, especially evident at the end of the apnea. The increases in sympathetic activity and blood pressure during sleep in these patients appear to carry over into the daytime such that patients with sleep apnea have an increased prevalence of hypertension and high levels of sympathetic nerve activity. Although the mechanism underlying the persistent elevation in sympathetic activity during the daytime is not known, it is likely that the increased sympathetic drive is implicated in the higher daytime blood pressures in these patients. Whereas patients with sleep apnea have an increased prevalence of hypertension, in those patients with sleep apnea who do have hypertension, the sympathetic response to apneic events may be potentiated. This may be secondary to impaired baroreflex sensitivity, since the baroreflexes exert an inhibitory influence on the chemoreflex responses to hypoxia. Treatment with continuous positive airway pressure results in an acute reduction in blood pressure and sympathetic activity during sleep. Prolonged effective treatment of sleep apnea may also reduce daytime blood pressure levels. This review examines the physiology of the chemoreflex responses to hypoxia, hypercapnia and apnea, as well as the physiologic responses to sleep in normal humans. These physiologic responses are compared with the pathophysiologic sympathetic and hemodynamic responses that characterize obstructive sleep apnea. Increases in sympathetic activity and blood pressure in patients with obstructive sleep apnea may play a role in linking sleep apnea to hypertension and cardiac and vascular events.


Storage capacity diverges with synaptic efficiency in an associative memory model with synaptic delay and pruning.
It is known that storage capacity per synapse increases by synaptic pruning in the case of a correlation-type associative memory model. However, the storage capacity of the entire network then decreases. To overcome this difficulty, we propose decreasing the connectivity while keeping the total number of synapses constant by introducing delayed synapses. In this paper, a discrete synchronous-type model with both delayed synapses and their prunings is discussed as a concrete example of the proposal. First, we explain the Yanai-Kim theory by employing statistical neurodynamics. This theory involves macrodynamical equations for the dynamics of a network with serial delay elements. Next, considering the translational symmetry of the explained equations, we rederive macroscopic steady-state equations of the model by using the discrete Fourier transformation. The storage capacities are analyzed quantitatively. Furthermore, two types of synaptic prunings are treated analytically: random pruning and systematic pruning. As a result, it becomes clear that in both prunings, the storage capacity increases as the length of delay increases and the connectivity of the synapses decreases when the total number of synapses is constant. Moreover, an interesting fact becomes clear: the storage capacity asymptotically approaches 2/pi due to random pruning. In contrast, the storage capacity diverges in proportion to the logarithm of the length of delay by systematic pruning and the proportion constant is 4/pi. These results theoretically support the significance of pruning following an overgrowth of synapses in the brain and may suggest that the brain prefers to store dynamic attractors such as sequences and limit cycles rather than equilibrium states.


Thermal conductivity measurements of laser crystals by infrared thermography. Application to Nd:doped crystals.
We present a thermal conductivity measurement method for laser crystals based on thermal mapping of the crystal face by an infrared camera. Those measurements are performed under end-pumping of the laser crystal and during laser operation. The calculation of the fraction of pump power converted into heat is therefore simplified, and it is possible to link easily the temperature in the crystal to the thermal conductivity. We demonstrate the efficiency of this measurement method with a Nd:YAG crystal, before using it to compare Nd:YVO(4) and Nd:GdVO(4) crystals.


Large-scale pre-diagnosis study of fetal RHD genotyping by PCR on plasma DNA from RhD-negative pregnant women.
The routine prenatal determination of fetal RhD blood group would be very useful in the management of pregnancies in RhD-negative women, as up to 40% of these pregnancies bear a RhD-negative fetus. The fetal DNA present in maternal plasma offers an opportunity for risk-free prenatal diagnosis. This study focused on the feasibility and accuracy of large-scale RhD fetal diagnosis in non-immunized and anti-D immunized RhD-negative women. Plasma DNA was extracted from 893 RhD-negative pregnant women and amplified in exons 7 and 10 of the RHD gene using conventional and real-time PCR. The results were then compared with the RHD fetal genotype determined on amniotic cells and/or the RhD phenotype of the red blood cells of the infants at birth. After exclusion of 42 samples from women exhibiting a nonfunctional or rearranged RHD gene, fetal RhD status was predicted with a 99.5% accuracy. A strategy is also proposed to avoid the small number of false-positive and -negative results. Fetal RHD genotyping from maternal plasma DNA in different clinical situations may be used with confidence.


[Mexican guidelines on the diagnosis and treatment of urticaria].
Urticaria is a disease that a fifth of the population shallsuffer once in a lifetime. Recent clinical guidelines have proposed some fundamental changes in the diagnosis and treatment of urticaria, making the development of a national, multidisciplinary guideline, with wide acceptability among different professional groups -both specialists and primary health care workers-, necessary in Mexico. Internationally recognized tools for guidelinedevelopment were used. An interdisciplinary group of clinical experts (some of them knowledgeable in methodology of guideline development) determined the objectives and scope of the Evidence Based Clinical Practice Guideline with SCOPE. It was decided to adapt and transculturize international guidelines on the diagnosis and treatment of urticaria. With AGREE-II three high-quality guidelines (Zuberbier 2014, Sánchez-Borges 2012, Powell 2007) were selected to function as basic guidelines (BG). A set of Clinical Questions was formulated that lead to recommendations/suggestions, based on these BG, taking into account the cultural and economic background of Mexico, according to GRADE recommendation development. By a formal process of discussion and voting during several working-sessions, experts and first level healthcare physicians determined the wording of the final guideline, taking particularly care of developing a document, adjusted to the reality, values and preferences of the Mexican patients. The use of oral second generation, non-sedating antihistamines as first line treatment is emphasized. This document is an Evidence Based Clinical Practice Guideline for the diagnosis and treatment of acute and chronic urticaria, based on three, high quality, international guidelines. It was developed by a multidisciplinary group. Tables and algorithms make the guideline user-friendly for both, first line health care physicians and specialists.


Tumor length assessed by miniprobe endosonography can predict the survival of the advanced esophageal squamous cell carcinoma with stricture receiving concurrent chemoradiation.
There were tumor strictures commonly encountered in the esophageal squamous cell carcinoma (ESCC) to limit the conventional echoendoscope for exact tumor staging and size measurements. This study evaluated the role of miniprobe endosonography (EUS) to predict the survival of ESCC patients after concurrent chemoradiation therapy (CCRT). This study prospectively enrolled ESCC patients to receive high-frequency miniprobe EUS for the assessments of the tumor size and tumor-node-metastasis (TNM) stage. For the patients defined with advanced stages to receive CCRT as initial therapy, the tumor size parameters assessed by EUS were analyzed for their correlation with the treatment response and the patients' survivals. Fifty-four patients, >96% with advanced TNM stage III or IV, were enrolled with a medium follow-up of 320.5 days. Almost all of the 54 cases had partial or complete stricture of the esophageal lumens due to the tumor obstructions at enrollment. The overall median survival was 18.6 months, and the 1- and the 2-year survival rates were 64.9 and 45.2%, respectively. Patients with initial tumor length <6 cm assessed by the pre-CCRT EUS had a better survival than those with length ≥6 cm (median survival: >56.5 months vs. 11.5 months, P= 0.006). The patients with initial tumor length <6 cm had a higher rate of downstage than those with tumor length ≥6 cm after the first course of CCRT (80.0% vs. 16.7%, P= 0.035). Multivariate Cox regression confirmed the initial tumor length (hazard ratio [HR]= 1.21, P= 0.034) as well as the presence of distal metastasis are both independent predictors of the survival in ESCC patients receiving CCRT. For the ESCC patients, commonly with tumor stricture, the miniprobe EUS to assess tumor length before CCRT can predict the treatment response and the survivals.


An integration engineering framework for machine learning in healthcare.
Machine Learning offers opportunities to improve patient outcomes, team performance, and reduce healthcare costs. Yet only a small fraction of all Machine Learning models for health care have been successfully integrated into the clinical space. There are no current guidelines for clinical model integration, leading to waste, unnecessary costs, patient harm, and decreases in efficiency when improperly implemented. Systems engineering is widely used in industry to achieve an integrated system of systems through an interprofessional collaborative approach to system design, development, and integration. We propose a framework based on systems engineering to guide the development and integration of Machine Learning models in healthcare. Applied systems engineering, software engineering and health care Machine Learning software development practices were reviewed and critically appraised to establish an understanding of limitations and challenges within these domains. Principles of systems engineering were used to develop solutions to address the identified problems. The framework was then harmonized with the Machine Learning software development process to create a systems engineering-based Machine Learning software development approach in the healthcare domain. We present an integration framework for healthcare Artificial Intelligence that considers the entirety of this system of systems. Our proposed framework utilizes a combined software and integration engineering approach and consists of four phases: (1) Inception, (2) Preparation, (3) Development, and (4) Integration. During each phase, we present specific elements for consideration in each of the three domains of integration: The Human, The Technical System, and The Environment. There are also elements that are considered in the interactions between these domains. Clinical models are technical systems that need to be integrated into the existing system of systems in health care. A systems engineering approach to integration ensures appropriate elements are considered at each stage of model design to facilitate model integration. Our proposed framework is based on principles of systems engineering and can serve as a guide for model development, increasing the likelihood of successful Machine Learning translation and integration.


Relationship Between Confidence, Gender, and Career Choice in Internal Medicine.
Understanding factors in internal medicine (IM) resident career choice may reveal important needed interventions for recruitment and diversity in IM primary care and its subspecialties. Self-reported learner confidence is higher in men than in women in certain areas of practicing medicine, but has never been explored as a factor in career choice. The purpose of this study is to elucidate associations between confidence, gender, and career choice. IM residents completed a 31-item survey rating confidence in procedural, clinical, and communication skills on a 9-point Likert scale. Residents also reported anticipated career choice and rated influence of factors. Associations between gender and confidence scale scores, gender and career choice, and confidence and career choice were analyzed using t tests, ANOVA, and multiple linear regression controlled for postgraduate year (PGY), institution, and specialty choice. 292 IM residents at Northwestern and University of Texas (UT) Southwestern MAIN MEASURES: Resident gender, self-reported confidence, career choice KEY RESULTS: Response rate was 79.6% (n = 292), of them 50.3% women. Overall self-reported confidence increased with training (PGY-1 4.9 (1.1); PGY-2 6.2 (1.0); PGY-3 7.4 (1.0); p < 0.001). Men had higher confidence than women (men 6.6 (1.5); women 6.3 (1.4), p = 0.06), with the greatest difference in procedures. High confidence in men was associated with choice of procedural careers, whereas there was no association between confidence and career in women. This is the first study demonstrating a gender difference in self-reported confidence and career choice. There is a positive correlation in men: higher self-reported confidence with procedural specialties, lower with general internal medicine. Women's self-reported confidence had no association. Further investigation is needed to elucidate causative factors for differences in self-reported confidence by gender, and whether alterations in level of self-reported confidence produce a downstream effect on career choice.


Biological Impact of Phenolic Compounds from Coffee on Colorectal Cancer.
Colorectal cancer is one of the leading death-related diseases worldwide, usually induced by a multifactorial and complex process, including genetic and epigenetic abnormalities and the impact of diet and lifestyle. In the present study, we evaluated the biological impact of two of the main coffee polyphenols, chlorogenic acid (CGA) and caffeic acid (CA), as well as two polyphenol-rich coffee extracts (green coffee extract and toasted coffee Extract) against SW480 and SW620 colorectal cancer cells. First, the total phenolic content and the antioxidant capability of the extracts were determined. Then, cytotoxicity was evaluated by MTT and SBR. Finally, a wound healing assay was performed to determine the impact on the cell migration process. The results showed a cytotoxic effect of all treatments in a time and dose-dependent manner, which decreased the viability in both cell lines at 24 h and 48 h; likewise, the migration capability of cells decreased with low doses of treatments. These results suggest the potential of coffee to modulate biological mechanisms involved in colorectal cancer development; however, more studies are required to understand the mechanistic insights of these observations.


In silico prediction of the 3D structure of trimeric asialoglycoprotein receptor bound to triantennary oligosaccharide.
In this study, we present a general-purpose methodology for deriving the three-dimensional (3D) arrangement of multivalent transmembrane complexes in the presence of their ligands. Specifically, we predict the most likely families of structures of the experimentally intractable trimeric asialoglycoprotein receptor (ASGP-R), which consists of human hepatic subunits (two subunits of H1 and one subunit of H2), bound to a triantennary oligosaccharide (TA). Because of the complex nature of this multivalent type-II transmembrane hetero-oligomeric receptor, structural studies have to date been unable to provide the 3D arrangement of these subunits. Our approach is based on using the three-pronged ligand of ASGP-R as a computational probe to derive the 3D conformation of the complex and then using this information to predict the relative arrangement of the protein subunits on the cell surface. Because of interprotein subunit clashes, only a few families of TA conformers are compatible with the trimeric structure of ASGP-R. We find that TA displays significant flexibility, matching that detected previously in FRET experiments, and that the predicted complexes derived from the viable TA structures are asymmetric. Significant variation exists with respect to TA presentation to the receptor complex. In summary, this study provides detailed information about TA-ASGP-R interactions and the symmetry of the complex.


Large Follicular Odontogenic Keratocyst affecting Maxillary Sinus mimicking Dentigerous Cyst in an 8-year-old Boy: A Case Report and Review.
Cyst with relatively high recurrence and having nature to invade the underlying tissue is "odontogenic keratocyst (OKC)." Radiographically, OKC can appear as different varieties, such as follicular, replacemental, extraneous, envelopmental, and collateral. Each radiographic variety of OKC varies in biological behavior, prognosis, recurrence, and therapeutic approaches. Many studies done till date have not established any relationship between markers of proliferation and aggressiveness in regard to radiographic varieties of OKC. The present article reports a case of follicular OKC in an 8-year-old boy which was concluded as a dentigerous cyst by radiographic features. How to cite this article: Madhireddy MR, Prakash AJ, Mahanthi V, Chalapathi KV. Large Follicular Odontogenic Keratocyst affecting Maxillary Sinus mimicking Dentigerous Cyst in an 8-year-old Boy: A Case Report and Review. Int J Clin Pediatr Dent 2018;11(4):349-351.