Identification of glial-cell-line-derived neurotrophic factor-regulated proteins of striatum in mouse model of Parkinson disease.
Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for dopaminergic neurons, and hence serves as a therapeutic candidate for the treatment of Parkinson's disease. However, despite the potential clinical and physiological importance of GDNF, its mechanism of action is unclear. Therefore, we employed a state-of-the-art proteomic technique, DIGE, along with MS and a bioinformatics tool called Database for Annotation, Visualization and Integrated Discovery (DAVID), to profile proteome changes in the parkinsonian mouse striatum after GDNF challenge. Forty-six unique differentially expressed proteins were successfully identified, which were found either up-regulated and/or down-regulated at the two time points 4 and 72 h compared with the control. Proteins involved in cell differentiation and system development formed the largest part of the proteins regulated under GDNF. Furthermore, the aberrant expression of HSPs and mitochondria-associated proteins were noticeable. Moreover, mitochondrial stress 70 protein and heat shock cognate 71 kDa protein, whose relative levels increased significantly in GDNF-treated striatum, were further evaluated with Western blot and RT-PCR, demonstrating a good agreement with quantitative proteomic data. These data will provide some clues for understanding the mechanisms by which GDNF promotes the survival of dopaminergic neurons.


Anatomical variations analysis of the external jugular vein, great auricular nerve, and posterosuperior border of the platysma muscle.
This article describes the observations collected from the dissection of 10 nonformalinized cadavers analyzed in respect to the anatomical relation variations between the external jugular vein, the great auricular nerve, and the posterosuperior border of the platysma muscle.


HbA1C variability and the risk of renal status progression in Diabetes Mellitus: a meta-analysis.
To explore the association between glycated hemoglobin (A1C) variability and renal disease progression in patients with diabetes mellitus. A comprehensive search was performed using the PubMed and Embase databases (up to April 26, 2014). The hazard ratio (HR) was pooled per unit increase in the standard deviation of A1C (A1C-SD) to evaluate the dose-response relationship between A1C-SD and the risk of nephropathy. Eight studies with a total of 17,758 subjects provided the HR for A1C-SD and were included in the final meta-analysis. The pooled HR results demonstrated that A1C-SD was significantly associated with the progression of renal status (HR for both T1DM and T2DM 1.43, 95% confidence interval [CI] 1.24-1.64; HR for T1DM 1.70, 95%CI 1.41-2.05; HR for T2DM 1.20, 95%CI 1.12-1.28). A1C-SD was significantly correlated with new-onset microalbuminuria (HR for T1DM 1.63, 95%CI 1.28-2.07; HR for T2DM 1.23, 95%CI 1.08-1.39). These outcomes were also supported in subgroup analyses. Furthermore, sensitivity analyses demonstrated that the results were robust. A1C variability is independently associated with the development of microalbuminuria and the progression of renal status in both type 1 and 2 diabetes patients. A standard method for measuring A1C variability is essential for further and deeper analyses. In addition, future studies should assess the effect of reducing A1C variability on nephropathy complication.


Reduction malarplasty using a simulated surgical guide for asymmetric/prominent zygoma.
The present study introduces a reduction malarplasty using a three-dimensional (3D)-printed surgical guide and evaluates the guide's technical applicability. Twenty malarplasties were performed for 12 subjects with zygomatic asymmetry/prominency using the current method. 3D reconstruction of the craniomaxillofacial region and fine dental occlusion was made with image data from computed tomograpy and dental scanning. A computer-assisted surgical simulation was performed for reduction malarplasty and a surgical guide was designed for later 3D printing. The manufactured surgical guide was introduced to the operation field to guide the surgery; its surgical accuracy was confirmed by comparing five corresponding points from preoperative simulation and postoperative data. We successfully performed the reduction malarplasty with the surgical guide. The accuracy level of surgery fell to 0.93 mm of total median difference for the corresponding zygoma points of preoperative simulations and postoperative zygoma. The anterior and upper points showed less error level (0.59 and 0.73 mm difference, respectively) than did other points. We developed a computer-assisted surgical technique using a surgical guide for asymmetrical/prominent zygoma which proved to be simple, practical, and accurate; it is expected to help surgeons perform reduction malarplasty with ease and accuracy.


Modulation of human neutrophil function by C-reactive protein.
Investigation of the effect of C-reactive protein (CRP), an acute-phase reactant, on the functional capacities of human neutrophils was carried out as the basis for elucidating the biological function of C-reactive protein. An initial stimulation at low concentrations, followed by inhibition of superoxide production, and secretion of vitamin-B12-binding protein in the presence of two stimulants, phorbol myristate acetate and concanavalin A, and of neutrophil chemotaxis with increasing concentration of CRP was observed. Correlation between modulation of cell function, at least at relatively high CRP concentrations (greater than 50 micrograms/ml) and an increase in the intracellular level of cAMP is suggested. CRP was also found to enhance neutrophil phagocytosis of particles not containing phosphorylcholine, the native CRP ligand. The proposed role of CRP in neutrophil function is one of regulation and as a negative feedback for potential cytotoxic neutrophil functions.


Lectin staining of carbohydrates of haemic cells; the cells of normal blood and bone marrow and of the myeloid leukaemias.
Plant proteins and aprotinin (a protein of beef lung), labelled with fluorescein isothiocyanate, were used as histochemical tools for the demonstration of carbohydrates. Sialic acid (or glucuronate) was stained with aprotinin (FLA); galactose was stained with Ricinus communis agglutinin (FL-RCA) and mannose (or glucose) with Concanavalin A (FL-Con-A). Normal human bone marrow and blood were examined as were the cells of patients with acute and chronic myelogenous leukaemia. The plasmalemma, cytoplasm and nuclear membrane of the cells of the normal granulocytic series were stained well with FLA, but the corresponding leukaemic cells fluoresced less intensely. Chromatin was weakly stained in both normal and leukaemic cells. FLA-RCA and FL-Con A stained the plasmalemma, cytoplasm and nuclear membrane weakly, but did not demonstrate chromatin. There was no detectable difference between normal and leukaemic cells. Eosinophil and basophil granules--in contrast to those of the neutrophils--stained well with all three compounds, in both the normal and leukaemic cells. In megakaryocytes and platelets the plasmalemma and cytoplasm were well stained with FLA. The cytoplasm of megakaryocytes and the plasmalemma of platelets stained particularly well with FL-RCA. The cytoplasm of both platelets and megakaryocytes showed up strongly with FL-Con A. In the erythroblastic series all three compounds stained the plasmalemma. The remaining cellular components were weakly stained, except the chromatin; that of the late erythroblasts showed up particularly well with FLA. Lymphocytes, monocytes and reticulin cells of the bone marrow were also stained with all three reagents. Reticulin fibres were stained strongly with FLA and FL-Con-A.


Guidelines for the management of anaphylaxis in the emergency department.
An algorithm for the emergency treatment of anaphylaxis is presented. The need for early hands-on involvement of senior personnel is stressed. Continuous assessment, monitoring of response to treatment, and a low threshold for hospital admission for observation and further treatment if necessary are required.


Pituitary stalk interruption syndrome presenting as short stature: a case report.
Pituitary stalk interruption syndrome is a rare congenital abnormality of the pituitary that is responsible for anterior pituitary deficiency. It is characterized by a classic triad of interrupted pituitary stalk, absent or ectopic posterior pituitary, and anterior pituitary hypoplasia or aplasia. Clinical presentation varies according to age. In adults it presents as short stature and anterior pituitary deficiency. Without early diagnosis and treatment, mortality and morbidity in these patients is high. Early diagnosis and treatment of this rare disease can prevent permanent short statue of the patient. We report the first case of pituitary stalk interruption syndrome from Pakistan. A 17-year-old Pakistani young man presented with short stature and underdeveloped secondary sexual characters. His siblings and parents were healthy, with normal height. An examination showed his blood pressure was 90/60 mmHg, and his height, weight, and body mass index were 142 cm, 34.5 kg, and 17.10 kg/m2, respectively. He had no hair growth on his face, axilla, or pubis. His testes were between 1 and 2 mL in size, with a 4 cm-at-stretch micropenis. His lab investigations showed that his thyroid stimulating hormone (TSH) was 8.58 uIU/mL (0.4 to 4.2), his free thyroid hormone level FT4 was 0.46 ng/dL (0.89 to 1.76), his prolactin was 21.1 ng/mL (3.0 to 14.7), and his baseline cortisol was 0.30 ug/dL (4.3 to 22.4). His cortisol level after 60 minutes of cosyntropin injection was 3.5 ug/dL (4.3 to 22.4), his insulin like growth factor IGF-1 was 31.56 ng/mL (247.3 to 481.7), his testosterone level was under 2.5 ng/dL (2 to 800), his follicle stimulating hormone FSH was 0.41 uIU/mL (0.0 to 10.0), and his leutinizing hormone LH was under 0.1 uIU/mL (1.2 to 7.8). His bone age was 10 years according to the Greulich and Pyle method, as shown by X-rays. The results from his pituitary magnetic resonance imaging scan were consistent with pituitary stalk interruption syndrome. We describe a young man who presented with short stature and was found to have pituitary stalk interruption syndrome. Despite the fact that this is a rare disorder, it should always be kept in the differential diagnosis of a patient presenting with short stature. Patients with this disease have an excellent opportunity to reach normal height if they present before the joining of epiphyses.


Age-related differences among patients with follicular lymphoma and the importance of prognostic scoring systems: analysis from a population-based non-Hodgkin's lymphoma registry.
The influence of age on the outcome of follicular non-Hodgkin's lymphoma (FL) was studied in a population-based non-Hodgkin's lymphoma registry. This study comprised 214 follicular lymphoma patients. Grade I/II was considered separately from grade III FL. The data were analyzed with respect to three age groups: <60, 60-69 and >or=70 years. The overall survival rate decreased in the older age groups. Grade III patients showed a statistically significant decrease in overall survival in comparison with grade I/II patients (P = 0.03). Cause-specific survival analysis showed that in the older age groups, there was an increasing influence of concomitant disease on the death rate, especially among grade III FL patients >70 years of age. The survival curve in grade III FL patients was shown to reach a plateau. The prognostic scoring system, according to the Italian Lymphoma Intergroup, fitted better to grade I/II patients, while the International Prognostic Index showed better discrimination amongst grade III patients. Separate grading for follicular lymphoma is useful. An age >70 years has a negative impact on outcome, but the contribution of concomitant disease herein is important. Different prognostic scoring systems should be applied to the different grades of FL.


Spontaneous and Simultaneous Oxidation and Reduction of o-Quinones in Water Microdroplets.
Microdroplet chemistry has been an emerging new field for its large plethora of unique properties, among which an especially intriguing one is the strong oxidizing and reducing powers. The hydroxide ion in water microdroplets is considered to split into a hydroxyl radical and an electron at the air-water interface, and the former is responsible for the oxidizing capability while the latter is responsible for the reducing power, making a unity of opposites. However, to date there are only two examples showing that oxidation and reduction occur simultaneously to the same substrates, which might be a result of the redox properties of the substrate per se. In this study, we carefully chose a group of ο-quinone compounds as the substrates in water microdroplets and discovered that they can be both oxidized by the hydroxyl radical and reduced by the electron. These results keep pushing the limit of the unique redox properties of microdroplet chemistry.


Sustainability assessment and causality nexus through ecosystem service accounting: The case of water purification in Europe.
The paper builds on the Supply and Use Tables module within the System of integrated Environmental and Economic Accounts - Experimental Ecosystem Accounts (SEEA EEA) developed by the UN. We explore the evolution of Supply and Use Tables from the System of National Accounts (SNA) to the System of integrated Environmental and Economic Accounts - Central Framework (SEEA CF) and then to the SEEA EEA, and we propose a further extension: we propose that ecosystem types should be treated as accounting units able to produce, consume and exhibit changes in regeneration and absorption rates. The implications are first explained in the methodological section and then shown in the application where the water purification service is tested against two major policy issues: sustainability assessment (we show how to assess whether the ecosystem service is used sustainably by comparing the quantification of potential and actual flow) and causality nexus (we quantify the connection between the value of agricultural production and that of the ecosystem service used). The paper highlights how the overall outcomes change when considering different scales. A contrast emerges, for example, between the positive balance at the continental scale, where water purification services appear to be used sustainably (thanks to the high potential flow of Northern European countries) and the negative balance of almost all European countries when considered at a national scale. Taking advantage of the experimental opportunities offered by operating with external satellite accounts, we are able to show how the proposed complementary tables could support policy action.


Adverse reactions associated with immune checkpoint inhibitors and bevacizumab: A pharmacovigilance analysis.
Immune checkpoint inhibitors (ICIs) combined with the anti-angiogenesis drug bevacizumab is one of the future directions of immunotherapy. However, the potential adverse drug reactions (ADRs) caused by combination therapy remain unclear. Current research on ADRs of combination therapy in cancer patients is extremely limited. Our study aims to help determine the safety of combination therapy. We downloaded the ADR reports on combination therapy, from the first quarter of 2012 to the fourth quarter of 2021, from the FDA adverse event reporting system (FAERS) database and conducted a large-scale retrospective study. The ADR signals were monitored by reporting odds ratio (ROR) and analyzing the risk of different ADRs in patients with Pan-cancer. A total of 2094 cases were selected, after excluding duplicate data and the use of chemotherapy drugs. We evaluated the risk of ADR in Pan-cancer patients. Combination therapy was an independent risk factor for adverse drug reactions associated with interstitial lung disease (OR: 8.62; 95% CI: 6.14-12.10, P < .0001), hypertension (OR: 1.35; 95% CI: 1.11-1.65, P < .01) and gastrointestinal bleeding (OR: 3.16; 95% CI: 2.21-4.51, P < .0001). A subgroup analysis revealed that the risk of endocrine system-related ADRs was elevated in patients receiving different combination therapies or with certain tumor types. We retrospectively studied the ADR of combination therapy in Pan-cancer patients and analyzed the distribution characteristics of ADR from the perspectives of treatment strategy and cancer types to provide recommendations for the individualized management of patients receiving combination therapy.


[Menstrual disturbances and alternations in hypophyseal gonadal axis in end-stage premenopausal women undergoing hemodialysis: a multi-center study].
The results of the studies of hypophyseal-gonadal axis in dialysis women are not uniform. Mostly the increased serum concentrations of prolactine and pituitary gonadotropins are observed; the data about ovarian secretion are much more scanty and contradictory. The aim of this crossectional study was to assess changes in sexual hormones secretion and their associations with menstrual disturbations in premenopausal women with end-stage renal failure undergoing hemodialysis. Sixty three women from six mazovian dialysis units, aged 18-45 years (mean 35 +/- 7 years) were enrolled into the study. They were divided into four groups according to their menstrual pattern: I--eumenorrhoea (n = 17), II--polymenorrhoea (n = 9), III--oligomenorrhoea (n = 16) i IV--amenorrhoea n = 21). There were no differences between both groups in respect to age, age of menarche, time on hemodialysis, and body mass index. In all subjects gynecological examination was performed and serum prolactin, FSH, LH, estradiol, progesterone and testosterone concentrations were assayed. In 49% women high serum prolactin concentrations were noted (the highest in group IV--1699 +/- 1022 vs 441 +/- 205 microIU/ml in group I; p < 0.05). Mean serum FSH and LH were increased in group IV only (33 +/- 59 and 22 +/- 31 mIU/ml); no significant differences among groups examined were seen. Serum estradiol was increased in groups I-III (95 +/- 46, 72 +/- 33, and 83 +/- 55 pg/ml, respectively) and decreased in group IV (27 +/- 22 pg/ml; p < 0.001 in respect to remaining groups). Mean serum progesterone and testosterone concentrations were normal in all four groups, but serum progesterone was significantly lower in groups II-IV than in group I (p < 0.05). No differences in hormonal status between patients receiving and not receiving rHuEpo were observed. Menstrual disturbances are common (73%) in premenopausal women with end-stage renal failure, with amenorrhea constituting a half of them. Hyperprolactinemia is the most frequently seen alteration in their hormonal profile with the highest concentrations in those with secondary amenorrhea. Increased serum gonadotropins and reduced serum estradiol concentrations are mostly seen in amenorrheic women, whereas in menstruating women serum estradiol is often slightly increased.


Four-Week Unstructured Break Improved Athletic Performance in Collegiate Rugby Players.
Jensen, CD, Gleason, D, and VanNess, JM. Four-week unstructured break improved athletic performance in collegiate rugby players. J Strength Cond Res 32(6): 1671-1677, 2018-This study analyzed the changes in athletic performance and anthropometric characteristics in collegiate male club rugby athletes (n = 14) after a 4-week winter break. All measurements were collected before and after the break. Body composition was assessed by body mass index and hydrostatic weighing. Performance measurements were as follows: V[Combining Dot Above]O2max, vertical jump, 10-yard sprint, squat max, and bench press max. Before testing, each subject was acclimated to the protocols to reduce learning effects. During the 4-week break, no workouts were provided for the athletes; it was unsupervised and unstructured. Participants were required to maintain and submit self-reported nutritional and activity logs during this period. After the break, the athletes demonstrated a 5.0% improvement in V[Combining Dot Above]O2max (absolute increase of 2.25 ml·kg·min), 6.8% improvement in vertical jump (1.50 inches), and a 14.3% increase in squat max (38.64 lb). Although increases in body mass (1.0%) were not significant, the body fat percentage exhibited a relative increase of 19.3% (absolute change from 13.35 to 15.93%). A significant discriminate function analysis indicated statistical differences between groups based on these variables. Self-reported behavior logs confirmed participation in >3 days of moderate to intense physical activity per week but somewhat poor dietary habits. These results indicate that collegiate rugby athletes may not need prescribed exercise routines during seasonal breaks in the athletic schedule. However, it may be beneficial to provide structured nutritional advice during unsupervised periods.


The Pharmacological Mechanisms and Therapeutic Activities of Hydroxychloroquine in Rheumatic and Related Diseases.
Hydroxychloroquine (HCQ) is known as one of the most fascinating synthetic antimalarial drugs during the last 50 years. It is currently among the most commonly employed medicines for the clinical treatment of rheumatic diseases, especially systemic lupus erythematosus and rheumatoid arthritis. In related mechanism studies, it has been found that HCQ possesses various immunomodulatory and anti-inflammatory activities. In addition, the effects of HCQ on anti-platelet, metabolic pathways, and antineoplasticity have also been disclosed in more recent studies. These significant findings on HCQ suggest the potential therapeutic applications of HCQ for treatment of many diseases, such as cancers, skin disease, antiphospholipid syndrome, etc. This review focuses on recent in vitro and clinical trials on its pharmacological mechanisms, therapeutic activities, and potential adverse effects.


Relationship of prenatal depression and comorbidities to infant outcomes.
The purpose of this study was to provide information on the effect of prenatal depression and anxiety as assessed in the context of obstetrical care on key infant outcomes (gestational age at birth, birth weight, and APGAR scores), while simultaneously considering interactions with maternal medical conditions among primarily Medicaid enrollees. Obstetrical medical records of 419 women presenting consecutively for prenatal care at a health system serving primarily Medicaid patients were examined. Information on maternal characteristics (age, race, education) and maternal medical health (BMI, high blood pressure, diabetes, and kidney problems), as well as mental health information, was extracted. Depression was assessed as part of routine care using the Patient Health Questionnaire-9 (PHQ-9), and any documentation of depression or anxiety by the obstetrics clinician was also used in the analyses. Approximately one-third of the sample showed some evidence of prenatal depression, either based on PHQ-9 score (≥10) or clinician documentation of depression, and close to 10% showed evidence of anxiety. Multivariate analyses showed significant interactions between depression and anxiety on gestational age and birth weight, between depression and high blood pressure on gestational age, and also between anxiety and kidney problems on gestational age. Among this sample, the effect of maternal depression and anxiety on birth outcomes was more evident when considered along with maternal chronic medical conditions. This information may be used to assist prenatal care clinicians to develop risk assessment based on knowledge of multiple risk factors that may exert and additive influence on poor birth outcomes.


Low expression of Toll-like receptors in peripheral blood mononuclear cells of pediatric patients with acute lymphoblastic leukemia.
Cancer is the second most common cause of death among children aged 1-14 years. Leukemia accounts for one-third of all childhood cancers, 78% of which is acute lymphoblastic leukemia (ALL). The development of cancer has been associated with malignant cells that express low levels of immunogenic molecules, which facilitates their escape from the antineoplastic immune response. It is thought that it may be possible to rescue the antineoplastic immune response through the activation of recognition receptors, such as Toll-like receptors (TLRs), which activate the innate immune system. TLRs are type I membrane glycoproteins expressed mainly in immune system cells such as monocytes, neutrophils, macrophages, dendritic cells, T, B and natural killer cells. The aim of the present study was to evaluate the expression of TLR1, TLR3, TLR4, TLR7 and TLR9 in peripheral blood mononuclear cells (PBMCs) in patients with ALL and prior to any treatment. PBMCs were obtained from 50 pediatric patients diagnosed with ALL and from 20 children attending the ophthalmology and orthopedics services. The mean fluorescence intensity was obtained by analysis of immunofluorescence. We found lower expression levels of TLR1, TLR3, TLR4, TLR7 and TLR9 in PBMCs from patients with ALL compared with those from control patients. We also observed that the PBMCs from patients with Pre-B and B ALL had lower TLR4 expression than controls and patients with Pro-B, Pre-B, B and T ALL had lower TLR7 expression than controls. The present study is the first to demonstrate reduced expression of TLRs in PBMCs from pediatric patients with ALL. This finding is of great relevance and may partly explain the reduction in the antineoplastic immune response in patients with ALL.


CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor alpha by cAMP.
The estrogen receptor alpha (ERalpha) is activated as a transcription factor by both estrogen and a large variety of other extracellular signals. The mechanisms of this ligand-independent activation, notably by cAMP signaling, are still largely unknown. We now close the gap in the signaling pathway between cAMP and ERalpha. Whereas the direct phosphorylation of ERalpha by the cAMP-activated protein kinase A (PKA) is dispensable, the phosphorylation of the coactivator-associated arginine methyltransferase 1 (CARM1) by PKA at a single serine is necessary and sufficient for direct binding to the unliganded hormone-binding domain (HBD) of ERalpha, and the interaction is necessary for cAMP activation of ERalpha. Sustained PKA activity promoting a constitutive interaction may contribute to tamoxifen resistance of breast tumors. Binding and activation involve a novel regulatory groove of the ERalpha HBD. As a result, depending on the activating signal, ERalpha recruits different coactivator complexes to regulate alternate sets of target genes.


Efficacy of Wii-Fit on Static and Dynamic Balance in Community Dwelling Older Veterans: A Randomized Controlled Pilot Trial.
Background/Objectives. Balance problems are well-established modifiable risk factors for falls, which are common in older adults. The objective of this study was to establish the efficacy of a Wii-Fit interactive video-game-led physical exercise program to improve balance in older Veterans. Methods. A prospective randomized controlled parallel-group trial was conducted at Veterans Affairs Medical Center. Thirty community dwelling Veterans aged 68 (±6.7) years were randomized to either the exercise or control groups. The exercise group performed Wii-Fit program while the control group performed a computer-based cognitive program for 45 minutes, three days per week for 8-weeks. The primary (Berg Balance Scale (BBS)) and secondary outcomes (fear of falling, physical activity enjoyment, and quality of life) were measured at baseline, 4 weeks, and 8 weeks. Results. Of 30 randomized subjects, 27 completed all aspects of the study protocol. There were no study-related adverse events. Intent-to-treat analysis showed a significantly greater improvement in BBS in the exercise group (6.0; 95% CI, 5.1-6.9) compared to the control group (0.5; 95% CI, -0.3-1.3) at 8 weeks (average intergroup difference (95% CI), 5.5 (4.3-6.7), p < 0.001) after adjusting for baseline. Conclusion. This study establishes that the Wii-Fit exercise program is efficacious in improving balance in community dwelling older Veterans. This trial is registered with ClinicalTrials.gov Identifier NCT02190045.


A Novel Approach of a Low-Cost UWB Microwave Imaging System with High Resolution Based on SAR and a New Fast Reconstruction Algorithm for Early-Stage Breast Cancer Detection.
In this article, a new efficient and robust approach-the high-resolution microwave imaging system-for early breast cancer diagnosis is presented. The core concept of the proposed approach is to employ a combination of a newly proposed delay-and-sum (DAS) algorithm and the specific absorption rate (SAR) parameter to provide high image quality of breast tumors, along with fast image processing. The new algorithm enhances the tumor response by altering the parameter referring to the distance between the antenna and the tumor in the conventional DAS matrices. This adjustment entails a much clearer reconstructed image with short processing time. To achieve these aims, a high directional Vivaldi antenna is applied around a simulated hemispherical breast model with an embedded tumor. The detection of the tumor is carried out by calculating the maximum value of SAR inside the breast model. Consequently, the antenna position is relocated near the tumor region and is moved to nine positions in a trajectory path, leading to a shorter propagation distance in the image-creation process. At each position, the breast model is illuminated with short pulses of low power waves, and the back-scattered signals are recorded to produce a two-dimensional image of the scanned breast. Several simulations of testing scenarios for reconstruction imaging are investigated. These simulations involve different tumor sizes and materials. The influence of the number of antennas on the reconstructed images is also examined. Compared with the results from the conventional DAS, the proposed technique significantly improves the quality of the reconstructed images, and it detects and localizes the cancer inside the breast with high quality in a fast computing time, employing fewer antennas.


Molecular Subtypes of Indonesian Breast Carcinomas - Lack of Association with Patient Age and Tumor Size
Objective: Breast carcinoma (BC) is a heterogeneous disease that exhibits variation in biological behaviour, prognosis and response to therapy. Molecular classification is generally into Luminal A, Luminal B, HER2+ and triple negative/basal-like, depending on receptor characteristics. Clinical factors that determined the BC prognosis are age and tumor size. Since information on molecular subtypes of Indonesian BCs is limited, the present study was conducted, with attention to subtypes in relation to age and tumor size. Methods: A retrospective cross-sectional study of 247 paraffin-embedded samples of invasive BC from Dr. Sardjito General Hospital Yogyakarta in the year 2012- 2015 was performed. Immunohistochemical staining using anti- ER, PR, HER2, Ki-67 and CK 5/6 antibodies was applied to classify molecular subtypes. Associations with age and tumor size were analyzed using the Chi Square Test. Results: The Luminal A was the most common subtype of Indonesian BC (41.3%), followed by triple negative (25.5%), HER2 (19.4%) and luminal B (13.8%). Among the triple negative lesions, the basal-like subtype was more frequent than the non basal-like (58.8 % vs 41.2%). Luminal B accounted for the highest percentage of younger age cases (< 40 years old) while HER2+ was most common in older age (> 50 years old) patients. Triple negative/basal-like were commonly large in size. Age (p = 0.080) and tumor size (p = 0.462) were not significantly associated with molecular subtypes of BC. Conclusion: The most common molecular subtype of Indonesian BC is luminal A, followed by triple-negative, HER2+ and luminal B. The majority of triple-negative lesions are basal-like. There are no association between age and tumor size with molecular subtypes of Indonesian BCs.


Bio-inspired self-healing structural color hydrogel.
Biologically inspired self-healing structural color hydrogels were developed by adding a glucose oxidase (GOX)- and catalase (CAT)-filled glutaraldehyde cross-linked BSA hydrogel into methacrylated gelatin (GelMA) inverse opal scaffolds. The composite hydrogel materials with the polymerized GelMA scaffold could maintain the stability of an inverse opal structure and its resultant structural colors, whereas the protein hydrogel filler could impart self-healing capability through the reversible covalent attachment of glutaraldehyde to lysine residues of BSA and enzyme additives. A series of unprecedented structural color materials could be created by assembling and healing the elements of the composite hydrogel. In addition, as both the GelMA and the protein hydrogels were derived from organisms, the composite materials presented high biocompatibility and plasticity. These features of self-healing structural color hydrogels make them excellent functional materials for different applications.


Why Biphasic? Assessment of the Effect on Cell Proliferation and Expression.
Tricalcium silicate (TCS)-based materials are used in endodontics because they are hydraulic and interact with blood, tissue fluids, and phosphate-based root canal irrigants, resulting in biomineralization. Newer-generation materials are biphasic; calcium phosphate is added to the TCS; thus, the material has 2 cementitious phases. The effect of this addition is not known; thus, the aim of this study was to characterize biphasic cements and assess cellular proliferation and expression. TCS cement mixed with calcium phosphate monobasic or hydroxyapatite in 1:1 proportion was prepared. The powders and the mixed cements soaked in Hank's balanced salt solution for 28 days were characterized by scanning electron microscopy (SEM), energy-dispersive spectroscopy, and X-ray diffraction analysis. Ion leaching was investigated using inductively coupled plasma mass spectroscopy. Cellular interaction with material leachate was investigated by exposing human primary osteoblasts to the leachate from the cements. Cell growth and proliferation were determined using methyltetrazolium assay and SEM. The addition of a calcium phosphate phase to tricalcium silicate changed the material hydration with a reduction in pH and calcium ion release in the leachate when calcium phosphate monobasic was added. No crystalline calcium hydroxide was formed for both biphasic materials. The biphasic cements exhibited a reduction in cell growth and proliferation. SEM of the materials showed heavy carbonation of the material surface caused by processing for microscopy. The addition of a second cementitious phase results in modification of the hydration characteristics of TCS cement with deterioration of material and biocompatibility properties.


Biodegradable Poly(Acetonide Gluconic Acid) for Controlled Drug Delivery.
We report here on the synthesis, characterization, degradation, and drug release of acetal-protected gluconic acid-based poly(α-hydroxy ester). This polyester was synthesized by ring-opening polymerization of O-carboxyanhydride of acetal-protected gluconic acid. The polymer undergoes hydrolytic degradation under mild acidic media, whereas minimal degradation takes place under physiological pH. Under acidic conditions, the acetal-protecting groups are hydrolyzed, resulting in a water-soluble polyester with saccharide side chains that erodes from the surface, leaving the bulk of the polymer matrix intact. At pH 3.5, zero-order kinetics was maintained for 50 days accounting for ∼75% drug release. These biodegradable, pH-responsive, sustained zero-order release kinetics of the polymer have application as drug carriers for oral drug delivery or medical implants or also for nonmedical applications.


Sudden cardiac death in COVID-19 patients, a report of three cases.
The mortality rate of coronavirus disease-19 (COVID-19) has been reported as 1-6% in most studies. The cause of most deaths has been acute pneumonia. Nevertheless, it has been noted that cardiovascular failure can also lead to death. Three COVID-19 patients were diagnosed based on reverse transcriptase-polymerase chain reaction of a nasopharyngeal swab test and radiological examinations in our hospital. The patients received medications at the discretion of the treating physician. In this case series, chest computed tomography scans and electrocardiograms, along with other diagnostic tests were used to evaluate these individuals. Sudden cardiac death in COVID-19 patients is not common, but it is a major concern. So, it is recommended to monitor cardiac condition in selected patients with COVID-19.


Monoclonal antibodies detecting discrete epitopes of human perforin.
Perforin is a cytolytic protein of natural killer (NK) cells and cytotoxic T cells (CTL). Purified perforin has been shown to cause cell lysis and to form stable pores in the target cell membrane, but its relevance to cytolysis in vivo is not clear. The gene for human perforin has been cloned, but monoclonal antibodies (mabs) have not been available. In order to study further its role in cytotoxicity, we have generated mabs to different regions of human perforin. Four mabs were produced from mice immunized with hybrid proteins comprising E. coli TrpE protein at the N-terminus and different regions of human perforin at the C-terminus. These proteins were made using the pATH expression plasmids into which fragments of perforin cDNA were subcloned. Monoclonal antibody PA1 was made from a mouse immunized with a hybrid protein containing the C-terminal 240 amino acids (AA) of perforin, PE1 - the N-terminal 118 AA, and PB1 and PB2 - the central 199 AA. The three plasmid constructs contained non-overlapping cDNA segments which covered the entire sequence of perforin. All mabs reacted with the immunizing hybrid protein, but not with the other hybrid proteins, indicating that at least three epitopes are recognized by this set of mabs. All mabs immunoprecipitated a molecule of about 68 kd from lysates of metabolically-labelled cytolytic large granular lymphocytic leukemia cells, but not from control lysates of non-cytolytic promyelocytic U937 cells. These mabs should be of use in determining structure-function relationships for perforin.


Population Responses of Potato Leafhopper (Hemiptera: Cicadellidae) to Insecticide in Glandular-Haired and Non-glandular-Haired Alfalfa Cultivars.
Conflicting results have been reported on the ability of glandular-haired alfalfa (Medicago sativa L.) cultivars to reduce potato leafhopper, Empoasca fabae Harris, population abundance in field environments. We measured potato leafhopper adult and nymph abundance and yield responses in a cultivar selected for high potato leafhopper resistance ('54H91') and in a non-glandular-haired susceptible cultivar ('54V54') with and without insecticide treatment across 3 yr. Treatments included no insecticide and insecticide applied either early or late in each summer growth cycle. Date × cultivar × treatment interactions were found for potato leafhopper population abundance. In the absence of insecticides, total potato leafhopper abundance (adults + nymphs per sweep) was lower in 54H91 than in 54V54 on 85% of sampling dates; cultivar differences were especially evident as potato leafhopper abundance peaked. Insecticide treatment reduced potato leafhopper populations in both cultivars, but populations recovered and often exceeded the normal action threshold in both cultivars within 2-3 wk of insecticide application. Yield gain from early insecticide treatment of 54V54 was >400 kg/ha in 11 of 14 summer harvests, whereas in 54H91 the yield gain was <250 kg/ha in 10 of 14 summer harvests. We conclude that glandular-haired alfalfa cultivars with high levels of potato leafhopper resistance significantly suppress potato leafhopper adult and nymph abundance, reduce yield losses in the absence of insecticides, and have potential within an integrated pest management strategy to reduce insecticide use in alfalfa production systems.


The therapeutic roller coaster : dilemmas in the treatment of childhood abuse survivors.
Survivors of severe childhood abuse often encounter profound difficulties. In addition to posttraumatic and dissociative symptomatology, abuse survivors frequently have characterologic problems, particularly regarding self-care and maintaining relationships. Backgrounds of abuse, abandonment, and betrayal are often recapitulated and reenacted in therapy, making the therapeutic experience arduous and confusing for therapists and patients. Efforts must be directed at building an adequate psychotherapeutic foundation before undertaking exploration and abreaction of past traumatic experiences. This discussion sets out a model for treatment of childhood abuse survivors, describing stages of treatment and suggesting interventions. Common treatment dilemmas or "traps" are discussed, with recommendations for their resolution.


A Community-Based Noncommunicable Disease Prevention Intervention in Punjab, India: Baseline Characteristics of 11,322 Adults.
Noncommunicable diseases (NCD) are the leading cause of death in India, with cardiovascular diseases (CVD) in particular accounting for nearly 1 in 3 deaths. The prevention of key CVD risk factors - namely, diabetes and hypertension - is a public health priority. The objective is to describe the results of large-scale, community-based NCD screening using the Government of India's Community Based Assessment Checklist (CBAC) scoring system. Trained enumerators visited each household in 10 villages in Punjab, India, between September 2019 and March 2020. Standardized methods were used to measure blood pressure, blood glucose, waist circumference, family medical history, and lifestyle behaviors. A total of 11,322 adults (52.1% women; mean age 48.3 years) completed the assessment and 14.4% were classified as high-risk (CBAC >4). Those classified as high-risk were significantly more likely to have hypertension (46.0% vs. 20.6% among low-risk, P < 0.0001) and diabetes (12.0% vs. 7.7%, P < 0.0001). Only 26.8% of those with hypertension were diagnosed and only 14.9% treated. Proportions among those with diabetes were similarly low: 29.2% diagnosed and 16.0% treated. To the best of our knowledge, this is the first study to estimate the prevalence of high-risk CBAC scores in a population-based sample. Given that the Government of India aims to undertake population-based screening of all adults >30 years for NCDs, the results of this study are directly translatable.


Two different forms of metarhodopsin II: Schiff base deprotonation precedes proton uptake and signaling state.
Rhodopsin is a retinal protein and a G-protein-coupled receptor; it shares with both of these families the seven helix structure. To generate the G-interacting helix-loop conformation, generally identified with the 380-nm absorbing metarhodopsin II (MII) photoproduct, the retinal Schiff base bond to the apoprotein must be deprotonated. This occurs as a key event also in the related retinal proteins, sensory rhodopsins, and the proton pump bacteriorhodopsin. In MII, proton uptake from the aqueous phase must be involved as well, since its formation increases the pH of the aqueous medium and is accelerated under acidic conditions. In the native membrane, the pH effect matches MII formation kinetically, suggesting that intramolecular and aqueous protonation changes contribute in concert to the protein transformation. We show here, however, that proton uptake, as indicated by bromocresol purple, and Schiff base deprotonation (380-nm absorption change) show different kinetics when the protein is solubilized in suitable detergents. Our data are consistent with a two-step reaction:


[Isolated intestinal angioedema induced by enalapril].
Angioedema induced by angiotensin converting enzyme inhibitors is a rare entity characterized by skin and mucosal edema, due to increased vascular permeability caused by inhibition of the converting enzyme and subsequent increase in bradykinin. It frequently presents with facial and mucosal involvement, being uncommon the intestinal or airway compromise. Intestinal angioedema may be associated with facial or isolated angioedema, the latter being exceptional. It is associated with recurrent episodes of pain, abdominal distention and watery diarrhea which complete recovery in two or three days. Although it is a rare entity, the fact that it is associated with frequently used drugs makes us include it in the differential diagnosis of recurrent abdominal pain. We report a case of isolated intestinal angioedema associated with the use of enalapril.


Temporal trends in mortality from diseases of the circulatory system after treatment for Hodgkin lymphoma: a population-based cohort study in Sweden (1973 to 2006).
Hodgkin lymphoma (HL) survival in Sweden has improved dramatically over the last 40 years, but little is known about the extent to which efforts aimed at reducing long-term treatment-related mortality have contributed to the improved prognosis. We used population-based data from Sweden to estimate the contribution of treatment-related mortality caused by diseases of the circulatory system (DCS) to temporal trends in excess HL mortality among 5,462 patients diagnosed at ages 19 to 80 between 1973 and 2006. Flexible parametric survival models were used to estimate excess mortality. In addition, we used recent advances in statistical methodology to estimate excess mortality in the presence of competing causes of death. Excess DCS mortality within 20 years after diagnosis has decreased continually since the mid-1980s and is expected to further decrease among patients diagnosed in the modern era. Age at diagnosis and sex were important predictors for excess DCS mortality, with advanced age and male sex being associated with higher excess DCS mortality. However, when accounting for competing causes of death, we found that excess DCS mortality constitutes a relatively small proportion of the overall mortality among patients with HL in Sweden. Excess DCS mortality is no longer a common source of mortality among Swedish patients with HL. The main causes of death among long-term survivors today are causes other than HL, although other (non-DCS) excess mortality also persists for as long as 20 years after diagnosis, particularly among older patients.


Molecular cloning and characterization of a novel calcium-dependent protein kinase gene IiCPK2 Responsive to polyploidy from tetraploid Isatis indigotica.
A novel calcium-dependent protein kinase gene (designated as IiCPK2) was cloned from tetraploid Isatis indigotica. The full-length cDNA of IiCPK2 was 2585 bp long with an open reading frame (ORF) of 1878 bp encoding a polypeptide of 625 amino acid residues. The predicted IiCPK2 polypeptide included three domains: a kinase domain, a junction domain (or autoinhibitory region), and a C-terminal calmodulin-like domain (or calcium-binding domain), which presented a typical structure of plant CDPKs. Further analysis of IiCPK2 genomic DNA revealed that it contained 7 exons, 6 introns and the length of most exons was highly conserved. Semi-quantitative RTPCR revealed that the expression of IiCPK2 in root, stem and leaf were much higher in tetraploid sample than that in diploid progenitor. Further expression analysis revealed that gibberellin (GA3), NaCl and cold treatments could upregulate the IiCPK2 transcription. All our findings suggest that IiCPK2 might participate in the cold, high salinity and GA3 responsive pathways.


Drug discrimination in methamphetamine-trained monkeys: effects of monoamine transporter inhibitors.
The involvement of brain monoamine systems in the discriminative stimulus effects of methamphetamine (MA) was studied in squirrel monkeys by evaluating the effects of differentially selective monoamine uptake inhibitors alone and in combination. In monkeys discriminating i.m. injections of 0.3 mg/kg MA from saline, methamphetamine (0.01-0.3 mg/kg), and dopamine transporter (DAT) inhibitors, including 1-[2-(bis(4-fluorophenyl)-methoxy)ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909; 1.0-17.8 mg/kg) and its analogs AM2502 (1.0-17.8 mg/kg), AM2506 (1.0-30.0 mg/kg), AM2515 (1.0-17.8 mg/kg), and AM2517 (1.0-5.6 mg/kg), produced dose-related increases in responding on the MA-associated lever and, at the highest doses, full substitution. The time course of MA-like effects was similar for equivalent (3.0 mg/kg) doses of GBR 12909 and its most potent analog, AM2517. Unlike the DAT blockers, the selective 5-hydroxytryptamine (serotonin) uptake inhibitor clomipramine (1.0-10.0 mg/kg) and the selective norepinepherine (NE) uptake inhibitor desipramine (1.0-10 mg/kg) produced responding primarily on the saline lever. The selective NE uptake inhibitor nisoxetine partially substituted at the highest dose tested (10.0 mg/kg). Pretreatment with GBR 12909 or AM2517 enhanced the discriminative stimulus effects of MA, shifting the dose-effect curve leftward. The NE uptake inhibitors desipramine or nisoxetine also enhanced the discriminative stimulus effects of MA, whereas clomipramine only attenuated them. These results support the view that dopaminergic mechanisms play a prominent role in the discriminative stimulus effects of MA in monkeys, whereas involvement of serotonergic and noradrenergic systems may be limited to a modulatory role.


Molecular Dynamics Simulations of Nanostructures Formed by Hydrophobins and Oil in Seawater.
Classical molecular dynamics simulations using the Martini coarse-grained force field were performed to study oil nanodroplets surrounded by fungal hydrophobin (HP) proteins in seawater. The class I EAS and the class II HFBII HPs were studied along with two model oils, namely, benzene and n-decane. Both HPs exhibit free energy minima at the oil-seawater interface, which is deeper in benzene compared to the n-decane systems. Larger constraint forces are required to keep both HPs within the n-decane phase compared to inside benzene, with HFBII being more affine to benzene compared to EAS. Smaller surface tensions are observed at benzene-seawater interfaces coated with HPs compared to their n-decane counterparts. In the latter the surface tension remains unchanged upon increases in the concentration of HPs, whereas in benzene systems adding more HPs lead to decreases in surface tension. EAS has a larger tendency to cluster together in the interface compared to HFBII, with both HPs having larger coordination numbers when surrounding benzene droplets compared to when they are around n-decane nanoblobs. The HP-oil nanostructures in seawater examined have radii of gyration ranging between 2 and 12 nm, where the n-decane structures are larger and have more irregular shapes compared to the benzene systems. The n-decane molecules within the nanostructures form a compact spherical core, with the HPs partially covering its surface and clustering together, conferring irregular shapes to the nanostructures. The EAS with n-decane structures are larger and have more irregular shapes compared to their HFBII counterparts. In contrast, in the HP-benzene structures both HPs tend to penetrate the oil part of the droplet. The HFBII-benzene structures having the larger oil/HP ratios examined tend to be more compact and spherical compared to their EAS counterparts; however, some of the HFBII-benzene systems that have smaller oil/HP ratios have a more elongated structure compared to their EAS counterparts. This simulation study provides insights into HP-oil nanostructures that are smaller than the oil droplets and gas bubbles recently studied in experiments and, thus, might be challenging to examine with experimental techniques.


[Parkinson disease--problems in long-term treatment. Dopamine agonists optimize L-dopa therapy].
In a 59-year-old male with a 10 year history of Parkinson's disease, progressive movement disorders occurred under medical treatment (end-of-dose akinesia and peak-dose dyskinesia). Thereupon his treatment was changed to a combination of L-dopa/ decarboxylase inhibitor administered during the day in 5 fractions, and additionally a slow-release dopa preparation given on retiring for the night. At the same time, the patient received the dopamine agonist lisuride. While the patient was hospitalized for surgery, his anti-parkinsonism regimen was initially stopped and then continued in changed form. In the following weeks he experienced a drastic impairment of mobility and, in particular, suffered pronounced nocturnal hypokinetic events. A second period of hospitalization became necessary, a complex medical therapeutic regimen similar to the previously successful combination was established. This resulted in satisfactory mobility, and the patient was able to go back to work.


Ternary naproxen: beta-cyclodextrin:polyethylene glycol complex formation.
The aim of this study was to investigate the effect of the presence of the water-soluble polymer polyethylene glycol (PEG)-MW=35000 g/mol-on the complexation of the phototoxic anti-inflammatory drug naproxen, in its sodium salt form, with beta-cyclodextrin (beta-CD). The data revealed that the polymer does not interact with the uncomplexed naproxen whereas it does with the beta-CD. The presence of different proportions of PEG, in the 0-1% (w/w) range, systematically lowers K(app) of the formation of the naproxen:beta-CD inclusion complex. The reason for the decrease in the complexed drug is the presence of other competing equilibria, the first one is an interaction of the polymer with the beta-CD, which in turn reduces the amount of free CD available for including the naproxen, and the second is the formation of a naproxen:beta-CD:PEG ternary complex with lower affinity than the binary complex. The binding constant of these processes are K(2)=(4.5+/-1.0) x 10(5) M(-1) and K(3)=870+/-19 M(-1), respectively. In addition the presence of the PEG produces an important change in the driving force of the complex formation. In this case the process is enthalpically unfavoured and entropically favoured; these are typical characteristics of processes governed by hydrophobic interactions.


Dental implant treatment planning with reformatted computed tomography.
By using specific software programmes, it is now possible to obtain reformatted CT images of the mandible and maxilla. This facility has proved to be valuable in the planning of fixed and removable suprastructures in implantology. We describe the use of a radiopaque prosthetic template to enable the optimal position and axial inclination of the fixtures in edentulous patients to be established.


Experimental evaluation of mechanical haemolysis with Starr-Edwards, Kay-Shiley and Björk-Shiley valves.
Mechanical cell damage was studied in vitro with three types of prostheses: Starr-Edwards, Kay-Shiley and Björk-Shiley valves. Mechanical cell damage was found to be closely related to the flow characteristics in the prosthesis. Considering valves of similar orifice diameter, Björk-Shiley valves produced the lowest rate of haemolysis. This is due to the improved haemodynamic characteristics of the valve which resulted from the laminar type of flow. With Starr-Edwards valves, smaller sizes produced unacceptably high rates of haemolysis. Increasing the mean forward flow across the valve resulted in a disproportionate rise in the energy loss and the rate of haemolysis when compared with Björk-Shiley valves of similar annulus diameters.


Coronary arterial tree remodeling in right ventricular hypertrophy.
We investigated coronary vascular adaptations occurring in right ventricular hypertrophy (RVH). Six pigs had RVH induced by pulmonary artery stenosis for 5 wk. Three pigs served as controls. At autopsy we made silicone elastomer casts of the right coronary arteries (RCA) and collected morphometric data. We organized the segments and their diameters and lengths into a framework of a modified Strahler's ordering scheme in which the order number of an offspring is increased only if its diameter is greater than the diameters of its parents by a specific amount. The segments of the same order arranged in series are combined into elements. In RVH the total number of orders of vessels was larger than the control by 1; the total number of elements in each order increased greatly, whereas the diameters and lengths of each order decreased somewhat. The total RCA resistance decreased in RVH mainly because the total cross-sectional area (CSA) of every order was increased. Because the diameters of the resistance vessels decreased, this decrease in total RCA resistance was due to a numerical increase in resistance vessels. These findings indicate that new flow channels have been established. In contrast, the RCA was remodeled in that the lumen diameter increased. Pressure-flow curves showed a decrease of coronary resistance in RVH, in agreement with the morphometric findings. We conclude that there is significant remodeling of the coronary arterial vasculature in RVH, and any future analysis of coronary hemodynamics of the right ventricle in hypertrophy must take the morphometric remodeling into account.


A mechanistic study of gold nanoparticles catalysis of O2 reduction by ascorbate and hydroethidine, investigating reactive oxygen species reactivity.
In this work, the mechanism of dioxygen reduction catalysed by gold nanoparticles (AuNPs) by two electron donors was investigated, i.e., by sodium ascorbate and hydroethidine, focusing on potential ROS (reactive oxygen species) formation, such as O2˙- and H2O2. According to our results, when AuNPs catalyse the reduction of O2, ROS are formed only as intermediates on the surface of nanoparticles, and they are unavoidably reduced to water, catalysed by the AuNPs. Thus, the statement on ROS production in the presence of AuNPs often reported in the literature is excessive. The AuNPs can catalyze the oxidation of electron donors in the cell, e.g., antioxidants causing oxidative stress. Therefore we propose that when explaining damage in the living cells observed in the presence of AuNP, the catalysis of redox reactions by AuNPs must be considered.


A current view of the epigenome in mouse primordial germ cells.
Primordial germ cells (PGCs) are undifferentiated germ line cells in embryos that emerge at early stages of embryonic development, and then differentiate into eggs or sperm in gonads to give rise to individuals of successive generations. During germ cell development, several dynamic changes in epigenetic modifications including DNA methylation and histone modifications occur, and these changes are thought to be reprogramming processes that are required for germ cells to confer totipotency to the zygote. Initially, the epigenetic status of particular gene loci in PGCs was studied, but more recently, genome-wide studies have provided more comprehensive views of the PGC epigenome. Mouse PGCs undergo global DNA demethylation that starts shortly after PGC specification in early embryos. Although the functional importance of global DNA demethylation is not fully understood, demethylation of imprinted genes is crucial for erasure of methylation-based imprinting, and demethylation of PGC-specific genes is crucial for proper transcriptional regulation. PGCs also have unique patterns of histone modification, such as hypomethylation of H3K9 and hypermethylation of H3K27, and experimental evidence suggests that the unique epigenetic modifications of histones are important to the proper development of PGCs.


Epidemiology and risk factors for non-Candida albicans candidemia in non-neutropenic patients at a Chinese teaching hospital.
The purpose of this study was to describe the epidemiology of nosocomial candidemia and identify risk factors involved in infections caused by non-C. albicans Candida species in a Chinese tertiary care center over a 10-year period. A total of 102 cases of nosocomial candidemia in non-neutropenic patients admitted from 1998 through 2007 were included in the study. Candida albicans remained the most common causative agent, accounting for 57.8% of all cases, followed by C. tropicalis (12.8%), C. parapsilosis (10.8%) and C. glabrata (10.8%). Comparison of C. albicans and non-C. albicans candidemia by multivariate logistic regression showed that factors independently associated with non-C. albicans candidemia included head trauma (OR, 5.34; 95% CI, 1.18-24.17; P = 0.029) and bacterial sepsis (OR, 3.58; 95% CI, 1.17-10.98; P = 0.026). Factors independently associated with C. albicans candidemia included tracheal intubation (OR, 0.26; 95% CI, 0.08-0.92; P = 0.037), and increased peripheral WBC count (OR, 0.84; 95% CI, 0.74-0.95; P = 0.006).


Preserved brain morphology after controlled automated reperfusion of the whole body following normothermic circulatory arrest time of up to 20 minutes.
Clinical outcomes following cardiac arrest (CA) and resuscitation remain a cause for concern. The use of Controlled Automated Reperfusion of the whoLe body (CARL) confers superior neurological outcome even after extended periods of CA. We aimed at investigating clinical outcome and brain morphology preservation when employing CARL following CA periods of 20 min. Twenty-eight pigs were allocated to four extracorporeal circulation treatment strategies; seven others served as magnetic resonance imaging (MRI) controls. In prompt cardiopulmonary resuscitation (CPR; n = 6), induced circulatory arrest was followed immediately by open cardiac massage of 15 min, thereafter by CARL for 60 min. In delayed CPR (n = 6), induced CA was maintained for 15 min, after that open cardiac massage of 10 min duration was performed prior to extracorporeal CPR (ECPR) of 60 min. Induced CA times of 15 min in the ECPR 15' group (n = 6) and CA of 20 min in the CARL 20' group (n = 10) were followed by ECPR of 60 min and CARL of 60 min, respectively, without prior CPR. Daily neurological deficit scoring (NDS) up to the seventh day, markers of cellular injury [alanine transaminase (ALT), aspartate transaminase (AST) and neuron-specific enolase (NSE)] and brain MRI were performed. 100% survival and normal NDSs were achieved in all animals in the prompt CPR and ECPR 15' groups. In CARL 20', nine animals survived. In contrast, only one animal in the delayed CPR group survived; three animals died within 24 h with a further two dying on Days 4 and 5, respectively. All markers of cellular injury were elevated in the delayed CPR group, ALT [38 (20.3) to 206 U/l (158.2); P = 0.0095], AST [26 (18.8) to 97 U/l (1965.8); P = 0.0095] and NSE [0.45 (0.25) to 7.95 µg/l (24.03); P = 0.0095]. In the ECPR 15' group, only NSE [0.45 (0.15) to 1.20 µg/l (2.40); P = 0.0065] remained elevated. In the CARL 20' group, differences in ALT [36 (10) to 53 U/l (20); P = 0.0005] and NSE [0.50 (0.40) to 1.5 µg/l (0.40); P < 0.0001] values were evident. T2-weighted MR images of the cerebellum [454 (28) to 495 mm2/s (55); U = 11; P = 0.0311], caudate nucleus [400 (59) to 467 mm2/s (42); U = 9; P = 0.0156], lentiform nucleus [377 (89) to 416 mm2/s (55); U = 11; P = 0.0311] and hippocampus [421 (109) to 511 mm2/s (58); U = 9; P = 0.0164] in the CARL 20' group showed higher signal intensities compared with controls. In delayed CPR, corresponding regions of interest on early apparent diffusion coefficient images showed a restricted diffusion. In our experimental animal model of CA, CARL results in satisfactory survival at CA periods of 20 min despite detected enzyme and morphological changes. These changes did not translate to clinical neurological deficits.


Regenerative capability of skeletal muscle in chicken muscular dystrophy.
To examine the morphological sequence of regenerating fibers after myonecrosis in dystrophic muscles, 0.5 ml of 0.5% bupivacaine hydrochloride (BPVC) (Marcaine) solution, a local anesthetic with a cytotoxic effect on the muscle fibers, was injected directly into the dystrophic (line 413) and nondystrophic (line 412) posterior latissimus dorsi (PLD) muscles of young and adult chickens. Although the dystrophic muscles after BPVC injection showed a rapid recovery with a similar tempo to that of nondystrophic ones, they showed different morphological behavior in the early phase of regeneration, including marked variability in the size of fibers and in the intracytoplasmic enzyme activities of nicotinamide adenine dinucleotide, reduced-tetrazolium reductase (NADH-TR), acetylcholinesterase (AChE), and nonspecific esterase (NSE).


Hand-arm vibration in tropical rain forestry workers.
Working conditions and health hazards including vibration syndrome related to forestry work using chain-saws were studied in Papua New Guinea and Indonesia. The subjects comprised 291 workers including 97 chain-saw operators. The health examination consisted of peripheral circulatory and sensory tests in the upper extremities. The vibration spectrum measured at the handle of the chain-saw indicated that these acceleration levels would lead to a moderately high risk of hand-arm vibration syndrome (HAVS). The peripheral circulatory function tests revealed dysfunction after more than five years vibration exposure. However, in general, the results of the function tests and subjective complaints showed fewer health problems compared to those of Japanese forestry workers. The reason of such differences of vibration effects seem to be the following: (1) warmer climate (more than 25 degrees C throughout the year), (2) young workers and short work experience. (3) short time vibration exposures on working days in the natural forests, (4) seasonal changes in logging work (5) healthy workers effects. Thus, we found no clear evidence that the workers of our study suffered from HAVS. A principal component analysis was applied. The factor score of the components of the reactive dynamics of peripheral circulation differed significantly after more than five years' exposure. On the other hand, we cannot deny the possibility that subclinical dysfunction of peripheral circulation may be caused by chain-saw operation in the tropics in future. Further investigations on the HAVS among forestry workers in the tropic environment are needed.


[Congenital analgesia].
The case of a 12 years old boy with a congenital anaesthesia covering all cutaneous and visceral districts is reported. There were no other neurological abnormalities apart a light mental retardation and loss of axon reflex after intradermal injection of hystamine. Notwithstanding this last finding a diagnosis of congenital indifference to pain was made. The differential diagnosis between indifference and insensitivity to pain is discussed.


Tissue-specific bioactivity of soluble tendon-derived and cartilage-derived extracellular matrices on adult mesenchymal stem cells.
Biological scaffolds composed of tissue-derived extracellular matrix (ECM) can promote homologous (i.e., tissue-specific) cell differentiation through preservation of biophysical and biochemical motifs found in native tissues. Solubilized ECMs derived from decellularized tendon and cartilage have recently been promoted as tissue-specific biomaterials, but whether tissue-specific bioactivity is preserved following solubilization is unknown. This study explored the tissue-specific bioactivity of soluble decellularized tendon and cartilage ECMs on human bone marrow-derived mesenchymal stem cells (MSCs) presented across different culture microenvironments, including two-dimensional (2D) tissue culture plastic, aligned electrospun nanofibers, cell pellets, and cell-seeded photocrosslinkable hydrogels. Tendon and cartilage ECMs were decellularized using established methods and solubilized either via pepsin digestion or urea extraction. The effect of soluble ECMs on cell proliferation and differentiation was initially explored by supplementing basal medium of human MSCs cultured on 2D tissue culture plastic. In subsequent experiments, MSCs were cultured on aligned electrospun nanofibers, ascell pellets, or encapsulated within photocrosslinkable methacrylated gelatin (GelMA) hydrogels. Urea-extracted tendon and cartilage ECMs were added as supplements. Pepsin-digested ECMs did not promote homologous differentiation in human MSCs, whether provided as a medium supplement or three-dimensional (3D) hydrogels. In contrast, urea-extracted ECMs tended to promote tissue-specific differentiation of MSCs cultured in 2D and 3D microenvironments. The application of the small molecule TGF-β signaling inhibitor SB-431542 largely negated the tissue-specific gene expression patterns mediated by tendon and cartilage ECMs. This suggests that the action of endogenous TGF-β was required, but was not sufficient, to impart tissue-specific bioactivity of urea-extracted ECMs. When urea-extracted cartilage ECM was incorporated within a photocurable GelMA hydrogel it independently enhanced chondrogenesis in encapsulated MSCs, and showed additive prochondrogenesis upon TGF-β supplementation in the medium. Urea-extracted ECM fractions of decellularized tendon and cartilage are soluble supplements capable of enhancing tissue-specific differentiation of adult stem cells.


Cardiovascular disease risk factor clustering among African American adults.
Although the co-occurrence of multiple risk factors increases the risk of cardiovascular disease (CVD) morbidity/mortality, few studies have examined the prevalence of risk factor clustering among African Americans in community-based faith settings. This study examined the prevalence and clustering of CVD risk factors in a sample of church members from South Carolina. Cross-sectional analysis of baseline data from a faith-based intervention, Faith, Activity, and Nutrition (FAN). African Methodist Episcopal churches in four geographically-defined districts in South Carolina. 1119 church members. Self-reported presence or absence of healthcare provider diagnosed diabetes, high cholesterol, and hypertension. Objectively measured blood pressure, height, and weight (body mass index) were also taken. The prevalence of single, multiple, and clustering of risk factors was computed. 62% of participants were obese, 64% had hypertension, 23% had diabetes, and 39% had high cholesterol; 15% had no risk factors, 24% had 1 risk factor, 30% had 2 risk factors, 22% had 3 risk factors, and 10% had 4 risk factors. The most common clusters of risk factors were: obese and hypertensive (18%), obese, hypertensive and hypercholesterolemic (13%), and obese, hypertensive, hypercholesterolemic, and diabetic (10%). The prevalence of risk factors and risk factor clustering in church members in South Carolina is exceedingly high. Culturally-relevant behavioral interventions targeting risk factor reduction in this population should be a public health goal.


Gaucher disease: Perspectives on a prototype lysosomal disease.
Gaucher disease is an autosomal recessive trait and the most common lysosomal storage disease. The pathogenesis evolves from the diminished activity of the lysosomal hydrolase, acid beta-glucosidase and the resultant accumulation of glucosylceramide within lysosomes. The pathogenic mechanisms are poorly understood. During the past 2 decades, progress has been made in understanding the biochemical basis and molecular biology of the disease, but more fundamental knowledge is required to relate these advances to the cell and whole body phenotypes. Despite this lack of understanding, enzyme replacement therapy has proved a successful and effective management for Gaucher disease. However, basic details of this therapeutic efficacy require elucidation. Here, we review the current state of the molecular pathogenesis and provide our perspective of some major issues for continued advances in this prototype lysosomal storage disease.


Induced pluripotent stem cells from patients with focal cortical dysplasia and refractory epilepsy.
Focal cortical dysplasia (FCD) is caused by numerous alterations, which can be divided into abnormalities of the cortical architecture and cytological variations; however, the exact etiology of FCD remains unknown. The generation of induced pluripotent stem cells (iPSCs) from the cells of patients with neurological diseases, and their subsequent tissue‑specific differentiation, serves as an invaluable source for testing and studying the initial development and subsequent progression of diseases associated with the central nervous system. A total of 2 patients demonstrating seizures refractory to drug treatment, characterized as FCD Type IIb, were enrolled in the present study. Fibroblasts were isolated from residual skin fragments obtained from surgical treatment and from brain samples obtained during surgical resection. iPSCs were generated following exposure of fibroblasts to viral vectors containing POU class 5 homeobox 1 (OCT4), sex determining region Y‑box 2 (SOX2), Kruppel‑like factor 4 and c‑MYC genes, and were characterized by immunohistochemical staining for the pluripotent markers homeobox protein NANOG, SOX2, OCT4, TRA1‑60 and TRA1‑81. The brain samples were tested with antibodies against protein kinase B (AKT), phosphorylated‑AKT, mechanistic target of rapamycin (mTOR) and phosphorylated‑mTOR. Analysis of the AKT/mTOR pathway revealed a statistically significant difference between the cerebral tissues of the two patients, which were of different ages (45 and 12 years old). Clones with the morphological features of embryonic cells were detected on the 13th day and were characterized following three subcultures. The positive staining characteristics of the embryonic cells confirmed the successful generation of iPSCs derived from the patients' fibroblasts. Therefore, the present study presents a method to obtain a useful cellular source that may help to understand embryonic brain development associated with FCD.


Hydration with mercuric acetate and the reduction with 9-BBN-H of 2-(1-alkenyl)-4,6-dimethyl-s-triazines.
Oxymercuration-demercuration of a double bond in conjugation with the 4,6-dimethyl-s-triazin-2-yl substituent as in alkenes 1a,b gave anti-Markovnikov regioselectivity, which is explained by the electron-withdrawing nature of the triazinyl substituent. However, hydroboration of the conjugated alkenes with 9-BBN-H gave the corresponding alkanes 5a-c under normal workup conditions with or without oxidation. With time and without workup the hydroboration of 1b gave spectral evidence for the formation of intermediates 9-13 resulting from the migration of the 9-BBN moiety from the alpha-carbon to a ring nitrogen with concurrent formation of an exocyclic double bond to an alpha-carbon of the ring. Hydrolysis of the intermediates gave 5a-c. A possible mechanism involving successive allylic rearrangements is presented.


Drug therapy of hypertensive crises.
The clinical features, pathogenesis, and pharmacologic management of hypertensive crises are reviewed, with emphasis on newer therapies. Hypertensive crises may be divided into hypertensive emergencies and hypertensive urgencies. Hypertensive emergencies, in which acute organ damage exists, require blood pressure reduction within one hour. In hypertensive urgencies no acute end-organ damage has yet occurred; however, blood pressure should be controlled within 24 hours. Factors that may precipitate a hypertensive crisis include renovascular hypertension, acute glomerulonephritis, head injuries, renin- or catecholamine-secreting tumors, antihypertensive-therapy withdrawal syndromes, eclampsia, and ingestion of tyramine by patients receiving monoamine oxidase inhibitors. The traditional drug of choice for therapy of hypertensive emergencies is sodium nitroprusside. Intravenous labetalol produces a prompt, controlled reduction in blood pressure and is a promising alternative. Other agents used are diazoxide, trimethaphan camsylate, hydralazine, nitroglycerin, and phentolamine. However, all these agents have disadvantages, including unpredictable antihypertensive effects, difficult blood pressure titration, and serious potential adverse effects such as profound hypotension, reduced renal blood flow, and increased myocardial workload. Most patients with hypertensive urgencies can be effectively treated with orally or sublingually administered agents. Older regimens of reserpine, methyldopa, or guanethidine, with their slow onsets and long durations of action, have been largely replaced by clonidine and nifedipine. Captopril and minoxidil have also been used with some success. Despite the lack of comparative trials with traditional agents, demonstrated efficacy and desirable pharmacologic characteristics have made several new agents acceptable for therapy of hypertensive crises.


The effects of pectin and wheat bran on the distribution of a meal in the gastrointestinal tract of the rat.
The effects of wheat bran and pectin on the gastrointestinal distribution of a radiolabelled, homogenized baked-bean meal were investigated in the rat. These fibres were chosen because of their very different physical characteristics; wheat bran is a coarse, particulate, mainly insoluble fibre whilst pectin is a soluble viscous polysaccharide. Sixty male rats were administered orally with control or test meals and five from each group were killed after 50, 100, 200 and 300 min. The gut was removed and the distribution of the meal established scintigraphically. Addition of the fibres altered the distribution of the meal with faster accumulation at the distal and caecal areas. Wheat bran delayed gastric emptying whilst pectin promoted gastric emptying and had a pronounced effect on increasing the distal accumulation of the meal. These alterations in the distribution of a homogenized baked bean meal show that dietary fibres with different physical characteristics may alter gastrointestinal motility in different ways and these differences may have implications for meal absorption and clinical treatments of gastrointestinal disorders.


Axial Colocalization of Single Molecules with Nanometer Accuracy Using Metal-Induced Energy Transfer.
Single-molecule localization based super-resolution microscopy has revolutionized optical microscopy and routinely allows for resolving structural details down to a few nanometers. However, there exists a rather large discrepancy between lateral and axial localization accuracy, the latter typically three to five times worse than the former. Here, we use single-molecule metal-induced energy transfer (smMIET) to localize single molecules along the optical axis, and to measure their axial distance with an accuracy of 5 nm. smMIET relies only on fluorescence lifetime measurements and does not require additional complex optical setups.


The adipocyte-derived hormone leptin has proliferative actions on androgen-resistant prostate cancer cells linking obesity to advanced stages of prostate cancer.
Background. Because obesity may be a risk factor for prostate cancer, we investigated proliferative effects of adipocytes-derived hormone leptin on human prostate cancer cells and assessed the role of mitogen-activated protein kinase (MAPK) signaling pathway in mediating these actions. Material and Methods. Three human prostate cancer cell lines were treated with increasing doses of recombinant leptin. Cell growth was measured under serum-free conditions using a spectrophotometric assay. Further, Western blotting was applied to detect the phosphorylation of an ERK1/2, and a specific inhibitor of MAPK (PD98059; 40 μM) was used. Results. In both androgen-resistant cell lines DU145 and PC-3, cell growth was dose-dependently increased by leptin after 24 hrs and 48 hrs of incubation, whereas leptin's proliferative effects on androgen-sensitive cell line LNCaP was less pronounced. Further, leptin caused dose-dependent ERK1/2 phosphorylation in both androgen-resistant cell lines, and pretreatment of these cells with PD98059 inhibited these responses. Conclusions. Leptin may be a potential link between obesity and risk of progression of prostate cancer. Thus, studies on leptin and obesity association to prostate cancer should differentiate patients according to androgen sensitivity.


Implementing a Fee-for-Service Cervical Cancer Screening and Treatment Program in Cameroon: Challenges and Opportunities.
Cervical cancer screening is one of the most effective cancer prevention strategies, but most women in Africa have never been screened. In 2007, the Cameroon Baptist Convention Health Services, a large faith-based health care system in Cameroon, initiated the Women's Health Program (WHP) to address this disparity. The WHP provides fee-for-service cervical cancer screening using visual inspection with acetic acid enhanced by digital cervicography (VIA-DC), prioritizing care for women living with HIV/AIDS. They also provide clinical breast examination, family planning (FP) services, and treatment for reproductive tract infection (RTI). Here, we document the strengths and challenges of the WHP screening program and the unique aspects of the WHP model, including a fee-for-service payment system and the provision of other women's health services. We retrospectively reviewed WHP medical records from women who presented for cervical cancer screening from 2007-2014. In 8 years, WHP nurses screened 44,979 women for cervical cancer. The number of women screened increased nearly every year. The WHP is sustained primarily on fees-for-service, with external funding totaling about $20,000 annually. In 2014, of 12,191 women screened for cervical cancer, 99% received clinical breast exams, 19% received FP services, and 4.7% received treatment for RTIs. We document successes, challenges, solutions implemented, and recommendations for optimizing this screening model. The WHP's experience using a fee-for-service model for cervical cancer screening demonstrates that in Cameroon VIA-DC is acceptable, feasible, and scalable and can be nearly self-sustaining. Integrating other women's health services enabled women to address additional health care needs. The Cameroon Baptist Convention Health Services Women's Health Program successfully implemented a nurse-led, fee-for-service cervical cancer screening program using visual inspection with acetic acid-enhanced by digital cervicography in the setting of a large faith-based health care system in Cameroon. It is potentially replicable in many African countries, where faith-based organizations provide a large portion of health care. The cost-recovery model and concept of offering multiple services in a single clinic rather than stand-alone "silo" cervical cancer screening could provide a model for other low-and-middle-income countries planning to roll out a new, or make an existing, cervical cancer screening services accessible, comprehensive, and sustainable.


Ethnicity, aging, and oral health outcomes: a conceptual framework.
An expanded version of Andersen's Behavioral Model of Health Services Utilization is used as the theoretical and analytical framework for the International Collaborative Study of Oral Health Outcomes (ICS-II). The conceptual framework for understanding determinants of oral health is based on a "systems" perspective. The framework posits that characteristics of the external environment, the dental care delivery system, and the personal characteristics of the population influence oral health behaviors. The expanded behavioral model conceptualizes health behaviors (oral hygiene practices and dental services utilization) as intermediate dependent variables, which in turn influence oral health outcomes (evaluated, perceived, patient satisfaction). The framework is presented with an increased focus on the effects of race-ethnicity and age cohort, the major exogenous variables used in this study for systematic assessment of the differences in the multitude of factors influencing oral health. The framework can be applied by policy analysis and health services managers to help describe, predict, and explain population-based health behaviors and health outcomes.


Using "click" chemistry to access a new class of tripodal P3-ligand containing P=C bonds.
High yielding "click" reactions between phosphaalkynes and organo-triazides have afforded examples of tris(triazaphosphole)s, the utility of which as a new class of tripodal P(3)-ligand has been demonstrated with the preparation of an unusual diplatinum complex.


NAD+ biosynthesis from tryptophan in the presence of nicotinic acid or vice versa by rat hepatocytes--effect of clofibrate-feeding.
NAD+ biosynthesis from tryptophan in the presence of nicotinic acid or vice versa by rat hepatocytes was investigated. In the control hepatocytes, NAD+ synthesis from tryptophan was not affected by nicotinic acid from 0.026 to 0.26 mM. NAD+ synthesis from nicotinic acid was slightly inhibited with varying concentrations of tryptophan from 0.1 to 1.0 mM. In the clofibrate-treated hepatocytes, NAD+ synthesis from tryptophan was greatly increased (234% of the control), while that from nicotinic acid was decreased (71.2% of the control). Both, NAD+ synthesis from tryptophan and that from nicotinic acid were decreased by the coexisting nicotinic acid or tryptophan. Total amount of NAD+ synthesized from tryptophan and nicotinic acid at their physiological concentrations was significantly higher than that in the control hepatocytes as a result of a large increase of NAD+ synthesized from tryptophan. When the metabolic flux of 0.1 or 0.5mM tryptophan was investigated, the glutarate pathway was suppressed in the clofibrate-treated hepatocytes, the quinolinic acid-NAD+ flux being elevated. Similarly to clofibrate, DEHP and CPP revealed an increase in NAD+ synthesis from tryptophan. Mutual relationship of NAD+ biosyntheses from tryptophan and nicotinic acid in rat hepatocytes is discussed and the relevance with peroxisomal proliferation is suggested.


Above-ground carbon stock and REDD+ opportunities of community-managed forests in northern Thailand.
This study aimed to investigate the structure of two deciduous forests and assess their above-ground carbon stock in order to promote community forest management (CFM) for REDD+ opportunities in the Ban Mae Chiang Rai Lum Community Forest in northern Thailand. A systematic sampling method was used to establish twenty-five sample plots of 40 m × 40 m (0.16 ha) each that were used to survey the entire 3,925 ha area of the community forest. Cluster analysis identified two different forest types: dry dipterocarp forest and mixed deciduous forest. It was determined that the above-ground carbon stock did not vary significantly between them. An analysis of carbon sequestration in the community forest indicates that carbon stock increased under CFM from 2007 to 2018 by an estimated 28,928 t C and participation in the carbon market would have yielded approximately US $339,730.43 or US $8.66 /ha/year to the community for that 10-year period. Projections for 2028 reflect that carbon stock will experience continual growth which indicates that maintaining CFM can increase carbon sequestration and reduce CO2 emissions. However, though further growth of carbon stock in the community forest is expected into 2038, that growth would be at a lesser rate than during the preceding decade. This suggests that CFM management should address forest utilization practices with a focus on maintaining long term carbon stock growth. Additional measures to address the impact of drought conditions and to safeguard against forest fires are required to sustain tree species' growth and expansion in order to increase their carbon accumulation potential. Thailand's community forest involvement in REDD+ and participation in its international carbon market could create more economic opportunities for local communities.


Nuclear receptors in herb-drug interactions.
Widespread usage of herbs as supplements or medicines raises the potential of herb-drug interactions (HDIs). Basically, HDIs occur by pharmacokinetic and/or pharmacodynamic pathways. Nuclear receptors (NRs) are a class of transcription factors whose role in drug interactions has been defined. A large number of herbs activate NRs, resulting in HDIs. NR-mediated HDIs are similar to drug-drug interactions, but are more complicated because of the presence of multiple compounds in herbs. Dosage and therapeutic sequence as well as various other factors, including the patient's gender, age, and genetic makeup, may affect outcomes of NR-mediated HDIs.


Anterior Capsular Reconstruction With Proximal Biceps Tendon for Large to Massive Rotator Cuff Tears.
Massive rotator cuff tears (RCT) have traditionally been a challenging clinical problem for shoulder surgeons. A broad variety of treatment options have been proposed to address this problem, but outcomes have been as variable as the techniques themselves. Superior capsular reconstruction has been presented as a way to restore the restraining effect of the superior joint capsule and balanced force couples in massive tears of the superior rotator cuff. The purpose of this article is to propose a technical modification of the superior capsular reconstruction in large to massive RCT, and, especially in anterior L-shaped RCT, using the long head of the biceps tendon autograft to reinforce the weakest area of the anterior capsule, not as an augmentation of the rotator cuff, but as a static stabilizer of the humeral head, allowing the rotator cuff repair to heal without tension.


Arterial embolism and thrombosis.
An effort should be made to differentiate between acute arterial embolism and acute arterial thrombosis. Most patients seen early with acute arterial embolism and a viable extremity should be heparinized and operated upon as soon as possible. Patients with acute arterial thrombosis should be treated with heparin and possibly streptokinase and not operated upon urgently. That group of patients in whom the diagnosis is in doubt and who have a viable extremity should be heparinized and have arterial exploration only if their general condition is satisfactory for an operation. Patients with a nonviable extremity should have an amputation as soon as their general condition permits. One important implication in the modern era of the management of peripheral arterial embolectomy is the requirement that the surgeon dealing with the embolus identify its source and institute appropriate treatment, whether it be replacement of a cardiac valve or removal of a proximal arterial aneurysm.


Ketoacidosis associated with SGLT2 inhibitor treatment: Analysis of FAERS data.
Regulatory agencies have concluded that sodium glucose cotransporter 2 (SGLT2) inhibitors lead to ketoacidosis, but published literature on this point remains controversial. We searched the FDA Adverse Event Reporting System (FAERS) for reports of acidosis in patients treated with canagliflozin, dapagliflozin, or empagliflozin (from the date of each drug's FDA approval until May 15, 2015). We compared the number of SGLT2 inhibitor-related reports to reports of acidosis in patients treated with the 2 most commonly used DPP4 inhibitors: sitagliptin and saxagliptin. We estimated relative risks of acidosis by relating the number of reports to cumulative drug sales (a surrogate for patient exposure). FAERS contained 259 reports of acidosis (including 192 reports of ketoacidosis) for SGLT2 inhibitors compared with 477 reports of acidosis for DPP4 inhibitors (including 71 reports of ketoacidosis). Based on estimated patient exposure, the overall risk of developing acidosis was ~14-fold higher for SGLT2 inhibitors. Among 51 SGLT2 inhibitor-related reports with quantifiable metabolic information, 20 cases occurred in patients with type 1 diabetes (T1D), 25 in type 2 diabetes (T2D), and 6 in patients with unspecified type of diabetes. After excluding patients with T1D and focusing on patients identified as having T2D, we estimate that SGLT2 inhibitors were associated with ~7-fold increase in developing acidosis. Seventy-one percent had euglycemic ketoacidosis. Our results support the FDA's warning that SGLT2 inhibitors lead to ketoacidosis, as evidenced by an increased reporting rate for acidosis above that in a comparator population treated with DPP4 inhibitors.


Anesthetic Considerations and Perioperative Management of Spinal Cord Stimulators: Literature Review and Initial Recommendations.
Patients with implanted spinal cord stimulators (SCS) present to the anesthesia care team for management at many different points along the care continuum. Currently, the literature is sparse on the perioperative management. What is available is confusing; monopolar electrocautery is contraindicated but often used, full body magnetic resonance imaging (MRI) is safe with particular systems but with other manufactures only head and specific extremities exams are safe. Moreover, there are anesthetizing locations outside of the operating room where implanted SCS can interact with surrounding medical equipment and pose significant risk to patient and device. The objective of this review is to present relevant known literature about the safe management of SCS in the perioperative period and to begin to develop recommendations. A review of current literature and each manufacturers' labeling was performed to assess risk of interference and patient harm between SCS and technology used in and around typical anesthetizing locations. A systematic search of the literature was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. A computerized search was conducted for English articles in print up to April 2016 via PubMed www.ncbi.nlm.nih.gov/pubmed; EMBASE www.embase.com; and Cochrane Library www.thecochranelibrary.com. Search terms included "spinal cord stimulator AND MRI," "spinal cord stimulator AND ECG," "spinal cord stimulator AND implanted cardiac device," "spinal cord stimulator AND electrocautery," and "spinal cord stimulator AND obstetrics." In addition, a search of Google and Google Scholar was performed. Websites of SCS manufactures were reviewed. Generalized recommendations include turning the amplitude of the SCS to the lowest possible SETTING and turning off prior to any procedure. Monopolar electrocautery is contraindicated but is still often utilized; placing grounding pads as far away from the device can reduce the risk to device and patient. Bipolar cautery is favored. Implanted cardiac devices can interfere with SCS, but risks can be minimized. Neuraxial anesthesia can be attempted in a patient with implanted SCS, provided the device is not in the expected path. MRI labeling differences present the biggest difference among SCS manufactures. Medtronic's SureScan SCS, Boston Scientific's Precision system, St. Jude's Proclaim, and Stimwave's Freedome SCS are full body MRI compatible under specific conditions, while other manufacturers have labeling that restricts exams of the trunk and certain extremities. This review was intended to be a comprehensive, cumulative review of recommendations for perioperative SCS management; however, the limitations of a review of this nature is the complete reliance on previously published research and the availability of these studies using the methods outlined. SCS is being used earlier in the treatment algorithm for patients with chronic pain. The anesthesia care team needs working knowledge of where the device resides in the neuraxial space and what risks different medical technologies pose to the patient and device. This understanding will lead to appropriate perioperative management which can reduce risk and improve patient outcomes.


[Endemic goiter in a non-goitrogenic country].
Although goiter is not endemic in Israel, an iodine-rich country due to its bordering on the Mediterranean, we see many adults with massive goiters among immigrants from Afro-Asian and eastern European countries. 702 thyroidectomies were performed between January 1986 and March 1993 and 39 consecutive cases of goiter were studied. The patients ranged in age from 32-83 years (mean, 48); the female/male ratio was 36/3. There were 15 cases (13%) of thyroid carcinoma. In 1 case hyperthyroidism was diagnosed and treated preoperatively (3%) and in 2 others subclinical hypothyroidism was found (5%). The cervical approach was used, including cases with substernal extension. In only 1 was sternal splitting necessary. In our experience enlarged nodular goiter, with or without substernal extension, should be operated before symptoms of tracheal pressure develop and to avoid the risk of neglected malignancy hidden in an enlarged thyroid.


Manifestation of psychiatric behaviors in a mouse model of griseofulvin-induced hepatic porphyria.
Most patients with hepatic porphyria exhibit neuropsychiatric symptoms, including abdominal pain, peripheral neuropathy, confusion, insomnia and mental disturbances such as anxiety and depression. Although heme deficiency and accumulation of heme precursors are thought to be responsible for neuropsychiatric manifestations in patients with acute porphyria, the pathogenetic mechanisms remain poorly understood. In the present study, we observed psychiatric behaviors in mice with hepatic porphyria induced by the ingestion of a griseofulvin (GF)-containing diet over a period of 12 weeks. GF ingestion by the mice caused an accumulation of porphyrins in the feces and a decrease in heme in the liver; these effects were observed throughout the entire duration of the experiment, with maximum levels observed after circa 1 week of ingestion of this diet. In addition, the mice developed enlargement of the liver, hepatocyte injury, and cholestasis. Mice with hepatic porphyria manifested an anxiety-like behavior by the long-term treatment (over 5 weeks) in a GF-dose and duration dependent manner. The hepatic porphyria mice also manifested depression-like behaviors by the short-term treatment (3 weeks) of GF2.0, which was reversed by administration of anti-depressant, imipramine. In conclusion, this study for the first time demonstrated psychiatric manifestations in GF-induced hepatic porphyria mice. The present results suggest that model animals could be useful for elucidating the mechanisms underlying psychiatric manifestations in syndromes such as hepatic porphyria and hepatic encephalopathy that are associated with the impairment of hepatic function.