Optimizing the Schedule of PARP Inhibitors in Combination with 177Lu-DOTATATE: A Dosimetry Rationale.
177Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells to repair 177Lu-induced DNA damage. To decrease the risk of side effects, the sequencing should be optimized according to the tumour-to-normal tissue enhanced dose ratio (TNED). The aim of this study was to investigate how to enhance 177Lu-DOTATATE by optimal timing of the addition of a PARP inhibitor. Biokinetic modelling was performed based on the absorbed dose to the bone marrow, kidneys and tumour; determined from SPECT/CT and planar images from 17 patients treated with 177Lu-DOTATATE. To investigate the theoretical enhanced biological effect of a PARP inhibitor during 177Lu-DOTATATE treatment, the concept of relative biological effectiveness (RBE) was used, and PARP inhibitor administration was simulated over different time intervals. The absorbed dose rate for the tumour tissue demonstrated an initial increase phase until 12 h after infusion followed by a slow decrease. In contrast, the bone marrow showed a rapid initial dose rate decrease. Twenty-eight days after infusion of 177Lu-DOTATATE, the full absorbed dose to the bone marrow and kidney was reached. Using an RBE value of 2 for both the tumour and normal tissues, the TNED was increased compared to 177Lu-DOTATATE alone. According to the modelling, the PARP inhibitor should be introduced approximately 24 h after the start of 177Lu-DOTATATE treatment and be continued for up to four weeks to optimize the TNED. Based on these results, a phase I trial assessing the combination of olaparib and 177Lu-DOTATATE in somatostatin receptor-positive tumours was launched in 2020 (NCT04375267).


Specialty food safety concerns and multilingual resource needs: an online survey of public health inspectors.
The province of Ontario, Canada, has a highly diverse and multicultural population. Specialty foods (i.e., foods from different cultures) are becoming increasingly available at retail food outlets and foods service establishments across the province; as a result, public health inspectors (PHIs) are increasingly required to assess the safety of foods with which they may be unfamiliar. The aim of this study was to investigate the concerns, perceptions, and self-identified needs of PHIs in Ontario with regard to specialty foods and food safety information resources in languages other than English. A cross-sectional online survey of 239 PHIs was conducted between April and June 2009. The study found that while some food safety information resources were available in languages other than English, fewer than 25% of respondents (56/239) were satisfied with the current availability of these resources. With regard to specialty foods, 60% of respondents (143/239) reported at least one specialty food with which they were not confident about their current food safety knowledge, and 64% of respondents (153/239) reported at least one specialty food with which they were dissatisfied with the current availability of food safety information. Therefore, the development of additional food safety information resources for specialty foods, and food safety resources in additional languages may provide enhanced support to PHIs involved in protecting and promoting a safe food supply.


The role of content knowledge in conceptions of teaching effectiveness in physical education.
Physical education teachers and the programs that prepare them find themselves in the early part of the 21st century in a public policy environment that differs significantly from that of the 20th century. This policy environment is grounded in an ideology that postulates that schools and teachers, rather than social forces, should be held responsible for academic outcomes, and in turn, economic success. For the first time, physical education teachers are being held accountable for student learning in the same way as their classroom peers. Improving the effectiveness of teachers is seen as the primary mechanism for improving student learning. In discussing how teaching effectiveness has evolved, I describe a relationship among the process-product paradigm, the ecological paradigm, and a neo-ecological paradigm called the instructional core. The latter paradigm extends our understanding of teaching effectiveness in new ways by describing the dynamic and interdependent relationship among teacher, student, and content in the gymnasium. It has significant implications for the professional development of teachers and the conduct of teaching effectiveness research. I conclude by discussing why content is so critical to conceptions of teaching effectiveness.


Calcium hydroxide intracanal dressing removal with different rotary instruments and irrigating solutions: a scanning electron microscopy study.
This study evaluated the efficacy of 2 types of rotary instruments employed in association with sodium hypochlorite (NaOCl) or EDTA in removing calcium hydroxide (CH) residues from root canals dentin walls. Forty-two mandibular human incisors were instrumented with the ProTaper System up to F2 instrument, irrigated with 2.5% NaOCl followed by 17% EDTA and filled with a CH intracanal dressing. After 7 days, the CH dressing was removed using 4 techniques: NiTi rotary instrument size 25, 0.06 taper (K3 Endo) and irrigation with 17% EDTA (Group 1), NiTi rotary F1 instrument (ProTaper) and irrigation with 17% EDTA (Group 2), NiTi rotary instrument size 25, 0.06 taper and irrigation with 2.5% NaOCl (Group 3) and NiTi rotary F1 instrument and irrigation with 2.5% NaOCl (Group 4). Two roots without intracanal dressing were used as negative controls. Teeth were evaluated by scanning electron microscopy, in the cervical and apical canal thirds. None of the techniques removed the CH dressing completely. In the apical and cervical thirds, F1 instrument was better than instrument size 25, 0.06 taper in removing CH residues (p<0.05), regardless of the final irrigating solution. No difference was found between the irrigating solutions in the groups of F1 instrument and of instrument size 25, 0.06 taper (p>0.05). The negative controls had no CH residues on the dentin walls. In conclusion, the ProTaper F1 instrument was better than K3 Endo instrument size 25, 0.06 taper in the removal of CH intracanal medication, regardless of irrigating solution used.


Exposure to third-hand smoke during pregnancy may increase the risk of postpartum depression in China.
Our aim was to investigate the association between third-hand smoke exposure (THS) during pregnancy and postpartum depression (PPD) among Chinese women. A total of 973 participants that completed the questionnaire and reviews were included in this cross-sectional study. The THS exposure was assessed based on a questionnaire with key questions from the Global Adult Tobacco Survey (2nd edition) while postpartum depression status was assessed using the Edinburgh Postnatal Depression Scale. Logistic regression models were used to estimate the association between THS exposure during pregnancy and risk of PPD, after adjustment for potential confounders. The prevalence of postpartum depression among all participants was 17.8%. Of the 973 participants, 725 (74.5%) were exposed to THS during pregnancy while 248 (25.5%) were not. Compared with those who were never exposed to passive smoking, puerperal women who were exposed to THS were at higher risk of PPD (OR=1.71, 95% CI: 1.12-2.60) in the logistic regression model. Our study suggests that exposure to third-hand smoke may be a risk factor for postpartum depression among Chinese women. Future preventive interventions should include strategies that target the puerperal women who are exposed to THS during pregnancy. Tobacco control measures that are effective in reducing the prevalence of smoking may have little effect in reducing women's exposure to THS during pregnancy, especially in private places that urgently need other public health strategies.


Targeting palmitoyl acyltransferase ZDHHC21 improves gut epithelial barrier dysfunction resulting from burn-induced systemic inflammation.
Clinical studies in burn patients demonstrate a close association between leaky guts and increased incidence or severity of sepsis and other complications. Severe thermal injury triggers intestinal inflammation that contributes to intestinal epithelial hyperpermeability, which exacerbates systemic response leading to multiple organ failure and sepsis. In this study, we identified a significant function of a particular palmitoyl acyltransferase, zinc finger DHHC domain-containing protein-21 (ZDHHC21), in mediating signaling events required for gut hyperpermeability induced by inflammation. Using quantitative PCR, we show that ZDHHC21 mRNA production was enhanced twofold when intestinal epithelial cells were treated with TNF-α-IFN-γ in vitro. In addition, pharmacological targeting of palmitoyl acyltransferases with 2-bromopalmitate (2-BP) showed significant improvement in TNF-α-IFN-γ-mediated epithelial barrier dysfunction by using electric cell-substrate impedance-sensing assays, as well as FITC-labeled dextran permeability assays. Using acyl-biotin exchange assay and click chemistry, we show that TNF-α-IFN-γ treatment of intestinal epithelial cells results in enhanced detection of total palmitoylated proteins and this response is inhibited by 2-BP. Using ZDHHC21-deficient mice or wild-type mice treated with 2-BP, we showed that mice with impaired ZDHHC21 expression or pharmacological inhibition resulted in attenuated intestinal barrier dysfunction caused by thermal injury. Moreover, hematoxylin and eosin staining of the small intestine, as well as transmission electron microscopy, showed that mice with genetic interruption of ZDHHC21 had attenuated villus structure disorganization associated with thermal injury-induced intestinal barrier damage. Taken together, these results suggest an important role of ZDHHC21 in mediating gut hyperpermeability resulting from thermal injury.NEW & NOTEWORTHY Increased mucosal permeability in the gut is one of the major complications following severe burn. Here we report the novel finding that zinc finger DHHC domain-containing protein-21 (ZDHHC21) mediates gut epithelial hyperpermeability resulting from an experimental model of thermal injury. The hyperpermeability response was significantly attenuated with a pharmacological inhibitor of palmitoyl acyltransferases and in mice with genetic ablation of ZDHHC21. These findings suggest that ZDHHC21 may serve as a novel therapeutic target for treating burn-induced intestinal barrier dysfunction.


Proteomic Characterisation of the Salt Gland-Enriched Tissues of the Mangrove Tree Species Avicennia officinalis.
Plant salt glands are nature's desalination devices that harbour potentially useful information pertaining to salt and water transport during secretion. As part of the program toward deciphering secretion mechanisms in salt glands, we used shotgun proteomics to compare the protein profiles of salt gland-enriched (isolated epidermal peels) and salt gland-deprived (mesophyll) tissues of the mangrove species Avicennia officinalis. The purpose of the work is to identify proteins that are present in the salt gland-enriched tissues. An average of 2189 and 977 proteins were identified from the epidermal peel and mesophyll tissues, respectively. Among these, 2188 proteins were identified in salt gland-enriched tissues and a total of 1032 selected proteins were categorized by Gene Ontology (GO) analysis. This paper reports for the first time the proteomic analysis of salt gland-enriched tissues of a mangrove tree species. Candidate proteins that may play a role in the desalination process of the mangrove salt glands and their potential localization were identified. Information obtained from this study paves the way for future proteomic research aiming at elucidating the molecular mechanism underlying secretion in plant salt glands. The data have been deposited to the ProteomeXchange with identifier PXD000771.


[Case-control study of markers of oxidative stress and metabolism of blood iron in Parkinson's disease].
Increasingly growing evidence exists of the involvement of oxidative stress mechanisms in Parkinson's disease. Lower levels of GSH in the sustantia nigra, an increase in iron buildup, an increase in the byproducts of lipid peroxidation and alterations in the mitochondrial complex I have been described. However, few studies have been made of levels of antioxidants in the peripheral bloodstream and of the influence of the intake of nutrients on the development of this disease. In a group of 79 patients afflicted with idiopathic Parkinson's disease and a control group comprised of 107 subjects, compared by age, sex and place of residence, the lowered levels in the plasma of glutathione (GSH), malon dialdehyde (MDA), uric acid, tocophenol, beta-carotene, lycopene and different iron metabolism parameters were studied. Likewise, the intake of certain antioxidants was estimated based on a dietary survey. Significant differences (p < or = 0.001) were found in the plasma levels of GSH between cases (0.10 mumol/ml +/- 0.06) and controls (0.29 mumol/ml +/- 0.12). Likewise, the plasma levels of uric acid were lower (p < or = 0.05) in the cases (4.96 mg/ml +/- 1.96) than in the control groups (5.39 mg/ml +/- 1.13). No significant difference was found in the plasma levels of MDA, tocopherol, beta-carotene and lycopene. With regard to iron metabolism, significantly higher ferritine and transferrin values were found in the patients with EP than in the control group, showing a lower transferrin saturation percentage (p < or = 0.05). The iron showed no significant changes between cases and control groups. The results of this study support the possible involvement of oxidative stress in the pathogenesis of Parkinson's disease and reveal, in turn, alterations in some peripheral blood parameters in keeping with known findings in the sustantia nigra.


Current status and future prospects of mesenchymal stem cell therapy for liver fibrosis.
Liver fibrosis is the end-stage of many chronic liver diseases and is a significant health threat. The only effective therapy is liver transplantation, which still has many problems, including the lack of donor sources, immunological rejection, and high surgery costs, among others. However, the use of cell therapy is becoming more prevalent, and mesenchymal stem cells (MSCs) seem to be a promising cell type for the treatment of liver fibrosis. MSCs have multiple differentiation abilities, allowing them to migrate directly into injured tissue and differentiate into hepatocyte-like cells. Additionally, MSCs can release various growth factors and cytokines to increase hepatocyte regeneration, regress liver fibrosis, and regulate inflammation and immune responses. In this review, we summarize the current uses of MSC therapies for liver fibrosis and suggest potential future applications.


Pulmonary function in patients with trophoblastic disease treated with low-dose methotrexate.
The Sheffield Trophoblastic Disease Centre treats about 25 patients with persistent trophoblastic disease each year. A total of 75% of patients are classified as low risk according to the Charing Cross Hospital prognostic scoring system and receive methotrexate (MTX) 50 mg, i.m., on days 1, 3, 5, 7 with folinic acid 7.5 mg orally 24 h after each methotrexate injection. There is a 7-day rest between treatment cycles. Remission is achieved in 85% of cases. Approximately 20% of patients experienced pleuritic chest pain and dyspnoea. We have evaluated prospectively lung function in 16 low-risk patients receiving methotrexate. All patients had pulmonary function tests [spirometry-forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR), and transfer factor - TLCO, kCO] performed before and after completed treatment. A mean of 7.5 cycles of MTX were administered (range 4-11). There was a significant reduction in the mean TLCO (mean pre/post 8.15/7.38 mmol min-1 kPa-1, P = 0.01), but there were no other statistically significant changes. Three patients experienced respiratory symptoms and were found to have a 39%, 28%, and 11% reduction in TLCO from baseline, improving on follow up to pretreatment levels. Low-dose MTX is an effective therapy but may cause troublesome pulmonary toxicity.


The drug regulatory and review process in Guyana.
After the old "Sale of Food and Drugs" Ordinance, Cap. 144 was repealed, the new Food and Drugs Act was enacted in 1971. This new Act has considerable flexibility and gives the Minister extensive authority to make Regulations (for carrying out the purposes and provisions of the Act). The Act controls the manufacture, importation, sale, advertising, labeling, packaging, and distribution of drug samples, and the testing of drugs. The Act also controls raw materials and finished products of drugs at the point of entry into the country, with a single agency coordinating both the inspection and analytical services. Developing countries could ensure the procurement of safe, good quality, and effective drugs and devices with the enactment of a similar Food and Drugs Act only. Rapid assessment of Drug Safety, Quality and Efficacy is done through Guyana's participation in the WHO Certification Scheme on the Quality of Pharmaceutical Products moving in International Commerce. This certification scheme is highly commendable especially to third-world countries. The Food and Drug Regulations (1977) have several unique features for drug, cosmetic and device control and they allow for a system of centralized control with limited staff to enforce the legislation. In summary, enforcement of legislative control of imported pharmaceuticals and product evaluation can be considered strong points in the drug regulatory and review process in Guyana. A cautious attitude is observed so as to ensure efficacy, safety, and quality of drugs entering the market. This Drug Regulatory and Review Process is recommended for implementation by third-world countries with outdated drug legislation.(ABSTRACT TRUNCATED AT 250 WORDS)


Molecular basis of hyperparathyroidism and potential targets for drug development.
Our appreciation of the molecular pathogenesis of primary hyperparathyroidism (HPT) has seen great advances over the past decade. This improved understanding may well lead to the development of new treatment options that are specifically targeted to defective pathways. This review summarizes recent advances in the molecular basis of HPT and associated endocrinopathies, and discusses the potential for these and future findings to provide targets for alternative approaches to therapy. The only proven contributors to common sporadic HPT, by virtue of clonal genetic abnormalities, are the cyclin D1 and MEN1 genes. Cyclin D1 is an oncogene that encodes a key regulator of the cell cycle, while MEN1 is a tumor suppressor gene that has also been implicated in familial multiple endocrine neoplasia type 1 (MEN1), in which primary HPT is common. In addition, other key parathyroid regulatory pathways may play a role in HPT pathogenesis. 1,25 (OH)2-vitamin D. Ca2+ and phosphate are regarded as principal regulators of parathyroid cell proliferation and PTH secretion. Therefore, prime candidate targets include the Ca2+ sensing receptor (CASR) gene, the vitamin D receptor (VDR) gene, a putative phosphate receptor gene, their cognate gene products, and other genes or proteins involved in their respective biochemical pathways. Attempts to identify new therapies based specifically on the defective pathways in HPT could complement or eventually supplant traditional approaches.


Damage control: Concept and implementation.
The concept of damage control (DC) is based on a sequential therapeutic strategy that favors physiological restoration over anatomical repair in patients presenting acutely with hemorrhagic trauma. Initially described as damage control surgery (DCS) for war-wounded patients with abdominal penetrating hemorrhagic trauma, this concept is articulated in three steps: surgical control of lesions (hemostasis, sealing of intestinal spillage), physiological restoration, then surgery for definitive repair. This concept was quickly adapted for intensive care management under the name damage control resuscitation (DCR), which refers to the modalities of hospital resuscitation carried out in patients suffering from traumatic hemorrhagic shock within the context of DCS. It is based mainly on specific hemodynamic resuscitation targets associated with early and aggressive hemostasis aimed at prevention or correction of the lethal triad of hypothermia, acidosis and coagulation disorders. Concomitant integration of resuscitation and surgery from the moment of admission has led to the concept of an integrated DCR-DCS approach, which enables initiation of hemostatic resuscitation upon arrival of the injured person, improving the patient's physiological status during surgery without delaying surgery. This concept of DC is constantly evolving; it stresses management of the injured person as early as possible, in order to initiate hemorrhage control and hemostatic resuscitation as soon as possible, evolving into a concept of remote DCR (RDCR), and also extended to diagnostic and therapeutic radiological management under the name of radiological DC (DCRad). DCS is applied only to the most seriously traumatized patients, or in situations of massive influx of injured persons, as its universal application could lead to a significant and unnecessary excess-morbidity to injured patients who could and should undergo definitive treatment from the outset. DCS, when correctly applied, significantly improves the survival rate of war-wounded.


Cell-free tumour DNA analysis detects copy number alterations in gastro-oesophageal cancer patients.
Analysis of cell-free tumour DNA, a liquid biopsy, is a promising biomarker for cancer. We have performed a proof-of principle study to test the applicability in the clinical setting, analysing copy number alterations (CNAs) in plasma and tumour tissue from 44 patients with gastro-oesophageal cancer. DNA was isolated from blood plasma and a tissue sample from each patient. Array-CGH was applied to the tissue DNA. The cell-free plasma DNA was sequenced by low-coverage whole-genome sequencing using a clinical pipeline for non-invasive prenatal testing. WISECONDOR and ichorCNA, two bioinformatic tools, were used to process the output data and were compared to each other. Cancer-associated CNAs could be seen in 59% (26/44) of the tissue biopsies. In the plasma samples, a targeted approach analysing 61 regions of special interest in gastro-oesophageal cancer detected cancer-associated CNAs with a z-score >5 in 11 patients. Broadening the analysis to a whole-genome view, 17/44 patients (39%) had cancer-associated CNAs using WISECONDOR and 13 (30%) using ichorCNA. Of the 26 patients with tissue-verified cancer-associated CNAs, 14 (54%) had corresponding CNAs in plasma. Potentially clinically actionable amplifications overlapping the genes VEGFA, EGFR and FGFR2 were detected in the plasma from three patients. We conclude that low-coverage whole-genome sequencing without prior knowledge of the tumour alterations could become a useful tool for cell-free tumour DNA analysis of total CNAs in plasma from patients with gastro-oesophageal cancer.


Long Non-coding RNA: Insight Into Mechanisms of Alzheimer's Disease.
Alzheimer's disease (AD), a heterogeneous neurodegenerative disorder, is the most common cause of dementia accounting for an estimated 60-80% of cases. The pathogenesis of AD remains unclear, and no curative treatment is available so far. Increasing evidence has revealed a vital role of non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), in AD. LncRNAs contribute to the pathogenesis of AD via modulating amyloid production, Tau hyperphosphorylation, mitochondrial dysfunction, oxidative stress, synaptic impairment and neuroinflammation. This review describes the biological functions and mechanisms of lncRNAs in AD, indicating that lncRNAs may provide potential therapeutic targets for the diagnosis and treatment of AD.


Simulation of a population-based model of coronary heart disease morbidity and mortality.
"The main objective of this study is to develop a modelling strategy useful to examine and predict major trends in coronary heart disease. Once we develop a model which can mimic population changes over time, then the models can be extended to provide information on intervention effects by changing the risk factors." The model is illustrated using data for North Karelia, Finland, for the period 1972-1978. (SUMMARY IN KOR)


Antibiotic resistance conferred by a conjugative plasmid and a class I integron in Vibrio cholerae O1 El Tor strains isolated in Albania and Italy.
Multidrug-resistant Vibrio cholerae O1 El Tor strains isolated during the 1994 outbreak of cholera in Albania and Italy were characterized for the molecular basis of antibiotic resistance. All strains were found to be resistant to tetracycline, streptomycin, spectinomycin, trimethoprim, sulfathiazole, and the vibriostatic compound O/129 (2,4-diamino-6,7-diisopropylteridine). Resistance genes were self-transferable by a conjugative plasmid of about 60 MDa, with the exception of spectinomycin resistance, which was conferred by the aadA1 gene cassette located in the bacterial chromosome within a class 1 integron. The resistance to trimethoprim and O/129 was conferred by the dfrA1 gene, which was present on the plasmid. Although the dfrA1 gene is known to be borne on an integron cassette, class 1, 2, or 3 intI genes were not detected as part of the plasmid DNA from the strains studied.


[Lazarus phenomenon: spontaneous resuscitation].
A 94-year-old woman undergoing surgery for simple repair of a duodenal perforation experienced a sudden massive hemorrhage (1500 mL) when the duodenum was separated from adjacent structures. Hemodynamic stability was re-established when fluids were replaced. After the abdominal wall was closed, increased amplitude of the QRS wave was observed and heart rate slowed until there was no pulse. Electromechanical dissociation (EMD) was diagnosed and cardiopulmonary resuscitation was started. When EMD persisted after 40 minutes, resuscitative measures were stopped and the ventilator was disconnected, though orotracheal intubation and arterial and electrocardiographic monitoring were maintained. After 2 or 3 minutes, heart rhythm restarted spontaneously and arterial pressure waves reappeared on the monitor. The patient progressed well for 72 hours, after which she developed septic shock and multiorgan failure, dying 18 days later. The Lazarus phenomenon may be more common than the medical literature would indicate, possibly because a large gap in our understanding of the pathophysiology of the phenomenon underlies anecdotes about "miracles". As we wait for adequate international consensus on a protocol for monitoring the withdrawal of resuscitative measures, we should act prudently before definitively certifying death. The case we report occurred during a surgical intervention in which the patient had received general anesthesia. We believe that the causes that might explain the Lazarus phenomenon are quite different in that context than they would be in a nonsurgical setting, such that it would be useful to create a national database to keep a record of such intraoperative events.


Severe Sepsis With Septic Shock as a Consequence of a Severe Community-Acquired Pneumonia Resulting From a Combined Legionella pneumophila and Streptococcus pneumoniae Infection.
Community-acquired pneumonia (CAP) is a frequent cause of intensive care unit (ICU) admission in adults and the sixth leading cause of death worldwide. Although co-infections have been previously reported, the co-existence of Streptococcus pneumoniae and Legionella pneumophila is exceedingly rare. Despite the fact that Streptococcus pneumoniae is the most common etiology in the majority of cases, atypical organisms such as Legionella pneumophila should be considered as etiologic agents among all CAP cases that require hospitalization. Unlike Legionella, extra-pulmonary findings are uncommon in patients with Streptococcus pneumoniae pneumonia. In this report, the authors describe an unusual case of septic shock resulting from a combined Legionella pneumophila and Streptococcus pneumoniae infection associated with rhabdomyolysis, acute kidney injury, acute hypoxemic respiratory failure, pancreatitis, and acute liver injury.


Atrophic dermatofibroma.
Dermatofibroma is a benign fibrohistiocytic tumor, common and easily diagnosed when classical clinicopathologic features are present. The atrophic variant of dermatofibroma is of uncertain origin. This lesion is characterized clinically by a flat or atrophic and depressible surface. Histopathological features show reduction of the thickness of the dermis and elastic fibers. We report a typical case of this uncommon and probably underdiagnosed variant.


Altered reflex control of cutaneous circulation by female sex steroids is independent of prostaglandins.
We tested the hypothesis that the shift in the cutaneous vasodilator response to hyperthermia seen with elevated female reproductive hormones is a prostaglandin-dependent resetting of thermoregulation to higher internal temperatures, similar to that seen in the febrile response to bacterial infection. Using water-perfused suits to control body temperature, we conducted heat stress experiments in resting women under conditions of low and high progesterone and estrogen and repeated these experiments after an acute dose of ibuprofen (800 mg). In six women the hormones were exogenous (oral contraceptives); three women had regular menstrual cycles and were tested in the early follicular and midluteal phases. Resting oral temperature (Tor) was significantly elevated with high hormone status (P < 0.05); this was not affected by ibuprofen treatment (P > 0.2). The Tor threshold for cutaneous vasodilation was significantly increased by high hormone status (+0.27 +/- 0.07 degrees C, P < 0. 02); the shift was not affected by ibuprofen treatment (with ibuprofen: +0.29 +/- 0.08 degrees C, P > 0.2 vs. control experiments). The Tor threshold for sweating was similarly increased by high hormone status (+0.22 +/- 0.05 degrees C, P < 0.05); this shift was not influenced by ibuprofen (with ibuprofen: +0.35 +/- 0. 05, P > 0.1 vs. control experiments). Thus the shift in thermoregulatory control of skin blood flow and sweating mediated by female reproductive steroids is not sensitive to ibuprofen; it therefore appears that this shift is independent of prostaglandins.


Membrane curvature generation by a C-terminal amphipathic helix in peripherin-2/rds, a tetraspanin required for photoreceptor sensory cilium morphogenesis.
Vertebrate vision requires photon absorption by photoreceptor outer segments (OSs), structurally elaborate membranous organelles derived from non-motile sensory cilia. The structure and function of OSs depends on a precise stacking of hundreds of membranous disks. Each disk is fully (as in rods) or partially (as in cones) bounded by a rim, at which the membrane is distorted into an energetically unfavorable high-curvature bend; however, the mechanism(s) underlying disk rim structure is (are) not established. Here, we demonstrate that the intrinsically disordered cytoplasmic C-terminus of the photoreceptor tetraspanin peripherin-2/rds (P/rds) can directly generate membrane curvature. A P/rds C-terminal domain and a peptide mimetic of an amphipathic helix contained within it each generated curvature in liposomes with a composition similar to that of OS disks and in liposomes generated from native OS lipids. Association of the C-terminal domain with liposomes required conical phospholipids, and was promoted by membrane curvature and anionic surface charge, results suggesting that the P/rds C-terminal amphipathic helix can partition into the cytosolic membrane leaflet to generate curvature by a hydrophobic insertion (wedging) mechanism. This activity was evidenced in full-length P/rds by its induction of small-diameter tubulovesicular membrane foci in cultured cells. In sum, the findings suggest that curvature generation by the P/rds C-terminus contributes to the distinctive structure of OS disk rims, and provide insight into how inherited defects in P/rds can disrupt organelle structure to cause retinal disease. They also raise the possibility that tethered amphipathic helices can function for shaping cellular membranes more generally.


Cell Therapy of Stroke: Do the Intra-Arterially Transplanted Mesenchymal Stem Cells Cross the Blood-Brain Barrier?
Animal model studies and first clinical trials have demonstrated the safety and efficacy of the mesenchymal stem cells' (MSCs) transplantation in stroke. Intra-arterial (IA) administration looks especially promising, since it provides targeted cell delivery to the ischemic brain, is highly effective, and can be safe as long as the infusion is conducted appropriately. However, wider clinical application of the IA MSCs transplantation will only be possible after a better understanding of the mechanism of their therapeutic action is achieved. On the way to achieve this goal, the study of transplanted cells' fate and their interactions with the blood-brain barrier (BBB) structures could be one of the key factors. In this review, we analyze the available data concerning one of the most important aspects of the transplanted MSCs' action-the ability of cells to cross the blood-brain barrier (BBB) in vitro and in vivo after IA administration into animals with experimental stroke. The collected data show that some of the transplanted MSCs temporarily attach to the walls of the cerebral vessels and then return to the bloodstream or penetrate the BBB and either undergo homing in the perivascular space or penetrate deeper into the parenchyma. Transmigration across the BBB is not necessary for the induction of therapeutic effects, which can be incited through a paracrine mechanism even by cells located inside the blood vessels.


High procedure volume is strongly associated with improved survival after lung cancer surgery.
Studies have reported an association between hospital volume and survival for non-small-cell lung cancer (NSCLC). We explored this association in England, accounting for case mix and propensity to resect. We analyzed data on 134,293 patients with NSCLC diagnosed in England between 2004 and 2008, of whom 12,862 (9.6%) underwent surgical resection. Hospital volume was defined according to number of patients with resected lung cancer in each hospital in each year of diagnosis. We calculated hazard ratios (HRs) for death in three predefined periods according to hospital volume, sex, age, socioeconomic deprivation, comorbidity, and propensity to resect. There was increased survival in hospitals performing > 150 surgical resections compared with those carrying out < 70 (HR, 0.78; 95% CI, 0.67 to 0.90; Ptrend < .01). The association between hospital volume and survival was present in all three periods of follow-up, but the magnitude of association was greatest in the early postoperative period. High-volume hospitals have higher resection rates and perform surgery among patients who are older, have lower socioeconomic status, and have more comorbidities; despite this, they achieve better survival, most notably in the early postoperative period.


Injection moulded microneedle sensor for real-time wireless pH monitoring.
This paper describes the development of an array of individually addressable pH sensitive microneedles using injection moulding and their integration within a portable device for real-time wireless recording of pH distributions in biological samples. The fabricated microneedles are subjected to gold patterning followed by electrodeposition of iridium oxide to sensitize them to 0.07 units of pH change. Miniaturised electronics suitable for the sensors readout, analog-to-digital conversion and wireless transmission of the potentiometric data are embodied within the device, enabling it to measure real-time pH of soft biological samples such as muscles. In this paper, real-time recording of the cardiac pH distribution, during ischemia followed by reperfusion cycles in cardiac muscles of male Wistar rats has been demonstrated by using the microneedle array.


Atrial fibrillation: focus on monitoring strategies after cryptogenic stroke.
Atrial fibrillation (AF) is responsible for up to one-third of ischemic strokes, with stroke potentially being the first manifestation of a previously undetected AF. Given the efficacy of oral anticoagulants in preventing AF-related ischemic events, searching for unknown AF after stroke requires a comprehensive diagnostic workup. Prospective data have demonstrated the benefits of long-term cardiac monitoring to identify AF in association with cryptogenic stroke, as most strokes are presumed to result from AF. However, strategies of empirical anticoagulation using oral anticoagulants following cryptogenic stroke failed to improve outcomes. We herein summarize contemporary evidence and knowledge gaps on searching for AF after a stroke and the potential secondary prevention strategies to prevent further recurrences.


Study of hematopoietic progenitor cells in thalassemia after bone marrow transplantation.
The hematopoietic committed progenitor cells (BFU-E and CFU-GM) in blood and bone marrow were studied in thalassemic patients before and after bone marrow transplantation. Eighteen transplants were performed in 17 patients with thalassemia. Five were homozygous beta-thalassemia and 12 were beta-thalassemia/hemoglobin E disease. The age ranged from 1.2-14 years (median = 3.4 years). The conditioning regimen comprised busulfan 3.5-4 mg/kg/day for 4 days and cyclophosphamide 50 mg/kg/day for 4 days. Cyclosporin in combination with methotrexate were administered post transplant for GVHD prophylaxis. Before transplantation, BFU-E and CFU-GM in the blood of the patients were significantly higher compared with normal (p < 0.05) but were normal in the bone marrow. Only the CFU-GM in the bone marrow of the successful cases after transplantation recovered to the normal level at the first month through the 12th month whereas the BFU-E were low. Both CFU-GM and BFU-E in the blood were lower than normal after follow up to the 12th month. Inspite of the low number of progenitor cells, there was hematological recovery in the blood of the patients. It may be due to the capacity of the hematopoiesis react to stress which could be amplified the differentiation compartment or the shortened-transit time through the stem cell compartment.


Use of Grafted Voltage Stabilizer to Enhance Dielectric Strength of Cross-Linked Polyethylene.
Aromatic voltage stabilizers can improve the dielectric properties of cross-linked polyethylene (XLPE); however, their poor compatibility with XLPE hinders their practical application. Improving the compatibility of aromatic voltage stabilizers with XLPE has, therefore, become a new research goal. Herein 1-(4-vinyloxy)phenylethenone (VPE) was prepared and characterized. It can be grafted onto polyethylene molecules during the cross-linking processes to promote stability of the aromatic voltage stabilizers in XLPE. Fourier transform infrared spectroscopy confirmed that VPE was successfully grafted onto XLPE, and effectively inhibited thermal migration. Thermogravimetric analysis showed that the grafted VPE/XLPE composite exhibits a better thermal stability than a VPE/PE blend composite. Evaluation of the electrical properties showed that the breakdown strength and electrical tree initiation voltage of the VPE/XLPE composite were increased by 15.5% and 39.6%, respectively, when compared to those of bare XLPE. After thermal aging, the breakdown strength and electrical tree initiation voltage of the VPE/XLPE composite were increased by 9.4% and 25.8%, respectively, in comparison to those of bare XLPE, which indicates that the grafted voltage stabilizer can effectively inhibit its migration and enhance the stability of the composite material.


Deciphering the Role of the Non-Coding Genome in Regulating Gene-Diet Interactions.
Protein encoding genes constitute a small fraction of mammalian genomes. In addition to the protein coding genes, there are other functional units within the genome that are transcribed, but not translated into protein, the so called non-coding RNAs. There are many types of non-coding RNAs that have been identified and shown to have important roles in regulating gene expression either at the transcriptional or post-transcriptional level. A number of recent studies have highlighted that dietary manipulation in mammals can influence the expression or function of a number of classes of non-coding RNAs that contribute to the protein translation machinery. The identification of protein translation as a common target for nutritional regulation underscores the need to investigate how this may mechanistically contribute to phenotypes and diseases that are modified by nutritional intervention. Finally, we describe the state of the art and the application of emerging '-omics' technologies to address the regulation of protein translation in response to diet.


[Municipal health council compositions in the state of São Paulo].
This article discusses the legal structure of the municipal Health Councils in a Health County in the state of Sao Paulo comprising six municipalities. This descriptive and exploratory study was based on documental research according to federal laws for the creation, organization, structure and routine work of the health councils. Results were presented and discussed in categories. The health councils were created in 1991, and four of them have changed their legal instruments, two of them have innovated in some procedures, such as election of the director, administration non-coincident with local majors, administrative structure and commissions. Some council regulations are in disagreement with local and federal laws, such as the deliberative character, parity representation of users, internal regiment, municipal staff in charge of council directory, and no guarantee of administrative and financial support for routine work. It can be concluded that it is necessary to improve and correct regulations to guarantee a suitable performance of health councils and also to improve the discussion about social participation in the nursing curriculum.


Systemic Lead Toxicity Secondary to Retained Intraosseous Bullet A Case Report and Review of Literature.
A 35-year-old female presented to orthopaedic clinic with a chief complaint of chronic left hip pain, beginning 17 years prior when she had sustained a gunshot wound to her left buttock. Imaging demonstrated significant left hip arthritis with a retained projectile in the femoral head. Lead levels were also found to be significantly elevated. The patient underwent successful left total hip arthroplasty, with subsequent postoperative pain relief and consistent decrease in serum lead level. This report presents a rare case that emphasizes lead intoxication as a potentially dangerous complication of gunshot wounds and retained projectiles in the orthopaedic patient. Recognition of lead intoxication as a potential complication of retained gunshot projectiles allows for efficient diagnosis and treatment, which may prevent associated future morbidity.


Cardiopulmonary resuscitation (CPR) during spaceflight - a guideline for CPR in microgravity from the German Society of Aerospace Medicine (DGLRM) and the European Society of Aerospace Medicine Space Medicine Group (ESAM-SMG).
With the "Artemis"-mission mankind will return to the Moon by 2024. Prolonged periods in space will not only present physical and psychological challenges to the astronauts, but also pose risks concerning the medical treatment capabilities of the crew. So far, no guideline exists for the treatment of severe medical emergencies in microgravity. We, as a international group of researchers related to the field of aerospace medicine and critical care, took on the challenge and developed a an evidence-based guideline for the arguably most severe medical emergency - cardiac arrest. After the creation of said international group, PICO questions regarding the topic cardiopulmonary resuscitation in microgravity were developed to guide the systematic literature research. Afterwards a precise search strategy was compiled which was then applied to "MEDLINE". Four thousand one hundred sixty-five findings were retrieved and consecutively screened by at least 2 reviewers. This led to 88 original publications that were acquired in full-text version and then critically appraised using the GRADE methodology. Those studies formed to basis for the guideline recommendations that were designed by at least 2 experts on the given field. Afterwards those recommendations were subject to a consensus finding process according to the DELPHI-methodology. We recommend a differentiated approach to CPR in microgravity with a division into basic life support (BLS) and advanced life support (ALS) similar to the Earth-based guidelines. In immediate BLS, the chest compression method of choice is the Evetts-Russomano method (ER), whereas in an ALS scenario, with the patient being restrained on the Crew Medical Restraint System, the handstand method (HS) should be applied. Airway management should only be performed if at least two rescuers are present and the patient has been restrained. A supraglottic airway device should be used for airway management where crew members untrained in tracheal intubation (TI) are involved. CPR in microgravity is feasible and should be applied according to the Earth-based guidelines of the AHA/ERC in relation to fundamental statements, like urgent recognition and action, focus on high-quality chest compressions, compression depth and compression-ventilation ratio. However, the special circumstances presented by microgravity and spaceflight must be considered concerning central points such as rescuer position and methods for the performance of chest compressions, airway management and defibrillation.


[Antiatherogenic action of omega-3 polyunsaturated fatty acids].
Recently, atherosclerosis has become a matter of great concern because of a rapid increase of aged people. It has been widely known that omega-3 polyunsaturated fatty acids, rich in marine fish oil, have an antiatherogenic action. The mechanism is ascribed to its action on serum lipids, functions of the platelets, endothelial cells, smooth muscle cells and macrophages, prostaglandin and leukotriene metabolism, growth factor and cytokine production, EDRF production, blood pressure, etc. In this paper the basic and clinical evidences concerning the effects of fish oil on these multifactors, which are deeply involved in the development of atherosclerosis are reviewed.


Conjunctive effects of reward and behavioral episodes on hippocampal place-differential neurons of rats on a mobile treadmill.
Previous studies reported context (or behavior)-dependent activities of hippocampal place cells, which are suggested to be the neural basis of episodic memory. However, it remains unclear what distinctive items these context-dependent activities encode. We investigated separately the effects of space, locomotion, and episodes with positive/negative reinforcements on activity of place-differential neurons in the hippocampal CA1 area. Rats were placed on a treadmill affixed to a motion stage translocated along a figure 8-shaped track. The track could be navigated by two different routes that shared a common central stem. The stage was paused at the start and end of the routes, where conditioned response tasks with different reinforcements were imposed. As the rats passed the common central stem, some neurons fired differently depending on the route. Comparison of hippocampal spatial firing patterns across different conditions with and without treadmill operation and/or the tasks indicated that these route-dependent spatial firing patterns were sensitive to locomotion, the tasks, and vestibular sensation or visual cues such as optic flow. The results suggest that external sensory inputs, path integration, and reinforcement context are all integrated in the hippocampus, which might provide the neural basis of episodic memory.


Toxic effects of TiO2 nanoparticles in primary cultured rat sertoli cells are mediated via a dysregulated Ca2+ /PKC/p38 MAPK/NF-κB cascade.
Although numerous studies have demonstrated that titanium dioxide nanoparticles (TiO2 NPs) can be accumulated in various animal organs and can cause toxicity, there is currently only limited data regarding reproductive toxicity especially on the toxic mechanisms of TiO2 NPs in Sertoli cells. In order to investigate the mechanism of reproductive toxicity, primary cultured rat Sertoli cells were exposed to 5, 15, or 30 μg/mL TiO2 NPs for 24 h, and TiO2 NPs internalization, expression of PKC (p-PKC) and p38 MAPK (p-p38 MAPK) as well as calcium homeostasis were examined. Our findings demonstrated that TiO2 NPs crossed the membrane into the cytoplasm or nucleus, and significantly suppressed cell viability of primary cultured rat Sertoli cells in a concentration-dependent manner. Furthermore, immunological dysfunction caused by TiO2 NPs was involved in the increased expression of NF-κB, TNF-α, and IL-1β, and decreased IκB expression. TiO2 NPs significantly decreased Ca2+ -ATPase and Ca2+ /Mg2+ -ATPase activity and enhanced intracellular Ca2+ levels, and up-regulated the expression of p-PKC and p-p38 MAPK in a dose-dependent manner in primary cultured rat Sertoli cells. Taken together, these findings indicate that TiO2 NPs may induce immunological dysfunction of primary cultured rat Sertoli cells by stimulating the Ca2+ /PKC/p38 MAPK cascade, which triggers NF-κB activation and ultimately induces the expression of inflammatory cytokines in primary cultured rat Sertoli cells. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1374-1382, 2017.


Identification of four novel variants that influence central corneal thickness in multi-ethnic Asian populations.
Central corneal thickness (CCT) is a highly heritable trait. Genes that significantly influence CCT can be candidate genes for common disorders in which CCT has been implicated, such as primary open-angle glaucoma (POAG) and keratoconus. Because the genetic factors controlling CCT in different Asian populations are unclear, we have built on previous work conducted on Singaporean Indians and Malays and extended our hypothesis to individuals of Chinese descent. We have followed up on all suggestive signals of association with CCT (P < 10(-4)) from the previously reported meta-analysis comprising Indians and Malays in a sample of Chinese individuals (n= 2681). In the combined sample (n= 7711), strong evidence of association was observed at four novel loci: IBTK on chromosome 6q14.1; CHSY1 on chromosome 15q26.3; and intergenic regions on chromosomes 7q11.2 and 9p23 (8.01 × 10(-11) < λ(GC) corrected P(meta) < 8.72 × 10(-8)). These four new loci explain an additional 4.3% of the total CCT variance across the sample cohorts over and above that of previously identified loci. We also extend on a previous finding at a fifth locus (AKAP13) where a new single-nucleotide polymorphism (rs1821481, P(meta) = 9.99 × 10(-9)) was found to be significantly more informative compared with the previously reported rs6496932 (P(meta) = 3.64 × 10(-5)). Performing association analysis in Asians may lead to the discovery of ethnic-specific genes that control CCT, offering further mechanistic insights into the regulation of CCT. In addition, it may also provide several candidate genes for interrogation for POAG, keratoconus and possible racial/ethnic variations.


Immunogenicity and safety of primary fractional-dose yellow fever vaccine in autoimmune rheumatic diseases.
Brazil faced a yellow fever(YF) outbreak in 2016-2018 and vaccination was considered for autoimmune rheumatic disease patients(ARD) with low immunosuppression due to YF high mortality. This study aimed to evaluate, prospectively for the first time, the short-term immunogenicity of the fractional YF vaccine(YFV) immunization in ARD patients with low immunossupression. A total of 318 participants(159 ARD and 159 age- and sex-matched healthy controls) were vaccinated with the fractional-dose(one fifth) of 17DD-YFV. All subjects were evaluated at entry(D0), D5, D10, and D30 post-vaccination for clinical/laboratory and disease activity parameters for ARD patients. Post-vaccination seroconversion rate(83.7%vs.96.6%, p = 0.0006) and geometric mean titers(GMT) of neutralizing antibodies[1143.7 (95%CI 1012.3-1292.2) vs.731 (95%CI 593.6-900.2), p<0.001] were significantly lower in ARD compared to controls. A lower positivity rate of viremia was also identified for ARD patients compared to controls at D5 (53%vs.70%, p = 0.005) and the levels persisted in D10 for patients and reduced for controls(51%vs.19%, p = 0.0001). The viremia was the only variable associated with seroconvertion. No serious adverse events were reported. ARD disease activity parameters remained stable at D30(p>0.05). Fractional-dose 17DD-YF vaccine in ARD patients resulted in a high rate of seroconversion rate(>80%) but lower than controls, with a longer but less intense viremia. This vaccine was immunogenic, safe and did not induce flares in ARD under low immunosuppression and may be indicated in YF outbreak situations and for patients who live or travel to endemic areas. This clinical trial was registered with Clinicaltrials.gov (#NCT03430388).


Systematic review of low-dose isotretinoin for treatment of acne vulgaris: Focus on indication, dosage, regimen, efficacy, safety, satisfaction, and follow up, based on clinical studies.
Oral isotretinoin is the most effective treatment for moderate to severe acne and its side effects are mostly dose-dependent. Low dose isotretinoin (0.5 mg/kg/day for 1 week every 4 weeks for 6-months) could be effective and even in its end result, comparable with high or optimal doses. In this systematic review, we aimed to sum up the results of clinical trials regarding indications, dosage, prescription protocol, effectiveness, side effects, patient satisfaction, recurrence rate, and follow-up period of low dose isotretinoin in treatment of acne. Cochrane, Google Scholar, Science Direct, PubMed, and Medline were searched. A total of 460 articles were searched electronically and 382 articles were excluded. About 4 were non-English and 2, before 1980. The full text of 72 articles was reviewed. Finally 15 documents met the inclusion criteria for entering this systematic review. The standard dose of isotretinoin is 0.5-1 mg/kg/day for 4 months with a total dose of 120-140 mg/kg/day. Daily doses between 0.1 and 0.3 mg/kg can be recommended for more than 6 months due to the occurrence of fewer side effects and more economical concerns. For greater effectiveness, it could be combined with other medications.


Friedrich Jakub Fuker and his universal preventive tincture.
Fridrich Jakub Fuker (1749-1805), a physician from Košice, is the author of works on medical topics, as well as works on social life. In addition to his medical practice, he also owned a pharmacy, and his short work on a universal preventive tincture is related to this. The author argues that there is no universal medicine, but it is possible to prepare a universal preventive preparation suitable for everyone, every age and sex. Fuker has announced that he will prepare such a tincture, available in his pharmacy, along with information on its use. However, he did not divulge its composition, as supposedly, any physician knowledgeable in the matter would figure it out on his own. With the universal tincture, Fuker abandoned rational medicine, perhaps suffering from involutional depression or acting as a salesman.


Graphene Quantum Dots with Pyrrole N and Pyridine N: Superior Reactive Oxygen Species Generation Efficiency for Metal-Free Sonodynamic Tumor Therapy.
Those responsible for the development of sonosensitizers are faced with a dilemma between high sonosensitization efficacy and good biosecurity that limited the development of sonodynamic therapy (SDT). Herein, inspired by the intriguing therapeutic features of SDT and the potential catalytic activity of graphene quantum dots, the potential of N-doped graphene quantum dots (N-GQDs) to act as a sonosensitizer is demonstrated. The superior sonosensitization effect of N-GQDs is believed to be three to five times higher than that of traditional sonosensitizers (such as porphyrin, porphyrin Mn, porphyrin Zn, TiO2 , etc.). More importantly, the sonochemical mechanism of N-GQDs is revealed. Pyrrole N and pyridine N are believed to form catalytic centers in sonochemical processing of N-GQDs. This knowledge is important from the perspective of understanding the structure-dependent SDT enhancement of carbon nanostructure. Moreover, N-GQDs modified by folic acid (FA-N-GQDs) show a high marker rate for tumor cells (greater than 96%). Both in vitro and in vivo therapeutic results have exhibited high tumor inhibition efficiency (greater than 90%) of FA-N-GQDs as sonosensitizers while the oxidative stress response of tumor cells is activated through the PEX pathway and induced apoptosis via the p53 pathway.


Design of RGDS Peptide-Immobilized Self-Assembling β-Strand Peptide from Barnacle Protein.
We designed three types of RGD-containing barnacle adhesive proteins using self-assembling peptides. In the present study, three types of RGD-containing peptides were synthesized by solid-phase peptide synthesis, and the secondary structures of these peptides were analyzed by CD and FT-IR spectroscopy. The mechanical properties of peptide hydrogels were characterized by a rheometer. We discuss the correlation between the peptide conformation, and cell attachment and cell spreading activity from the viewpoint of developing effective tissue engineering scaffolds. We created a peptide-coated cell culture substrate by coating peptides on a polystyrene plate. They significantly facilitated cell adhesion and spreading compared to a non-coated substrate. When the RGDS sequence was modified at N- or C-terminal of R-Y, it was found that the self-assembling ability was dependent on the strongly affects hydrogel formation and cell adhesion caused by its secondary structure.


Experience in multicatheter interstitial high-dose-rate breast brachytherapy: dose-volume histogram analysis of the first results.
To report characteristics of our treatment scheme of high-dose-rate (HDR) brachytherapy of breast cancer and to show the first outcomes of dosimetric planning analysis based on dose-volume histogram (DVH). Since August 2017, 25 patients diagnosed with T1N0M0 breast cancer have received a treatment in our center. There was lumpectomy and following breast HDR brachytherapy (10 fractions of 3.4 Gy) administered to each patient. A planning target volume (PTV) and organs at risk (OARs) were recorded with DVH analysis. The study describes the full procedure of breast HDR brachytherapy with the lumpectomy. Twenty-five patients were treated, including 9 with cancer of the left breast and 16 of the right breast. The median age was 65 years. The first analysis of DVH data shows that the main OARs were ribs and skin. Mean value of Dmax (ribs) for all patients was 19.90 Gy (55.88% of prescribed dose) and for the skin 30.88 Gy (90.74% of prescribed dose). During the treatment, there was only one case of toxic effects, which was pigmentation on the skin due to excess of dose limit of 1.4 Gy. Therefore, the limit exceeding of 1 Gy does not give any significant toxic effects. This study is the first stage of the dosimetric evaluation of a new method. The analysis allows treating complex localizations of the breast cancer, for example, in a close position to the skin or ribs. In order to minimize the toxic effects, it is necessary to consider patient selection, catheter administration, and dose optimization.


Static images with different induced intensities of human body movements affect subjective time.
Modulation of subjective time was examined using static images eliciting perceptions of different intensities of body movement. Undergraduate students were exposed to photographs of dancer sculptures in different dance positions for 36 sec. and asked to estimate the exposure duration. Lower movement intensities were related to shorter estimated durations. Mean durations for images of unmoving dancers were underestimated and for dancers taking a ballet step were overestimated. Temporal estimations were also related to the order of presentation of the stimuli, which suggested that subjective time estimations were influenced by the experimental context. Subjective time is related not only to the visual perception of moving images, but also of elicited perceptions of movement in static images, suggesting an embodiment effect on subjective time estimation.


Validity of dual tracer 99mTc-tetrofosmin and 99mTc-pertechnetate subtraction parathyroid scintigraphy in patients with primary and secondary hyperparathyroidism.
Primary hyperparathyroidism (pHPT) is an endocrine disease with the third highest incidence of all endocrine disorders after diabetes mellitus and hyperthyroidism. pHPT is typically caused by a solitary parathyroid adenoma, less frequently by multiple parathyroid gland disease (MGD) and rarely by parathyroid carcinoma. Secondary hyperparatyroidism (sHPT) is a common complication in patients with chronic renal failure. The aim of this study was to estimate sensitivity of dual tracer 99mTc-tetrofosmin and 99mTc-pertechnetate subtraction scintigraphy in detection of abnormal parathyroid glands in patients with pHPT and sHPT confirmed by histopathology. In 46 patients, (77 abnormal parathyroid glands), 30 with pHPT and 16 with sHPT parathyroid scintigraphy was done preoperatively. All the patients had histopathological confirmation of diagnosis. Abnormal parathyroid glands weighted from 0.1 to 7 g. After iv injection dynamic scintigraphy during 25 minutes (one frame-one minute) using 555 MBq of 99mTc-tetrofosmin, and three hours latter using 111 MBq of 99mTc/pertechnetate was performed. 99mTc-tetrofosmin dynamic study was followed by static scintigraphy of the neck and chest 30 minutes, 1, 2 and 3 hours after iv injection. An abnormal scintigraphic finding was found in 44 of 46 patients with sensitivity of 96%. In pHPT sensitivity was 93% (28 of 30 patients, and 28 of 30 glands). In sHPT scintigraphy was abnormal in all the patients (sensitivity 100%). In the patients with sHPT scintigraphy detected 30 of 47 abnormal parathyroid glands (sensitivity 64%). An overall sensitivity of scintigraphy per gland, for pHPT and sHPT in detecting 58 of 77 abnormal parathyroid glands was 75%. An abnormal scintigraphic result per patient was found in 44 patients (sensitivity 96%) and 58 of 77 abnormal parathyroid glands were detected (sensitivity 750/0). A high sensitivity of dual tracer subtraction 99mTc-tetrofosmin/99mTc-pertechnetate parathyroid scintigraphy in detecting abnormal parathyroid glands in primary and secondary hyperparathyroidism was achieved.


Relationship between methamphetamine-induced behavioral activation and hyperthermia.
Methamphetamine (METH) changes core temperature and induces behavioral activation. Behavioral activation is also known to change core temperature. The purpose of this report was to 1.) evaluate the extent to which the behavioral activation induced by METH showed a temporal relationship to METH-induced hyperthermia; and 2.) describe the temporal pattern of METH-induced hyperthermia over an extended dose range. Rats were treated with saline or METH (0.5-10.0mg/kg) in computer-controlled chambers with ambient temperature maintained at 24°C. Continuous telemetric core temperature measurements were made during a 7h test period. Behavioral observations were made once every 15 min using an 11-point scale ranging from 0 (quiet awake) to 10 (focused licking or biting). The onset of METH-induced behavioral activation occurred at 15-30 min after treatment for all doses and preceded core temperature increases; the onset of METH-induced hyperthermia ranged from 45 min post-treatment to 120 min post-treatment. This behavior-temperature delay was 15-30 min at the lowest (0.5 and 1.0mg/kg) and the highest (7.0, 8.0, and 10.0mg/kg) doses tested; the delay was increased between 1.0 and 4.0mg/kg METH (105 min delay at 4.0mg/kg) and then decreased again from 4.0 to 10.0mg/kg. The strongest relationship between core temperature and behavioral activation occurred at 180 min post-treatment. These data suggest that factors other than behavior are primarily responsible for the observed core temperature effects during the initial post-treatment period (60 min peak); possible effects from movement are masked. For the latter post-treatment period (180 min peak) the stronger relationship between temperature and behavior suggests a role for movement in METH-induced hyperthermia.


[Study on the dose-effect relationship of hypolipidemic effect of deepsea fish oil].
The dose-effect relationship of hypolipidemic effect of fish oil was studied. The rats were divided into four groups: 2.5, 5, 10 g/kg and high dietary fat control group. The experimental rat model of high serum lipids was developed. The results showed that there was a linear correlation between the levels of TG, HDL-c and the dosage of fish oil. Fish oil reduced TC level and elevated HDL-c level steadily. But no linear correlation was observed between TC, LDL-c and the dosage of fish oil. The level of TC and LDL-c decreased markedly at the dosage of 2.5 g/kg of fish oil.


Immunoglobulin specificity of low grade B cell gastrointestinal lymphoma of mucosa-associated lymphoid tissue (MALT) type.
The specificity of the tumor cell immunoglobulin in three cases of low grade B cell gastrointestinal mucosa-associated lymphoid tissue (MALT) lymphoma has been studied. Using anti-idiotypic antibodies to detect the reactivity of tumor immunoglobulin in tissue sections from the patients and other individuals, we observed specificity for normal tissue components in all three cases studied. Reactivity in one case was with follicular dendritic cells, in the second case with a novel antigen on mucosal post capillary venules, and, in the third case, a broad pattern of reactivity was observed. This study suggests that autoimmunity may play a role in the pathogenesis of gastric lymphoma.


Simultaneous quantification of etoposide and etoposide phosphate in human plasma by capillary electrophoresis using laser-induced native fluorescence detection.
A method using capillary electrophoresis with UV laser-induced native fluorescence detection was developed as a sensitive and selective assay for the simultaneous determination of etoposide and etoposide phosphate in human plasma. Laser-induced native fluorescence detection with a frequency-doubled argon ion laser at an excitation wavelength of 257 nm was used for the simultaneous assay of etoposide and etoposide phosphate in plasma to improve the sensitivity compared to that obtained with UV absorption. The detection system consists of an imaging spectrograph and an intensified CCD camera which views an illuminated 1.5-mm section of the capillary. This setup is able to record the whole emission spectra of the analytes to achieve additional wavelength-resolved electropherograms. In the concentration range of 200 microg/L-50 mg/L in plasma for etoposide and 100 microg/L-20 mg/L for etoposide phosphate, coefficients of correlation were better than 0.998. Within-day variation determined with three different concentrations showed accuracies ranging from 91.0 to 109.3% for etoposide and from 91.2 to 109.9% for etoposide phosphate (n = 6) with a precision of about 8%. Day-to-day variation presented accuracies ranging from 91.8 to 107.9% for etoposide and from 94.4 to 109.3% for etoposide phosphate with a relative standard deviation less than 6% (n = 5). To our knowledge, this is the first method for the simultaneous quantification of etoposide and etoposide phosphate in plasma samples.


The dipeptidyl peptidase IV, a membrane enzyme involved in the proliferation of T lymphocytes.
Dipeptidyl peptidase IV can be demonstrated in 60% of T lymphocytes from human peripheral blood. As could be shown recently, this enzyme is irreversibly inhibited by N-Ala-Pro-O-(nitrobenzoyl-)hydroxylamine, a substrate analogous enzyme-activated inhibitor of X-Pro-specific peptidases. We found that this inhibitor was able to suppress the proliferation of human lymphocytes stimulated with mitogens or allogeneic cells. Furthermore, after stimulation with pokeweed mitogen the development of lymphocytes containing cytoplasmic immunoglobulins and thiol proteindisulfide oxidoreductase was reduced in the presence of this inhibitor. It is concluded that dipeptidyl peptidase IV is involved or might represent a limiting factor in the process of regulation of T lymphocyte proliferation.


Guidelines for the prevention of malaria in travellers from the United Kingdom. PHLS Malaria Reference Laboratory, London School of Hygiene and Tropical Medicine.
These guidelines on malaria prevention are an aid to health care workers who advise travellers, particularly those who will be overseas for less than a year. They represent a virtual consensus of the views of 44 doctors, nurses, and pharmacists with special expertise in malariology or travel medicine who met to develop them in 1996 (see list on R152). The guidelines are in three parts. The first part is a summary that emphasises modifications to the advice given in the last set of guidelines, published in 1995. The second part discusses the issues addressed in formulating the guidelines. Doctors, practice nurses, and pharmacists are asked to read this section to avoid doing harm by giving chemoprophylaxis without due attention to the traveller's history or destination and by using oversimplified lists of recommendations by country. The second part also addresses the health care worker's consultation with prospective travellers. The third part gives specific recommendations for travellers to specific destinations and some details of individual drugs. Fuller information on some points was given in earlier versions of the guidelines, which should not be discarded. Meetings of the sort described above have been held since 1980 and the group's membership has included people with varied views and experience. The views expressed in these guidelines reflect experienced professional opinion, since data are inadequate for unequivocal views to be given on several issues. There is often a range of acceptable options, but to meet the requests of general practitioners the guidelines try to give one recommended option and state alternatives, suggesting when and how different regimens can be used to good effect. Decisions on the terms under which different drugs are licensed for use are the responsibility of the Licensing Authority, advised by the Committee on Safety of Medicines (not of these guidelines). The guidelines should be read as a supplement to and not as a substitute for the relevant data sheets. Chemoprophylaxis lies somewhere between vaccination (for which people expect governments to lay down schedules) and treatment of ill people (for which each physician does what seems most appropriate) in concept and practice. The risks of malaria need to be balanced against the risks of the preventive measures, on the basis of the data available. Travellers may ask for an explanation of these risks and doctors and practice nurses need to be well informed and able to present their knowledge to travellers. The second part of these guidelines may be of use to prospective travellers who wish to read about the options themselves. All readers are recommended to read part two in its entirety to get a balanced picture.


Current Challenges in Pain Management in Hip Fracture Patients.
The high incidence of hip fracture, together with considerable associated morbidity, mortality, and cost of care, makes this injury a major clinical challenge. Of particular importance is the pain associated with hip fracture, which can have potentially severe consequences and may lead to delayed recovery. The prevailing opioid-dependent model of analgesia, however, presents multiple drawbacks and risks that can compromise outcomes in the hip fracture population. The pain management process has essential preoperative, intraoperative, and postoperative components, yet data on the comparative effectiveness of different pain management interventions in patients undergoing surgery for hip fracture are not clear cut. A Cochrane database review that included 83 different pain management studies indicated that there are not enough well-designed studies to show unequivocally which pain management approaches work well after hip fracture surgery. Yet a growing body of data on certain interventions, such as nerve blocks and multimodal analgesia, supports consideration of these options.


Centrosome maturation - in tune with the cell cycle.
Centrosomes are the main microtubule-organizing centres, playing essential roles in the organization of the cytoskeleton during interphase, and in the mitotic spindle, which controls chromosome segregation, during cell division. Centrosomes also act as the basal body of cilia, regulating cilium length and affecting extracellular signal reception as well as the integration of intracellular signalling pathways. Centrosomes are self-replicative and duplicate once every cell cycle to generate two centrosomes. The core support structure of the centrosome consists of two molecularly distinct centrioles. The mother (mature) centriole exhibits accessory appendages and is surrounded by both pericentriolar material and centriolar satellites, structures that the daughter (immature) centriole lacks. In this Review, we discuss what is currently known about centrosome duplication, its dialogue with the cell cycle and the sequential acquisition of specific components during centriole maturation. We also describe our current understanding of the mature centriolar structures that are required to build a cilium. Altogether, the built-in centrosome asymmetries that stem from the two centrosomes inheriting molecularly different centrioles sets the foundation for cell division being an intrinsically asymmetric process.


Early mobilization of trauma patients admitted to intensive care units: A systematic review and meta-analyses.
To determine the effect of early mobilization (EM) in trauma patients admitted to the ICU. Outcomes of interest included mortality, hospital and ICU length of stay (LOS), and duration of mechanical ventilation. We performed a systematic review of 4 electronic databases (Ovid MEDLINE, Embase, CINAHL, Cochrane Library) and the grey literature. Eligible study designs included randomized control trials, prospective cohorts, or retrospective cohorts. Studies must have compared EM to usual care (i.e., delayed or no mobilization) in trauma patients admitted to ICU. Overall, there were 2982 articles screened and 9 were included in the analysis. Two authors independently performed data extraction using a standardized form. Pertinent study design and population characteristics were recorded, as were prespecified outcome measures. Meta-analyses were performed using random effects models. Study quality was assessed using the Newcastle-Ottawa Scale. Study cohorts ranged from 15 to 1132 patients (median 63) and varied in their inclusion criteria. Most studies utilized a progressive mobility protocol as their intervention. Mortality was reported in 5 studies, of which 3 observed a lower rate with EM; however, meta-analysis showed no difference in mortality between patients mobilized early and those receiving usual care. Eight studies reported on LOS (in-hospital and ICU); although all 8 studies found EM reduced LOS, the difference in LOS was not significant on meta-analysis. Finally, 3 studies reported on ventilator days, all of which observed a reduction in the EM group. On meta-analysis, duration of mechanical ventilation was significantly lower with EM (mean difference -1.18 days, 95% CI, -2.17 - -0.19). Few studies have investigated the effects of EM in trauma ICU patients. The available evidence suggests that patients who receive EM require fewer days of mechanical ventilation, but have similar mortality and LOS compared to those receiving usual care.


Simple low-noise power supply for electrical transient measurements.
A very simple means is described for rapidly applying and briefly maintaining a large, essentially noiseless, dc voltage across a capacitive load. The technique is suitable for various nonrepetitive electrical transient measurements, such as carrier mobility determination, occurring over timescales ranging from tens of microseconds to several seconds; it essentially eliminates capacitive currents caused by noise in the power supply voltage, which can interfere with measurement of the true transient current. In an example, the noise on a 10-ms transient current (driven by 2000 V dc, and observed as a voltage across a 100-kOmega load resistor) was barely more than the Johnson noise ( approximately 2x10(-11) A rms) to be expected from the resistor.


Effect of SQ20881 and captopril on pulmonary angiotensin II formation and blood pressure.
The lung is thought to be the major site for conversion of angiotensin I (AI) to angiotensin II (AII), although a significant amount of AI conversion is also known to occur in the peripheral circulation. Reports suggest that pulmonary conversion of AI to AII is more sensitive to inhibition by specific kininase II inhibitors than extrapulmonary conversion. This latter observation prompted us to seek for a dose of SQ20881 and/or captopril that would suppress the conversion of AI to AII in the lung without affecting extrapulmonary conversion of AI and thereby peripheral pressor responses to intravenously administered AI. Experiments were performed on 15 pentobarbital anaesthetized dogs. The AII arterial-venous difference across the lung was measured during an intravenous (i.v.) infusion of AI which produced a steady-state rise in blood pressure of 20 mmHg. This protocol was repeated with the same dose of AI following three graded doses of either SQ20881, captopril or vehicle. Results showed that the systemic pressor response to AI cannot be dissociated from pulmonary AI conversion.


Development of precise maps in visual cortex requires patterned spontaneous activity in the retina.
The visual cortex is organized into retinotopic maps that preserve an orderly representation of the visual world, achieved by topographically precise inputs from the lateral geniculate nucleus. We show here that geniculocortical mapping is imprecise when the waves of spontaneous activity in the retina during the first postnatal week are disrupted genetically. This anatomical mapping defect is present by postnatal day 8 and has functional consequences, as revealed by optical imaging and microelectrode recording in adults. Pharmacological disruption of these retinal waves during the first week phenocopies the mapping defect, confirming both the site and the timing of the disruption in neural activity responsible for the defect. Analysis shows that the geniculocortical miswiring is not a trivial or necessary consequence of the retinogeniculate defect. Our findings demonstrate that disrupting early spontaneous activity in the eye alters thalamic connections to the cortex.


Participation of cyclooxygenases in cutaneous thermal nociception under non-inflamed and inflamed conditions.
Effects of cyclooxygenase inhibitors on noxious thermal stimuli were investigated in non-inflamed and inflamed rats. Male Sprague-Dawley rats were used in this study. Cyclooxygenase inhibitors, indomethacin, mofezolac, NS-398, and JTE-522 were administered orally at a dose of 10 mg/kg 1 h prior to and 4 h after the intravenous injection of lipopolysaccharide (1 mg/kg). The nociceptive response was evaluated from the escape latency of foot withdrawal to the thermal stimuli with a beam of light. Expression ofcyclooxygenase was examined by reverse transcription-polymerase chain reaction. In normal rat, administration of indomethacin, relatively cyclooxygenase-1-selective inhibitor, mofezolac, or cyclooxygenase-2-selective inhibitors, NS-398 and JTE-522 had no effects on the escape latency against thermal stimuli. Injection of lipopolysaccharide into rat induced the expression of mRNA for cyclooxygenase-2 in the subcutaneous tissue of foot pad. The escape latency at 8 h was significantly shortened by the injection. This hyperalgesia could be reversed by pretreatment of rat with NS-398 or JTE-522, but not with mofezolac. Cyclooxygenases may have little participation in peripheral skin thermal nociception in non-inflamed condition, although cyclooxygenase-2 could be responsible for the hyperalgesia during inflammation induced by lipopolysaccharide.


Mannose-binding lectin and the prognosis of fulminant hepatic failure caused by HBV infection.
The mannose-binding lectin (MBL) gene was reported to play an important role in determining the clinical outcome of persistent hepatitis B virus (HBV) infection. We investigated serum MBL concentrations and MBL gene mutations to determine whether they were related to the prognosis of patients with fulminant hepatic failure (FHF) caused by HBV infection. We investigated serum MBL concentrations and MBL gene mutations in 43 HBV-infected Japanese patients with FHF and 260 HBsAg-negative healthy controls. Serum MBL concentrations were measured by an enzyme-linked immunosorbent assay, and mutations in the MBL gene were analysed by nested PCR and direct DNA sequencing. Only a mutation in codon 54 of the MBL gene was found. The frequency of this mutation in nonsurvivors (40%, 8/20) was higher than in survivors (13%, 3/23), and the difference was slightly significant (p = 0.043). The H allele frequency in survivors (70.5%, 31/44) was higher than in nonsurvivors (39.5%, 15/38) (p = 0.0048). Because of these factors the mean serum MBL concentration in survivors, 1.61 ,micro/ml (range 0.3-3.86), was significantly higher than in nonsurvivors, 0.79 microg/ml (range 0.04-1.51) (p < 0.0001). The likelihood ratio for nonsurvival was 0 for over 2.0 microg/ml, 0.67 for 1.0-2.0 microg/ml, and 2.24 for 0-1.0 microg/ml. The mutation in codon 54 of the MBL gene tended to be higher in nonsurvivors than in survivors. The H allele frequency (high producing allele in H/Y) in survivors was higher than that in nonsurvivors. High levels of serum MBL correlated with the survival of patients with FHF due to HBV infection. Serum MBL may be useful as a predictive factor for the survival of patients with FHF caused by HBV.


Should children's hospitals have special consideration in reimbursement policy?
Children's hospitals were excluded indefinitely from the prospective payment system until a methodology for their reimbursement could be developed. Special consideration in reimbursement policy could be made for children's hospitals if their patients were generally more resource intensive than the pediatric patients of other hospitals. The resource intensity of patients in children's hospitals was compared with pediatric patients in other hospital groups. The results indicate that the patient population of children's hospitals is similar to the pediatric patient population of university hospitals and considerably different from the pediatric patient populations of the urban and rural hospitals.


Rapid identification and quantitation of clotrimazole, miconazole, and ketokonazole in pharmaceutical creams and ointments by thin-layer chromatography-densitometry.
Thin-layer chromatography (TLC)-densitometry was used to separate, identify, and quantitate clotrimazole, miconazole, and ketokonazole (alone or combined with other drugs) in various pharmacopoeial or proprietary creams and ointments. Clotrimazole was extracted from the cream or ointment with ethyl alcohol, and miconazole and ketokonazole were extracted with a mixture of equal volumes of chloroform and isopropyl alcohol. Active ingredients were separated from excipients and other drugs by TLC on a precoated silica gel F254 plate with a solvent system of n-hexane-chloroform-methanol-diethylamine (50 + 40 + 10 + 1, v/v). The 3 azoles were well separated and easily identified in this chromatographic system. The separated azoles were visualized under short-wave UV light and quantitated by scanning densitometry at 220 nm by comparing the integrated areas of samples with those of standard (one azole was used as internal standard for the other). Recoveries from samples spiked with known amounts of azoles were excellent. The method was validated further by comparison with official liquid chromatographic methods.


Effect of 5-FU on modulation of disarrangement of immune-associated cytokines in experimental acute pancreatitis.
To investigate the effects of 5-Fluorouracil (5-FU) on modulation of pro-inflammatory and anti-inflammatory cytokines in acute pancreatitis and the mechanism of it in the treatment of acute pancreatitis. Male Sprague Dawley rats were assigned to 3 Groups: Group A, sham operated rats as controls (n = 7); Group B, acute pancreatitis induced by ductal injection with 5% sodium cholate at a volume of 1.0 mL/kg without any other treatment; Group C, after the pancreatitis was induced as in Group B, the rats were injected intravenously with 5-FU 40 mg/kg. The animals in Groups B and C were killed at 2, 6 and 24 h after operation (n = 7), and blood samples were taken for measurement of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6) (by bioassay), and interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta) (by ELISA). The wet weight of pancreatic tissue, serum amylase levels and white blood cells were also measured. Four rats in Group B and one in Group C died after pancreatitis was induced. Both pro-inflammatory cytokines (TNF-alpha, IL-1, IL-6) at the 2 and 6 h period and the anti-inflammatory cytokines (IL-10, TGF-beta) at 24 h increased significantly (P < 0.05) in rats of Group B. After treatment with 5-FU, TNF-alpha, IL-1, and IL-6 in serum of rats of Group C were inhibited at 2 and 6 h after operation (P < 0.05), and IL-10, TGF-beta were inhibited at 24 h compared to Group B (P < 0.05). Obvious improvements in the severity of the acute pancreatitis, including the amylase levels, wet weight of pancreatic tissue and neutrophil counts, were also observed after treatment with 5-FU. 5-FU is an anti-metabolic and immunosuppressive agent which can minimize the abnormal immune cytokine response and relieve the pathophysiological disorders associated with experimental acute pancreatitis.


Isolation and characterization of Azospirillum lipoferum locus that complements Rhizobium meliloti dctA and dctB mutations.
A DNA probe containing the structural gene for dicarboxylate transport (dct A) of Rhizobium meliloti hybridized strongly with the fragments of Azospirillum lipoferum genomic DNA. A genomic library of A. lipoferum was screened for the dct A gene by complementation of a dct A mutant of Rhizobium meliloti. A recombinant cosmid, p37D, capable of restoring growth of the dct A mutant on dicarboxylates was isolated and found to hybridize to the dctA probe. The ability of p37D to complement the dct B mutant of R. meloliti indicated that dct A and dct B genes in A. lipoferum may be organized adjacent to each other.


Comparison of acute and chronic protein-energy malnutrition on host antitumor immune mechanisms.
Protein-calorie malnutrition (PCM) is prevalent in cancer patients. However, the effect of PCM on anti-tumor immunity is unclear and critically important in an era of improving results with adoptive immunotherapy. This study examined the effect of short- and long-term PCM on tumor-specific and natural immune effector mechanisms in a murine neuroblastoma (C1300 NRB) model. A/J mice received an isocaloric 2.5% or 24% casein diet for 3 or 8 weeks before inoculation with tumor. Three weeks later lymphocytes from tumor-bearing mice were harvested for determination of cytotoxic T lymphocyte (CTL) generation and natural killer (NK) cell cytotoxicity. Both 3 and 8 weeks of PCM significantly reduced mean total body weight by 25% (p less than 0.001) and 41% (p less than 0.001), respectively, compared with regularly nourished mice. Short-term PCM did not inhibit CTL or NK cytotoxicity, whereas long-term PCM significantly diminished CTL generation (p less than 0.001) but preserved NK cytotoxic function. These results indicate that CTL development against autologous tumor, in contrast to basal NK function, is dependent on host nutritional status. Mean tumor growth, determined by tumor-weight to carcass-weight ratio, was unchanged for both short- and long-term protein-energy deprived groups compared with results in regularly nourished mice. These findings suggest that NK function is the predominant effector mechanism inhibiting C1300 NRB growth and that NK tumoricidal capacity is preserved during PCM.


Intrinsic Immune Mechanisms Restricting Human Cytomegalovirus Replication.
Cellular restriction factors (RFs) act as important constitutive innate immune barriers against viruses. In 2006, the promyelocytic leukemia protein was described as the first RF against human cytomegalovirus (HCMV) infection which is antagonized by the viral immediate early protein IE1. Since then, at least 15 additional RFs against HCMV have been identified, including the chromatin regulatory protein SPOC1, the cytidine deaminase APOBEC3A and the dNTP triphosphohydrolase SAMHD1. These RFs affect distinct steps of the viral replication cycle such as viral entry, gene expression, the synthesis of progeny DNA or egress. This review summarizes our current knowledge on intrinsic immune mechanisms restricting HCMV replication as well as on the viral strategies to counteract the inhibitory effects of RFs. Detailed knowledge on the interplay between host RFs and antagonizing viral factors will be fundamental to develop new approaches to combat HCMV infection.


Separation mixed semen of two individuals using magnetic beads coupled ABH blood group antibody.
In sexual assault cases, one of the most common samples collected is a mixed semen stain, which is often found on the vagina, female underwear, or bed sheets. However, it is usually difficult to identify the perpetrator based on this sample alone. One technique that has been developed to address this issue is magnetic bead-based separation. This method involves using modified magnetic microspheres to capture and enrich specific target cells, in this case, sperm cells. In this study, we utilized magnetic beads coupled with ABH blood group antibody to isolate sperm cells from an individual of a single ABO blood type. Subsequently, polymerase chain reaction amplification and capillary electrophoresis were employed to perform the genotyping the short tandem repeat (STR) loci. This approach allows for the identification of different individuals in a mixed seminal stain sample from two individuals, by first separating sperm cells based on ABH antigen differences and subsequently utilizing autosomal STR typing on the enriched single blood group cells.


Feasibility testing of smart tablet questionnaires compared to paper questionnaires in an amputee rehabilitation clinic.
Capturing the variability that exists among patients attending an amputee clinic using standardized paper-based questionnaires is time-consuming and may not be practical for routine clinical use. Electronic questionnaires are a potential solution; however, the benefits are dependent on the feasibility and acceptance of this mode of data collection among patients. To determine the feasibility and patient preference/comfort in using a tablet-based questionnaire for data collection in an outpatient amputee rehabilitation clinic compared to a traditional paper-based questionnaire. Observational study. In all, 48 patients with major extremity amputations completed both tablet and paper questionnaires related to their amputation and prosthetic use. Both trials were timed; patients then completed a semi-structured questionnaire about their experience. In all, 20.5% of patients needed hands-on assistance completing the paper questionnaire compared to 20.8% for the tablet. The majority of participants (52.1%) indicated a preference for the tablet questionnaire; 64.6% of patients felt the tablet collected a more complete and accurate representation of their status and needs. In all, 70.8% of participants described themselves as comfortable using the tablet. Despite comorbidities, patients with amputations demonstrated excellent acceptance of the electronic tablet-based questionnaire. Tablet questionnaires have significant potential advantages over paper questionnaires and should be further explored. Clinical relevance A custom electronic questionnaire was found to be beneficial for routine clinic use and was well received by patients in an amputee rehabilitation clinic. Development of such questionnaires can provide an efficient mechanism to collect meaningful data that can be used for individual patient care and program quality improvement initiatives.


centrosomin's beautiful sister (cbs) encodes a GRIP-domain protein that marks Golgi inheritance and functions in the centrosome cycle in Drosophila.
The mechanism of inheritance of the Golgi complex is an important problem in cell biology. In this study, we examine the localization and function of a Golgi protein encoded by centrosomin's beautiful sister (cbs) during cleavage in Drosophila melanogaster. Cbs contains a GRIP domain that is 57% identical to vertebrate Golgin-97. Cbs undergoes a dramatic relocalization during mitosis from the cytoplasm to an association with chromosomes from late prometaphase to early telophase, by a transport mechanism that requires the GRIP domain and Arl1, the product of the Arf72A locus. Additionally, Cbs remains independent of the endoplasmic reticulum throughout cleavage. The use of RNAi, Arf72A mutant analysis and ectopic expression of the GRIP domain, shows that cycling of Cbs during mitosis is required for the centrosome cycle. The effects on the centrosome cycle depend on Cbs concentration and Cbs transport from the cytoplasm to DNA. When Cbs levels are reduced centrosomes fail to mature, and when Cbs transport is impeded by ectopic expression of the GRIP domain, centrosomes undergo hypertrophy. We propose that, Cbs is a trans-Golgi protein that links Golgi inheritance to the cell cycle and the Drosophila Golgi is more vertebrate-like than previously recognized.


Current issues: women and bipolar disorder.
While the treatment of bipolar disorder (BD) is typically complex, the treatment of women with bipolar disorder is even more challenging because clinicians must also individualize treatment based on the potential for pregnancy, drug interactions with oral contraceptives, and an increased risk of endocrine diseases that can either impact the course of illness or become manifest with some treatments. Women with BD should be checked for hypothyroidism, and if prescribed antidepressants, carefully watched for rapid cycling or a mood switch to mania, hypomania, or a mixed state. Several medications interact with oral contraceptives or increase the risk of developing polycystic ovary syndrome. Consideration of possible pregnancy is essential, and should be planned in advance whenever possible. Rates of recurrence have been shown to be equal in pregnant and nonpregnant women with BD. Risks of medication to the fetus at various points of development must be balanced against the risks of not treating, which is also detrimental to both fetus and mother. The postpartum period is a time of especially high risk; as many as 40% to 67% of women with BD report experiencing a postpartum mania or depression. The decision to breastfeed must also take into account the adverse impact of sleep deprivation in triggering mood episodes. In order to best address these issues, clinicians must be familiar with the data and collaborate with the patient to assess risks and benefits for the individual women and her family.


Targeting protein kinase C (PKC) and telomerase by phenethyl isothiocyanate (PEITC) sensitizes PC-3 cells towards chemotherapeutic drug-induced apoptosis.
Prostate cancer is the leading cause of cancer-related death in men, incidences of which are increasing gradually in India. Protein kinase C (PKC), an enzyme, gets overexpressed in prostate cancer and results in a resistance to chemotherapy. Telomerase, a reverse transcriptase, is highly activated in prostate cancer cells. Both of these enzymes can be considered as potential molecular markers for prostate cancer. The present study investigates the effects of natural isothiocyanate phenethyl isothiocyanate (PEITC) in modulating the activities of PKC and telomerase in the androgen-independent human prostate adenocarcinoma (PC-3) cell line. We observed that PEITC downregulated the antiapoptotic isoforms (PKC alpha and epsilon) efficiently and zeta moderately. Basal level of PKC delta, a proapoptotic form, was very poor and its modulation was not significant. PEITC also inhibited the activity of telomerase. Studies were conducted to measure the degree of apoptotic cell death induced either by PEITC alone or in combination with adriamycin or etoposide. Apoptosis was evident from the release of mitochondrial cytochrome c, apoptotic index, and by the induction of caspases 3 and 8. PEITC exhibited remarkable efficacy in sensitizing PC-3 cells to undergo cell death by adriamycin and etoposide, which might prove to be of considerable value in synergistic therapy of cancer.