Psychological Predictors of Acute Postoperative Pain After Hysterectomy for Benign Causes.
Psychological parameters have been shown to contribute significantly to the development of acute postoperative pain (APOP). For the prediction of APOP in chest malformation patients and cancer patients, we found pain-specific psychological predictors to be of higher relevance than general psychological predictors. The current study aims to further substantiate these findings. In a sample of 73 middle-aged hysterectomy patients, 3 predictor sets were assessed 1 day before surgery: attentional biases (toward pain-related, social threat, and positive words in a dot-probe task), pain-related emotions and cognitions (pain anxiety, pain catastrophizing, and pain hypervigilance), and affective state variables (depression and somatization). APOP intensity rated 2 to 3 days after surgery and analgesic consumption during the first 48 postoperative hours were used as outcome measures. APOP intensity ratings were significantly explained by their best single predictors in a multiple regression analysis: social threat words of the dot-probe task, pain anxiety, and somatization (14.7% of explained variance). When comparing standardized β coefficients, pain-specific psychological predictors appeared to be of higher explanatory relevance than general psychological predictors. In contrast, analgesic consumption could not be significantly predicted by the psychological variables. Hysterectomy patients at risk for high APOP intensity could be characterized by the psychological variables used, whereas their predictive value for analgesic consumption was limited. The high predictive potency of pain-specific psychological variables should be considered for further improvement of pain management and prevention, because pain-specific variables such as pain anxiety can be the target of focal psychological interventions when preparing for surgery.


MiR-21 Participates in the PD-1/PD-L1 Pathway-Mediated Imbalance of Th17/Treg Cells in Patients After Gastric Cancer Resection.
The programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway has been shown to be involved in trauma-induced immunosuppression and to influence CD4+ T cell differentiation. MicroRNA (miR)-21 is a critical player in immune responses. However, it remains largely unknown whether miR-21 is regulated by PD-1 and influences CD4+ T-cell lineage choice after gastric cancer resection. In the present study, we analyzed the percentages of T-helper (Th)-17/regulatory T (Treg) cells and PD-1/PD-L1 expression on peripheral blood mononuclear cells (PBMCs) during the perioperative period. We also detected the secretion of interleukin (IL)-17 and transforming growth factor (TGF)-β1 using enzyme-linked immunosorbent assays (ELISAs). Furthermore, PBMCs isolated from patients were transfected with or without adenovirus-short hairpin-PD-1 (Ad-sh-PD1), pre-miR-21 or adenovirus-green fluorescent protein (Ad-GFP), and the percentages of Th17/Treg cells and related transcription factors were measured. In patients who underwent gastric cancer resection, the number of Th17 cells decreased, whereas the number of Treg cells increased, accompanied by an increased expression of PD-1/PD-L1. In addition, the expression of RORγt and IL-17 decreased, whereas the expression of Foxp3 and TGF-β1 increased. In vitro, silencing PD-1 via Ad-sh-PD1 promoted the expression of miR-21 and increased the percentage of Th17 cells, but decreased the percentage of Treg cells. The overexpression of miR-21 increased the percentage of Th17 cells but decreased the percentage of Treg cells. Our study demonstrated that gastric cancer resection altered the balance of Th17/Treg cells and increased PD-1/PD-L1 expression. In the in vitro experiments, the transfection of Ad-sh-PD1 ameliorated Th17/Treg cell imbalance partially by increasing the expression of miR-21.


Anti-Clogging Effect of Continuous Hemodiafiltration With Blood Recirculation.
Pediatric dialysis requires low flow from the body, but greater flow is needed to prevent clogging. As a solution, we developed a new continuous hemodiafiltration system with blood recirculation (CHDF-R), which enables separate settings for blood flow from the body and to the hemofilter. We compared CHDF-R with conventional continuous hemodiafiltration (CHDF) of bovine plasma and blood by monitoring the transmembrane pressure (TMP) and observing the hemofilter membrane surface. When using bovine plasma, the postdialysis TMP with CHDF-R was significantly lower than with CHDF (median CHDF, 23.7; median CHDF-R, 18.1; p = 0.029). Likewise, when using bovine blood, the postdialysis TMP was also significantly lower with CHDF-R than with CHDF (median CHDF, 150; median CHDF-R, 100; p = 0.029). Moreover, the area of clogged membrane was significantly smaller with CHDF-R than with CHDF, and the inner membrane surface showed less material deposition with CHDF-R than CHDF. CHDF-R thus appears to suppress accumulation of clogging substances by producing higher shear stress within hollow fiber membranes.


Effect of ethanol on the structure and function of rabbit esophageal epithelium.
Epidemiological studies indicate a relationship between alcohol consumption and esophageal epithelial disease. We therefore sought the contribution of the direct effects of ethanol on esophageal epithelial structure and (transport and barrier) function. Epithelium from the rabbit was mounted in Ussing chambers and exposed luminally for 1 h to 1-40% ethanol. At concentrations of 1-5% potential difference (PD) increased, and at 10-40% PD decreased. The increase in PD with 1-5% ethanol was accompanied by an increase in short-circuit current (Isc), and this increase in Isc could be blocked by ouabain pretreatment. The decrease in PD with 10-40% ethanol was associated with a decrease in electrical resistance (R), and this decrease in R was paralleled by an increase in transepithelial [14C]mannitol flux. Reversibility of these changes was limited at ethanol concentrations > or = 10%, and these were associated morphologically by patchy or diffuse tissue edema. Moreover, as with ethanol exposure in vitro, exposure in vivo produced dose-dependent changes in PD, Isc, R, and morphology. These observations indicate that exposure to ethanol in concentrations and under conditions reflecting alcohol consumption in humans can alter and impair esophageal epithelial transport and barrier functions. Such impairments are likely to contribute to the observed increase in risk of esophageal disease with regular consumption of alcoholic beverages.


Clinical trial of oral artesunate with or without high-dose primaquine for the treatment of vivax malaria in Thailand.
We studied prospectively 801 Thai patients admitted to the Bangkok Hospital for Tropical Diseases with acute, symptomatic Plasmodium vivax malaria to determine the optimum duration of treatment with oral artesunate and the safety, tolerability, and effectiveness of a high dose of primaquine in prevention of relapse. Patients were randomly assigned to one of four treatment groups: 1) a five-day course of artesunate (Group A5); 2) a seven-day course of artesunate (Group A7); 3) a five-day course of artesunate plus a 14-day course of high-dose primaquine (0.6 mg/kg, maximum dose = 30 mg) (Group A5 + P); and 4) a seven-day course of artesunate plus a 14-day course of high-dose primaquine (Group A7 + P). During 28 days of observation, P. vivax reappeared in the blood of 50% of those who received artesunate alone (Groups A5 and A7), compared with none of those who received primaquine (Groups A5 + P and A7 + P; P < 0.0001). Adverse effects were confined to the 13 patients with a deficiency for glucose-6-phosphate dehydrogenase; high-dose primaquine (0.6 mg/kg of base a day) had to be stopped in four (31%) patients because of a significant decrease in the hematocrit. The combination of five days of artesunate and 14 days of primaquine is a highly effective and generally well-tolerated treatment regimen for vivax malaria in Thailand.


Comparison of Recovery Quality Following Medetomidine versus Xylazine Balanced Isoflurane Anaesthesia in Horses: A Retrospective Analysis.
Medetomidine partial intravenous anaesthesia (PIVA) has not been compared to xylazine PIVA regarding quality of recovery. This clinical retrospective study compared recoveries following isoflurane anaesthesia balanced with medetomidine or xylazine. The following standard protocol was used: sedation with 7 µg·kg-1 medetomidine or 1.1 mg·kg-1 xylazine, anaesthesia induction with ketamine/diazepam, maintenance with isoflurane and 3.5 µg·kg-1·h-1 medetomidine or 0.7 mg·kg-1·h-1 xylazine, and sedation after anaesthesia with 2 µg·kg-1 medetomidine or 0.3 mg·kg-1 xylazine. Recovery was timed and, using video recordings, numerically scored by two blinded observers. Influence of demographics, procedure, peri-anaesthetic drugs, and intraoperative complications (hypotension, hypoxemia, and tachycardia) on recovery were analysed using regression analysis (p < 0.05). A total of 470 recoveries (medetomidine 279, xylazine 191) were finally included. Following medetomidine, recoveries were significantly longer (median (interquartile range): 57 (43-71) min) than xylazine (43 (32-59) min) (p < 0.001). However, the number of attempts to stand was similar (medetomidine and xylazine: 2 (1-3)). Poorer scores were seen with increased pre-anaesthetic dose of xylazine, intraoperative tetrastarch, or salbutamol. However, use of medetomidine or xylazine did not influence recovery score, concluding that, following medetomidine-isoflurane PIVA, recovery is longer, but of similar quality compared to xylazine.


Which patients are candidates for lung transplantation? Indications for unilateral, bilateral, and heart-lung procedures.
Single-lung transplantation, long successful in resolving interstitial lung disease, can now be used in COPD patients and shows promise in managing pulmonary hypertension. The bilateral procedure, which often avoids cardiopulmonary bypass, is preferred when chronic airway infection is present. Heart-lung transplants, now rare, are used when pulmonary hypertension is complicated by congestive cardiomyopathy or irreparable cardiac defects. Mechanical ventilation, prior cardiothoracic surgery, and corticosteroid use no longer constitute absolute contraindications to lung transplantation. The growing scarcity of donor organs is increasing waiting times; thus, earlier recognition of potential recipients is necessary.


B cell-associated LFA-1 and T cell-associated ICAM-1 transiently cluster in the area of contact between interacting cells.
TNP-specific B cells interact with carrier-specific T hybridoma cells in an antigen-specific, MHC-restricted manner. The formation of T cell/B cell conjugates is time and temperature dependent and results in the formation of a broad area of close contact between the interacting cells. In order to determine which surface molecules on the two cells cluster at the interaction site. T cell/B cell conjugates were formalin-fixed at different times following conjugation and were stained with antibodies directed against cell surface molecules. Results of these studies indicate that the alpha- and beta-subunits of LFA-1 on B cells transiently cluster in the area of cell contact. Maximum clustering of LFA-1 occurs at 45 min, after which time LFA-1 redistributes on the surface of the B cells. Several other B cell-associated molecules (MHC Class II, ICAM-1, Ig, B220, J11D, or CD23) do not cluster at the interaction site at any time point. T cell-associated LFA-1 does not cluster with any specific pattern, but ICAM-1 does. Maximum clustering of ICAM-1 occurs 60 to 90 min after intercellular contact. After this time, ICAM-1 redistributes on the surface of the T cells. Although both the alpha- and beta-subunits of LFA-1 cluster at the interaction site on B cells, antibodies recognizing these subunits differ in their ability to affect conjugation. One antibody recognizing the alpha chain of LFA-1 (M17/4.2) inhibits T-cell/B cell conjugation, whereas another antibody that also recognizes the alpha chain-(G-48) enhances conjugation. In contrast, an antibody that recognizes LFA-1 beta (M18/2.a.8) has no effect. An antibody that recognizes ICAM-1 (YN/1.7), the ligand for LFA-1, inhibits conjugation. These data show that, during T cell/B cell interaction. LFA-1 on B cells and ICAM-1 on T cells transiently cluster with similar, albeit not identical, kinetics to the site of cell-cell contact.


Equity and adequacy in school funding.
Since 1971, most states have been subject to lawsuits seeking to reform their education funding systems. These cases are litigated on the basis of state (not federal) constitutional language and generally seek either greater equity in funding among school districts or a guaranteed level of adequate funding for education. State supreme courts have found the finance systems unconstitutional in 16 states, and many states are still actively involved in litigation. Even where litigation has not occurred or has not succeeded, the prospect of litigation has prompted revisions of state funding policies. Despite the predominant role equity and adequacy play in litigation, there are no universally accepted definitions for either of these words in education funding. Most commonly, equity is measured in terms of the variation in per-pupil revenues among school districts in a single state. By this measure, some states have greater funding equity than others, and in most states wealthy districts have significantly higher per-pupil expenditures than do poor districts. Equity is likely to be greater when the residents of poor districts pay higher taxes. (In some states, residents in poorer areas pay twice as much of their income in local taxes as do residents of wealthier communities.) Equity is also greater in those states where the state's share of the education budget is higher and where the state consistently targets its contributions to lower-income districts. Much of current litigation and legislative activity in education funding seeks to assure "adequacy," that is, a sufficient level of funding to deliver an adequate education to every student in the state. Most states have not explicitly addressed the questions of how much education is "adequate" or how educational standards can be converted to a finance formula. Several approaches to calculating the cost of an adequate education are described.


Endografting under Assistance of Transapical Body Floss Through-and-Through Wiring Technique and Rapid Ventricular Pacing for an Ascending Aortic Tuberculous Pseudoaneurysm.
To demonstrate an ascending aortic tuberculosis pseudoaneurysm successfully treated with endografts under assistance of trans-apical body floss wiring technique and rapid ventricular pacing support. A 77-year-old woman with a non-healing anteromedial chest wound presented with sudden hypotension and hemoptysis. The computed tomography (CT) scan revealed a 9-cm-diameter pseudoaneurysm of ascending aorta, with sternal erosion close to the wound. Conventional open repair was not preferred due to possible contamination of interposition graft and difficult sternum closure. The feasibility of endografting was confirmed based on appropriate landing zones. After endografts modification at back table, we made a left mini-thoracotomy and establish a through-and-through body floss wire from left ventricular apex to femoral artery. Retrograde delivery over this wire from femoral artery to ascending aorta and deployment of endografts under rapid ventricular pacing support were performed smoothly. Final angiography showed no endoleaks with patent coronary and arch vessels. Further wound debridement was done at the same time and wound culture yielded tuberculosis. After completing anti-tuberculosis therapy, no recurrent infection occurred. Postoperative 6-month CT scan disclosed optimal result. With adequate landing zones and delicate surgical strategy, endografting with anti-tuberculosis therapy may be an alternative treatment for ascending aortic tuberculosis pseudoaneurysm.


The Psychiatric Status Schedule for epidemiological research. Methodological considerations.
The Psychiatric Status Schedule (PSS) was designed to improve the research value of clinical judgments in the assessment of psychopathology. Although constructed with data from psychiatric patients, it is also intended for use in case finding, as in epidemiological studies of the general population. Its usefulness for this purpose has been questioned on the basis of the low internal consistency of many of the PSS scales in a general population sample and strata thereof. We challenged this methodological stance. Using the same data set, the PSS can be shown to have validity for epidemiological use, in that it discriminates outpatients from the general population and identifies psychiatric "cases" variously defined.


[Urinary tract infections in patients with type 2 diabetes mellitus with pharmacological glucosuria].
Selective inhibitors of sodium-glucose cotransporter belong to a new class of drugs for the treatment of type 2 diabetes mellitus. The mechanism of their action is based on insulin-independent reduction of glucose reabsorption in the proximal renal tubules, which leads to stimulation of its excretion in the urine and, accordingly, to a decrease in the concentration of glucose in the blood plasma. Drugs of this group demonstrate effectiveness in the treatment of type 2 diabetes, but their use may be associated with an increased frequency of urinary tract infections. Pharmacological glucosuria, which leads to a decrease in the concentration of glucose in the blood, creates the preconditions for the occurrence of urinary tract infections. Urinary tract and genital infections are the most common adverse events associated with the use of sodium-glucose cotransporter inhibitors. In the presented literature review for 20162019, the relationship between urinary tract infections in patients with type 2 diabetes mellitus and therapy with sodium-glucose cotransporter inhibitors was analyzed.


Are seeded endothelial cells the origin of neointima on prosthetic vascular grafts?
Although endothelial cell seeding has been demonstrated to be effective in producing uniform endothelial coverage on prosthetic grafts, no one has demonstrated that the seeded cells are the genetic precursors of the endothelial cells that ultimately line the graft. This study was performed to determine whether seeded endothelial cells were the source of the neoendothelial surface on Dacron vascular grafts implanted in the pig. Eight pairs of littermate male and female pigs were selected at birth and allowed to grow until their weight reached 20 to 25 kg. Endothelial cells were enzymatically harvested from the jugular vein of the female siblings and seeded onto 8 mm diameter grafts, 25 cm in length. The grafts were then implanted as a thoracoabdominal bypass into the male siblings. Seven other randomly selected pigs of similar size (four males and three females) had thoracoabdominal bypass with similar grafts, which were preclotted with autologous blood only, but not seeded. After 4 weeks, grafts in both groups were covered with a neointima that was more than 90% thrombus-free. The graft surface cells were grown in culture and were documented to be endothelium. Chromosome analysis demonstrated that the surface cells on the seeded grafts were from the male host and did not originate from the donor female cells. We conclude that seeded endothelial cells are not the source for the neointima on Dacron grafts in the porcine model. In addition, we have again documented that spontaneous endothelial coverage of grafts does occur without endothelial seeding.


Exercise training normalizes ACE and ACE2 in the brain of rabbits with pacing-induced heart failure.
Exercise training (EX) normalizes sympathetic outflow and plasma ANG II in chronic heart failure (CHF). The central mechanisms by which EX reduces this sympathoexcitatory state are unclear, but EX may alter components of the brain renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) may mediate an increase in sympathetic nerve activity (SNA). ACE2 metabolizes ANG II to ANG-(1-7), which may have antagonistic effects to ANG II. Little is known concerning the regulation of ACE and ACE2 in the brain and the effect of EX on these enzymes, especially in the CHF state. This study aimed to investigate the effects of EX on the regulation of ACE and ACE2 in the brain in an animal model of CHF. We hypothesized that the ratio of ACE to ACE2 would increase in CHF and would be reduced by EX. Experiments were performed on New Zealand White rabbits divided into the following groups: sham, sham + EX, CHF, and CHF + EX (n = 5 rabbits/group). The cortex, cerebellum, medulla, hypothalamus, paraventricular nucleus (PVN), nucleus tractus solitarii (NTS), and rostral ventrolateral medulla (RVLM) were analyzed. ACE protein and mRNA expression in the cerebellum, medulla, hypothalamus, PVN, NTS, and RVLM were significantly upregulated in CHF rabbits (ratio of ACE to GAPDH: 0.3 +/- 0.03 to 0.8 +/- 0.10 in the RVLM, P < 0.05). EX normalized this upregulation compared with CHF (0.8 +/- 0.1 to 0.4 +/- 0.1 in the RVLM). ACE2 protein and mRNA expression decreased in CHF (ratio of ACE2 to GAPDH: 0.3 +/- 0.02 to 0.1 +/- 0.01 in the RVLM). EX increased ACE2 expression compared with CHF (0.1 +/- 0.01 to 0.8 +/- 0.1 in the RVLM). ACE2 was present in the cytoplasm of neurons and ACE in endothelial cells. These data suggest that the activation of the central RAS in animals with CHF involves an imbalance of ACE and ACE2 in regions of the brain that regulate autonomic function and that EX can reverse this imbalance.


Evaluation of the effects of group psychotherapy on cognitive function in patients with multiple sclerosis with cognitive dysfunction and depression.
This study will evaluate how decreasing depression severity via group psychotherapy affects the cognitive function of patients with multiple sclerosis (MS) who are also diagnosed with depression and cognitive dysfunction. MS patients completed the Brief Repeatable Battery of Neuropsychological Tests and Beck Depression Inventory (BDI). The group members diagnosed with depression and cognitive dysfunction underwent group psychotherapy for 3 months. Upon completion of psychotherapy, both tests were readministered. Depression and cognitive dysfunction were comorbid in 15 (13.9%) of patients. Although improvement was detected at the end of the 3-month group psychotherapy intervention, it was limited to the BDI and the Paced Auditory Test. Group psychotherapy might decrease cognitive impairment in MS patients.


High thermoelectric performances of monolayer SnSe allotropes.
α-SnSe is one of the most promising thermoelectric materials with low thermal conductivity and a high power factor. Since the thermoelectric properties of a material have a strong dependence on its crystal structure, we study the energetic and thermoelectric properties of four new monolayer phases of SnSe (β, γ, δ and ε) together with α-SnSe using the ab initio density functional theory method. The calculated electronic structures show that all five phases are semiconductors with different band gaps. The α, β, γ, and δ phases have an indirect band gap with the hybridization of sp2 orbitals, whereas the ε phase has a direct band with the hybridization of sp3 orbitals. The thermoelectric transport properties and coefficients are obtained from the electronic structure using semi-classical Boltzmann theory, and the results indicate that the four new phases of SnSe (β, γ, δ and ε) all have better thermoelectric properties compared with the reported α phase. The predicted ZT value for the β-SnSe phase is 2.06 at 300 K, suggesting that it has great potential for novel thermoelectric applications.


Activation of RAW264.7 mouse macrophage cells in vitro through treatment with recombinant ricin toxin-binding subunit B: involvement of protein tyrosine, NF-κB and JAK-STAT kinase signaling pathways.
Ricin toxin-binding subunit B (RTB) is a galactose-binding lectin protein. In the present study, we investigated the effects of RTB on inducible nitric oxide (NO) synthase (iNOS), interleukin (IL)-6 and tumor necrosis factor (TNF)-α, as well as the signal transduction mechanisms involved in recombinant RTB-induced macrophage activation. RAW264.7 macrophages were treated with RTB. The results revealed that the mRNA and protein expression of iNOS was increased in the recombinant RTB-treated macrophages. TNF-α production was observed to peak at 20 h, whereas the production of IL-6 peaked at 24 h. In another set of cultures, the cells were co-incubated with RTB and the tyrosine kinase inhibitor, genistein, the phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, the p42/44 inhibitor, PD98059, the p38 inhibitor, SB203580, the JNK inhibitor, SP600125, the protein kinase C (PKC) inhibitor, staurosporine, the JAK2 inhibitor, tyrphostin (AG490), or the NOS inhibitor, L-NMMA. The recombinant RTB-induced production of NO, TNF-α and IL-6 was inhibited in the macrophages treated with the pharmacological inhibitors genistein, LY294002, staurosporine, AG490, SB203580 and BAY 11-7082, indicating the possible involvement of protein tyrosine kinases, PI3K, PKC, JAK2, p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB in the above processes. A phosphoprotein analysis identified tyrosine phosphorylation targets that were uniquely induced by recombinant RTB and inhibited following treatment with genistein; some of these proteins are associated with the downstream cascades of activated JAK-STAT and NF-κB receptors. Our data may help to identify the most important target molecules for the development of novel drug therapies.


Decreased Urethral Volume Is Comparable to Funneling as a Predictor of Intrinsic Sphincter Deficiency.
The aims of this study were to determine the association between x-ray funneling and ultrasound urethral sphincter complex measurements and to compare the reliability of funneling versus urethral volume measurement in the detection of intrinsic sphincter deficiency (ISD). This was a retrospective analysis, which included 54 stress incontinent women dichotomized into those with (1) ISD and (2) no ISD. The presence of bladder neck funneling was diagnosed by fluoroscopic images obtained at the time of video-urodynamics testing. Measurements of the urethral sphincter complex were obtained from ultrasound volumes. Reliability measures were obtained for both funneling and urethral volume measurements. Rhabdomyosphincter length and area were found to be smaller in patients with funneling compared with those with no funneling (P = 0.0161, P = 0.0359). The urethral volume was significantly smaller in the ISD versus no-ISD group (P = 0.0002). For those who had funneling, the ISD group had smaller urethral volume compared with the no-ISD group (P = 0.0019). For those who did not have funneling, the ISD group still had a smaller urethral volume compared with the no-ISD group (P = 0.0054). An ultrasound urethral volume of less than 3.5 cm had a sensitivity of 81% and a specificity of 64% for the presence of ISD, whereas x-ray funneling had a sensitivity of 76% and a specificity of 73%. Smaller rhabdomyosphincter length and area on ultrasound are associated with x-ray funneling. Ultrasound urethral volume of 3.5 cm as a cutoff provides the same reliability as x-ray funneling for the diagnosis of ISD.


Inhibition of interferon secretion by vinblastine.
The plant alkaloids vinblastine and colchicine are known to arrest cells in mitosis by virtue of their binding to spindle protein. These drugs are also capable of binding to microtubule protein and causing these structures to disaggregate into nonfunctional subunits (1, 2). Microtubular structures are thought to be involved in the secretory process of a number of proteins including insulin (7), collagen (4), and thyroid hormone (12). In this report we present our findings on the effects of these two drugs on the synthesis and secretion of interferon in a high producing human foreskin fibroblast strain (FS-4) (11).


Applying commodity chain analysis to changing modes of alcohol supply in a developing country.
Development sociology has used global commodity chains as one way of analyzing the dynamics of power and profit-taking in globalized production networks made up of multiple firms and occurring in multiple national settings. A substantial portion of the alcohol supply in developing countries is now produced through such production networks. Particularly in the beer and spirits trade, a small number of transnational firms control networks of local producers, importers, advertisers and distributors. These networks serve to embed transnational or transnationally backed brands in the local culture, using the tools of market research, product design and marketing to influence local drinking practices. Case materials from Malaysia's beer industry help to illustrate how the transnational firms dominate in those links of the commodity chain in which monopoly or oligopoly control is most likely to be found: the design/recipe and marketing/advertising nodes. Their control of the commodity chains and extraction of monopoly or oligopoly profits from them places substantial resources and influence over drinking settings and practices in foreign hands. The impact of this influence on state efficacy and autonomy in setting alcohol policy is an important subject for future research on the creation and implementation of effective alcohol policies in developing societies.


A partial set covering model for protein mixture identification using mass spectrometry data.
Protein identification is a key and essential step in mass spectrometry (MS) based proteome research. To date, there are many protein identification strategies that employ either MS data or MS/MS data for database searching. While MS-based methods provide wider coverage than MS/MS-based methods, their identification accuracy is lower since MS data have less information than MS/MS data. Thus, it is desired to design more sophisticated algorithms that achieve higher identification accuracy using MS data. Peptide Mass Fingerprinting (PMF) has been widely used to identify single purified proteins from MS data for many years. In this paper, we extend this technology to protein mixture identification. First, we formulate the problem of protein mixture identification as a Partial Set Covering (PSC) problem. Then, we present several algorithms that can solve the PSC problem efficiently. Finally, we extend the partial set covering model to both MS/MS data and the combination of MS data and MS/MS data. The experimental results on simulated data and real data demonstrate the advantages of our method: 1) it outperforms previous MS-based approaches significantly; 2) it is useful in the MS/MS-based protein inference; and 3) it combines MS data and MS/MS data in a unified model such that the identification performance is further improved.


Immune modulation of innate and adaptive responses restores immune surveillance and establishes anti-tumor immunological memory.
Current immunotherapies have proven effective in strengthening anti-tumor immune responses, but constant opposing signals from tumor cells and the surrounding microenvironment eventually lead to immune escape. We hypothesized that in situ release of antigens and regulation of both the innate and adaptive arms of the immune system would provide a robust and long-term anti-tumor effect by creating immunological memory against tumors. To achieve this, we developed CARG-2020, a genetically modified virus-like vesicle (VLV) that is a self-amplifying RNA with oncolytic capacity and encodes immune regulatory genes. CARG-2020 carries three immune modulators: 1) the pleiotropic antitumor cytokine, IL12, in which the subunits (p35 and p40) are tethered together; 2) the extracellular domain (ECD) of the pro-tumor IL17RA, which serves as a dominant-negative antagonist; and 3) a shRNA targeting PD-L1. Using a mouse model of ovarian cancer, we demonstrated the oncolytic effect and immune-modulatory capacities of CARG-2020. By enhancing IL12 and blocking IL17 and PD-L1, CARG-2020 successfully reactivated immune surveillance by promoting M1, instead of M2, macrophage differentiation, inhibiting MDSC expansion and establishing a potent CD8+ T cell-mediated anti-tumoral response. Furthermore, we demonstrated that this therapeutic approach provided tumor-specific and long-term protection against the establishment of new tumors. Our results provide rationale for the further development of this platform as a therapeutic modality for ovarian cancer patients to enhance anti-tumor responses and prevent recurrence.


Generation of Insulin-Expressing Cells in Mouse Small Intestine by Pdx1, MafA, and BETA2/NeuroD.
To develop surrogate insulin-producing cells for diabetes therapy, adult stem cells have been identified in various tissues and studied for their conversion into β-cells. Pancreatic progenitor cells are derived from the endodermal epithelium and formed in a manner similar to gut progenitor cells. Here, we generated insulin-producing cells from the intestinal epithelial cells that induced many of the specific pancreatic transcription factors using adenoviral vectors carrying three genes: PMB (pancreatic and duodenal homeobox 1 [Pdx1], V-maf musculoaponeurotic fibrosarcoma oncogene homolog A [MafA], and BETA2/NeuroD). By direct injection into the intestine through the cranial mesenteric artery, adenoviruses (Ad) were successfully delivered to the entire intestine. After virus injection, we could confirm that the small intestine of the mouse was appropriately infected with the Ad-Pdx1 and triple Ad-PMB. Four weeks after the injection, insulin mRNA was expressed in the small intestine, and the insulin gene expression was induced in Ad-Pdx1 and Ad-PMB compared to control Ad-green fluorescent protein. In addition, the conversion of intestinal cells into insulin-expressing cells was detected in parts of the crypts and villi located in the small intestine. These data indicated that PMB facilitate the differentiation of mouse intestinal cells into insulin-expressing cells. In conclusion, the small intestine is an accessible and abundant source of surrogate insulin-producing cells.


[Deaths caused by venomous snakes in the State of São Paulo: evaluation of 43 cases from 1988 to 1993].
The prognostic factors and the causes for obit occurrence in ophidian envenoming are yet not completely clear. To determine the prognostic factors and the most probable causes for obit occurrence in ophidian envenoming. In the State of São Paulo were notified 12,639 cases of accidents by venomous snakes from 1988 to 1993. There were 43 deaths (0.34%). The variables from the accident notification reports were compared with the promptuary notes and/or with the death records (in lethal cases). The snake genus was classified in 11,297 accidents and in 41 from the lethal ones. Bothrops was responsible for 9,828 (87%) accidents and 28 (68.3%) deaths, Crotalus for 1,359 (12.0%) accidents and 13 deaths (31.7%) and Micrurus for 110 (1%) accidents and no death (p < 0.05). The information regarding to sex and age of the patients was available, respectively, in 12,620 and 12,527 accidents and in all lethal ones. There were 9,783 (77.5%) male patients in the accidents and 35 (81.4%) in the lethal cases (p > 0.05). Regarding to age, 15.9% of the patients and 41.8% of the ones who died were 50 years-old or more (p < 0.05). The most frequently bitten anatomic regions were: foot (42.2%), hand (20.6%), leg (17.6%), and ankle (13.1%) in the accidents, and foot (35.7%) and leg (35.7%) in the lethal cases (p < 0.05). Coagulation disorders occurred in 34 (91.9%) from 37 patients who died (those where this datum was available). The information above was not available in non lethal cases. The most common manifestations and complications implicated as possible death causes were: acute renal failure (34-79.1%), acute respiratory failure (28-65.1%), shock (18-41.9%), and sepsis (18-41.9%). Among all lethal cases but one without information, 29.4% of the patients died within the first two days after bite and 67.6% within the first 5 days. Acute respiratory failure was most common among the patients who died owing to crotalic envenoming, and sepsis was only seen in bothropic envenoming. Most of the accidents and obits are caused by Bothrops; Crotalus envenoming, leg bites, and accidents in 50 year-old patients (or more) are frequently lethal; the most common complication in lethal cases is acute renal failure.


Glucose metabolism in perfused skeletal muscle. Interaction of insulin and exercise on glucose uptake.
1. The interaction of insulin and isometric exercise on glucose uptake by skeletal muscle was studied in the isolated perfused rat hindquarter. 2. Insulin, 10 m-i.u./ml, added to the perfusate, increased glucose uptake more than 10-fold, from 0.3-0.5 to 5.2-5.4 mumol/min per 30g of muscle in hindquarters of fed and 48h-starved rats respectively. In contrast, it did not stimulate glucose uptake in hindquarters from rats in diabetic ketoacidosis. 3. In the absence of added insulin, isometric exercise, induced by sciatic-nerve stimulation, increased glucose uptake to 4 and 3.4 mumol/min per 30g of muscle in fed and starved rats respectively. It had a similar effect in rats with moderately severe diabetes, but it did not increase glucose uptake in rats with diabetic ketoacidosis or in hindquarters of fed rats that had been "washed out" with an insulin-free perfusate. Insulin, at concentrations which did not stimulate glucose uptake in resting muscle, restored the stimulatory effect of exercise in these situations. 4. The stimulation of glucose uptake by exercise was independent of blood flow and the degree of tissue hypoxia; also it could not be reproduced by perfusing resting muscle with a medium previously used in an exercise experiment. 5. At rest glucose was not detectable in muscle cell water of fed and starved rats even when perfused with insulin. In the presence of insulin, a small accumulation of glucose, 0.25 mM, was noted in the muscle of ketoacidotic diabetic rats, suggesting inhibition of glucose phosphorylation, as well as of transport. 6. During exercise, the calculated intracellular concentration of glucose in the contracting muscle increased to 1.1-1.6mM in the fed, starved and moderately diabetic groups. Insulin significantly increased the already high rates of glucose uptake by the hindquarters of these animals but it did not alter the elevated intracellular concentration of glucose. 7. In severely diabetic rats, exercise did not cause glucose to accumulate in the cell in the absence of insulin. In the presence of insulin, it increased glucose uptake to 6.1 mumol/min per 30g of muscle and intracellular glucose to 0.72 mM. 8. The data indicate that the stimulatory effect of exercise on glucose uptake requires the presence of insulin. They suggest that in the absence of insulin, glucose uptake is not enhanced by exercise owing to inhibition of glucose transport into the cell.


A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis.
The endothelial cell protein C (PC) receptor (EPCR) facilitates PC activation by the thrombin-thrombomodulin complex. A soluble form of this receptor (sEPCR) found in plasma inhibits both activated PC (aPC) activity and PC activation by competing for PC with membrane-associated EPCR. Elevated sEPCR levels are found in approximately 20% of healthy subjects, but the mechanisms underlying this interindividual variability are unknown. We measured sEPCR levels in 100 healthy male volunteers, and observed 2 phenotypic groups of subjects. The temporal stability of sEPCR levels suggested genetic control. Extensive analysis of the EPCR gene in these subjects revealed 13 polymorphisms in complete linkage disequilibrium; these defined 3 haplotypes, 1 of which (A3) was strongly associated with high sEPCR levels. The high constitutive sEPCR levels observed in A3 haplotype carriers might reduce the efficiency of the PC system and predispose these subjects to venous thrombosis. By studying 338 patients with venous thrombosis and 338 age- and sex-matched healthy subjects, we found that the A3 haplotype was overrepresented in the patients. In multivariate analysis, subjects carrying the A3 haplotype had an increased risk of thrombosis (odds ratio [OR] = 1.8; P =.004). Thus, the A3 haplotype, which is associated with elevated plasma sEPCR levels, is a candidate risk factor for venous thrombosis.


Clinical characteristics and treatment outcomes of angiosarcoma of the head and neck: A 17-year single-centre experience.
Angiosarcomas in the head and neck region are aggressive tumours associated with high local recurrence and metastatic rates. We present our 17-year experience at the North of England Bone and Soft Tissue Tumour Service. A retrospective review of our prospectively maintained database was undertaken, looking for patients diagnosed with angiosarcomas affecting the head and neck. Data were gathered using a pre-defined proforma to include demographics, histological characteristics, treatment modalities, adjuvant therapies, local recurrence, distant spread, and disease-specific survival. A total of 23 patients (17 males, 6 females) were identified, with a mean age of 76 years at presentation. Fourteen presented with scalp lesions, whereas the remainder arose on the face. Eighteen patients underwent resection with curative intent, whereas three received palliative radiotherapy and two received comfort-based care only. Of the patients undergoing surgery, 12 had local flap reconstruction and 6 underwent free tissue transfer. Clear resection margins were obtained in nine cases (50%). Fourteen patients (78%) presented with local recurrence after surgery, and 11 (61%) developed distant metastases. The median disease-specific survival time for patients treated with curative intent was 38 months. Eight patients had mapping biopsies ahead of their resection; however, complete resection was achieved in only two cases. Angiosarcomas of the head and neck are associated with a poor prognosis, with most patients rapidly developing local recurrence, resulting in adverse clinical outcomes. Mapping biopsies do not demonstrate a clear advantage for achieving complete surgical resection. A radical surgical approach is warranted, given the aggressiveness of the pathology. However, there remains no consensus on optimal surgical management; we recommend further synthesising studies to determine the most appropriate treatment pathway.


Soft Tissue Changes After Clockwise Rotation of Maxillo-Mandibular Complex in Class III Patients: Three-Dimensional Stereophotogrammetric Evaluation.
To evaluate the linear, angular, and volumetric changes of soft tissue after clockwise repositioning of the maxillo-mandibular complex in skeletal class III patients using three-dimensional (3D) stereophotogrammetry and to determine the correlation between changes in the skeletal and soft tissue variables. This study included 18 skeletal class III patients who underwent two-jaw surgery; superior impaction and clockwise rotational movement of the maxilla with the rotation center at upper incisors, and setback of the mandible. Lateral cephalograms and 3D photographs taken before and 6 months after surgery were compared. After maxillary impaction of anteriorly 1.7 mm and posteriorly 3.1 mm, and mandibular setback of 8.7 mm, the volume of lower lip and chin region decreased significantly by 33.6 cm3 (13% net change, P < 0.001), while paranasal and upper lip region volume increased by 3.2 cm3 (2%) and 7.2 cm3 (4%), respectively. The clockwise rotation of maxillo-mandibular complex in class III patients significantly reduced lower lip and chin volume with minimal increase in paranasal and upper lip volumes. 3D stereophotogrammetry can provide quantitative evaluation of facial soft tissue volumetric changes.


Deficiency of glycerol kinase (EC 220.127.116.11).
We describe the case of a 10-year-old boy who had been admitted on several occasions with a diagnosis of gastroenteritis. He had been severely ill, and on one occasion lost consciousness. He had a metabolic acidosis on these occasions. Examination of the urine by gas chromatography-mass spectrometry showed a large peak, identified as glycerol. The concentration of glycerol in the urine was 40-280 mmol/L and the concentration in plasma about 2 mmol/L. He was subjected to a fast of 21 h, at the end of which he expressed feelings of discomfort and nausea, began vomiting, and became somnolent. During this period the blood glucose concentration was only slightly decreased, the plasma glycerol concentration increased to 4.9 mmol/L, and the plasma lactate concentration increased to 3.8 mmol/L. During work on a bicycle ergometer for 35 min (40 W) he complained of muscle pain and became nauseated, but there was no significant increase in the concentration of plasma glycerol. The activity of glycerol kinase (EC 188.8.131.52) in leukocytes and cultured fibroblasts was less than 1% of the value for healthy subjects.


Association of Early Physical Therapy With Long-term Opioid Use Among Opioid-Naive Patients With Musculoskeletal Pain.
Nonpharmacologic methods of reducing the risk of new chronic opioid use among patients with musculoskeletal pain are important given the burden of the opioid epidemic in the United States. To determine the association between early physical therapy and subsequent opioid use in patients with new musculoskeletal pain diagnosis. This cross-sectional analysis of health care insurance claims data between January 1, 2007, and December 31, 2015, included privately insured patients who presented with musculoskeletal pain to an outpatient physician office or an emergency department at various US facilities from January 1, 2008, to December 31, 2014. The sample comprised 88 985 opioid-naive patients aged 18 to 64 years with a new diagnosis of musculoskeletal shoulder, neck, knee, or low back pain. The data set (obtained from the IBM MarketScan Commercial database) included person-level International Classification of Diseases, Ninth Revision or Tenth Revision diagnosis codes, Current Procedural Terminology codes, and date of service as well as pharmaceutical information (National Drug Code, generic name, dose, and number of days supplied). Early physical therapy was defined as at least 1 session received within 90 days of the index date, the earliest date a relevant diagnosis was provided. Data analysis was conducted from March 1, 2018, to May 18, 2018. Opioid use between 91 and 365 days after the index date. Of the 88 985 patients included, 51 351 (57.7%) were male and 37 634 (42.3%) were female with a mean (SD) age of 46 (11.0) years. Among these patients, 26 096 (29.3%) received early physical therapy. After adjusting for potential confounders, early physical therapy was associated with a statistically significant reduction in the incidence of any opioid use between 91 and 365 days after the index date for patients with shoulder pain (odds ratio [OR], 0.85; 95% CI, 0.77-0.95; P = .003), neck pain (OR, 0.92; 95% CI, 0.85-0.99; P = .03), knee pain (OR, 0.84; 95% CI, 0.77-0.91; P < .001), and low back pain (OR, 0.93; 95% CI, 0.88-0.98; P = .004). For patients who did use opioids, early physical therapy was associated with an approximately 10% statistically significant reduction in the amount of opioid use, measured in oral morphine milligram equivalents, for shoulder pain (-9.7%; 95% CI, -18.5% to -0.8%; P = .03), knee pain (-10.3%; 95% CI, -17.8% to -2.7%; P = .007), and low back pain (-5.1%; 95% CI, -10.2% to 0.0%; P = .046), but not for neck pain (-3.8%; 95% CI, -10.8% to 3.3%; P = .30). Early physical therapy appears to be associated with subsequent reductions in longer-term opioid use and lower-intensity opioid use for all of the musculoskeletal pain regions examined.


Exploring the ability of self-report measures to identify risk of high treatment burden in chronic disease patients: a cross-sectional study.
Effective self-management of chronic health conditions is key to avoiding disease escalation and poor health outcomes, but self-management abilities vary. Adequate patient capacity, in terms of abilities and resources, is needed to effectively manage the treatment burden associated with chronic health conditions. The ability to measure different elements of capacity, as well as treatment burden, may assist to identify those at risk of poor self-management. Our aims were to: 1. Investigate correlations between established self-report tools measuring aspects of patient capacity, and treatment burden; and 2. Explore whether individual questions from the self-report tools will correlate to perceived treatment burden without loss of explanation. This may assist in the development of a clinical screening tool to identify people at risk of high treatment burden. A cross-sectional survey in both a postal and online format. Patients reporting one or more chronic diseases completed validated self-report scales assessing social, financial, physical and emotional capacity; quality of life; and perceived treatment burden. Logistic regression analysis was used to explore relationships between different capacity variables, and perceived high treatment burden. Respondents (n = 183) were mostly female (78%) with a mean age of 60 years. Most participants were multimorbid (94%), with 45% reporting more than five conditions. 51% reported a high treatment burden. Following logistic regression analyses, high perceived treatment burden was correlated with younger age, material deprivation, low self-efficacy and usual activity limitation. These factors accounted for 50.7% of the variance in high perceived treatment burden. Neither disease burden nor specific diagnosis was correlated with treatment burden. This study supports previous observations that psychosocial factors may be more influential than specific diagnoses for multimorbid patients in managing their treatment workload. A simple capacity measure may be useful to identify those who are likely to struggle with healthcare demands.


Comparison of adaptive multiple phenotype association tests using summary statistics in genome-wide association studies.
Genome-wide association studies have been successful mapping loci for individual phenotypes, but few studies have comprehensively interrogated evidence of shared genetic effects across multiple phenotypes simultaneously. Statistical methods have been proposed for analyzing multiple phenotypes using summary statistics, which enables studies of shared genetic effects while avoiding challenges associated with individual-level data sharing. Adaptive tests have been developed to maintain power against multiple alternative hypotheses because the most powerful single-alternative test depends on the underlying structure of the associations between the multiple phenotypes and a single nucleotide polymorphism (SNP). Here we compare the performance of six such adaptive tests: two adaptive sum of powered scores (aSPU) tests, the unified score association test (metaUSAT), the adaptive test in a mixed-models framework (mixAda) and two principal-component-based adaptive tests (PCAQ and PCO). Our simulations highlight practical challenges that arise when multivariate distributions of phenotypes do not satisfy assumptions of multivariate normality. Previous reports in this context focus on low minor allele count (MAC) and omit the aSPU test, which relies less than other methods on asymptotic and distributional assumptions. When these assumptions are not satisfied, particularly when MAC is low and/or phenotype covariance matrices are singular or nearly singular, aSPU better preserves type I error, sometimes at the cost of decreased power. We illustrate this trade-off with multiple phenotype analyses of six quantitative electrocardiogram traits in the Population Architecture using Genomics and Epidemiology (PAGE) study.


Calcification of the vertebral artery.
A series of 3,648 computed tomographic (CT) scans was reviewed to determine the incidence of intracranial vertebral artery calcification. Calcification was identified in one or both vertebral arteries in 3.4% and was more frequent in the higher age groups. Skull radiographs demonstrated vertebral artery calcification in only one of 48 patients in whom CT studies showed it. A high correlation was observed between vertebral artery calcification on CT and vertebral artery stenosis on cerebral angiography.


Nasal Extranodal Natural Killer/T-cell Lymphoma Imitating Squamous Cell Carcinoma: A Case Report.
Nasal extranodal NK/T-cell lymphoma (NNKTL) is a lethal disease due to poor prognosis with rapid progress. A 56-year-old man complained of left nasal obstruction and blood-stained nasal drip for two months. Incisional biopsies were performed at the outpatient department three times, and the diagnosis of SCC was made. The patient underwent wide excision of the entire lesion via endoscopic sinus surgery with navigation. Final pathologic report revealed NNKTL. Pathological examination of the tumor revealed overlying epithelium presenting as pseudoepitheliomatous hyperplasia (PEH), which mimicked SCC invasion, with infiltration of atypical lymphocytes in the deeper sections. Immunohistochemistry supported the diagnosis of NNKTL. Chemoradiotherapy was administered, and a complete response was achieved at the two-year follow-up. The correct diagnosis of NNKTL is essential for prompt treatment and prevention of superfluous surgery. Although the link between PEH and NNKTL may lead to a misdiagnosis of SCC, multiple large and deep biopsies can prevent this dilemma. A biopsy showing ulceration or necrosis can indicate PEH and imply potential malignancy. Repeated biopsies and complete immunohistochemical studies are important for diagnosing NNKTL.


Linking Entropy at Rest with the Underlying Structural Connectivity in the Healthy and Lesioned Brain.
The brain is a network that mediates information processing through a wide range of states. The extent of state diversity is a reflection of the entropy of the network. Here we measured the entropy of brain regions (nodes) in empirical and modeled functional networks reconstructed from resting state fMRI to address the connection of entropy at rest with the underlying structure measured through diffusion spectrum imaging. Using 18 empirical and 18 modeled stroke networks, we also investigated the effect that focal lesions have on node entropy and information diffusion. Overall, positive correlations between node entropy and structure were observed, especially between node entropy and node strength in both empirical and modeled data. Although lesions were restricted to one hemisphere in all stroke patients, entropy reduction was not only present in nodes from the damaged hemisphere, but also in nodes from the contralesioned hemisphere, an effect replicated in modeled stroke networks. Globally, information diffusion was also affected in empirical and modeled strokes compared with healthy controls. This is the first study showing that artificial lesions affect local and global network aspects in very similar ways compared with empirical strokes, shedding new light into the functional nature of stroke.


Promiscuity in alkaline phosphatase superfamily. Unraveling evolution through molecular simulations.
We here present a theoretical study of the alkaline hydrolysis of a phosphodiester (methyl p-nitrophenyl phosphate or MpNPP) in the active site of Escherichia coli alkaline phosphatase (AP), a monoesterase that also presents promiscuous activity as a diesterase. The analysis of our simulations, carried out by means of molecular dynamics (MD) simulations with hybrid quantum mechanics/molecular mechanics (QM/MM) potentials, shows that the reaction takes place through a D(N)A(N) or dissociative mechanism, the same mechanism employed by AP in the hydrolysis of monoesters. The promiscuous activity observed in this superfamily can be then explained on the basis of a conserved reaction mechanism. According to our simulations the specialization in the hydrolysis of phosphomonoesters or phosphodiesters, developed in different members of the superfamily, is a consequence of the interactions established between the protein and the oxygen atoms of the phosphate group and, in particular, with the oxygen atom that bears the additional alkyl group when the substrate is a diester. A water molecule, belonging to the coordination shell of the Mg(2+) ion, and residue Lys328 seem to play decisive roles stabilizing a phosphomonoester substrate, but the latter contributes to increase the energy barrier for the hydrolysis of phosphodiesters. Then, mutations affecting the nature or positioning of Lys328 lead to an increased diesterase activity in AP. Finally, the capacity of this enzymatic family to catalyze the reaction of phosphoesters having different leaving groups, or substrate promiscuity, is explained by the ability of the enzyme to stabilize different charge distributions in the leaving group using different interactions involving either one of the zinc centers or residues placed on the outer side of the catalytic site.


Evaluation of standard versus nonstandard vital signs monitors in the prehospital and emergency departments: results and lessons learned from a trauma patient care protocol.
This study aimed to determine the effectiveness of using a wireless, portable vital signs monitor (WVSM) for predicting the need for lifesaving interventions (LSIs) in the emergency department (ED) and use a multivariate logistic regression model to determine whether the WVSM was an improved predictor of LSIs in the ED over the standard of care monitor currently being used. This study analyzed 305 consecutive patients transported from the scene via helicopter to a Level I trauma center. For 104 patients in the study, a WVSM was also attached to the patient's arm and used to record and display prehospital and hospital physiologic data in real time on a handheld computer and in the trauma bay. Multivariate logistic regression analyses were performed for accuracy in predicting needs for LSIs in control and WVSM subjects. In addition, receiver operating characteristic curves were obtained to examine the discriminating power of the models for the outcome of one or more LSIs in the ED. Of the 305 patients, 73 underwent 109 LSIs in the ED. Of these, 21 patients wore the WVSM during transport in addition to the standard monitor. Logistic regression analysis revealed that heart rate, respiratory rate, and systolic blood pressure were significantly associated with an increased risk for LSIs in the ED (p < 0.05). Receiver operating characteristic curve analysis also demonstrated better prediction for LSIs performed in the ED in WVSM subjects than in control subjects (area under the curve, 0.86 vs. 0.81, respectively). The WVSM system leads to improved LSI accuracy in the ED. In addition, many important lessons have been learned in preparation for this study. Adoption of nonstandard vital signs monitors into critical care/trauma medicine may require a new paradigm of personnel education, training, and practice. Therapeutic/care management, level IV.


A comparison of the cardioselectivity of five beta-adrenoceptor blocking drugs.
The cardioselectivities of five beta-adrenoceptor antagonists were compared. Six normal subjects received, in a double-blind random order, 200 mg acebutolol, 50 mg atenolol, 10 mg betaxolol, 100 mg metoprolol, 80 mg propranolol, and placebo. All beta-adrenoceptor antagonists produced a similar reduction in exercise tachycardia. Isoprenaline infusions in incremental doses were given. Dose-response curves were constructed and the doses of isoprenaline required to increase heart rate by 25 beats/min (I25), forearm blood flow by 3 ml/100 ml/min (IF3), and finger tremor by 200% (IT200), and decrease diastolic blood pressure by 25 mm Hg (ID25), after each treatment were compared. After propranolol, I25, ID25, IF3, and IT200 were greater (p less than 0.02) than after atenolol, betaxolol, and metoprolol; I25, ID25, and IT200 were greater than after acebutolol. After acebutolol I25, ID25, and IF3 were greater than after atenolol and betaxolol; IT200 was greater than after betaxolol. Atenolol and betaxolol caused less reduction in the isoprenaline-induced changes in blood glucose, plasma potassium, lactate, renin activity, and serum insulin than propranolol. Acebutolol caused less attenuation of blood glucose and plasma lactate, and metoprolol less attenuation of plasma renin activity, than propranolol. It is concluded that acebutolol, atenolol, betaxolol, and metoprolol cause less blockade of beta 2-adrenoceptors than propranolol, and atenolol and betaxolol are more cardioselective than acebutolol.


[Effects of ischemic preconditioning on the serum testosterone level and spermatogenic cell apoptosis in rabbits with testicular ischemia-reperfusion].
To explore the effects of ischemic preconditioning on the level of serum testosterone (T) and apoptosis of spermatogenic cells in rabbits with testicular ischemia-reperfusion injury induced by testicular torsion. A total of 15 New Zealand male rabbits were randomly divided into groups A (control), B (ischemia-reperfusion), and C (ischemic preconditioning). The animals of group A were subjected to exposure of the right spermatic cord without ischemia, those of group B received 60-minute non-invasive occlusion of the right spermatic cord followed by 3 days of reperfusion, and those of group C underwent 5-minute occlusion plus 5-minute reperfusion of the right spermatic cord followed by the same procedure as that for group B. Then the rabbits were narcotized with 3% barbital sodium, the whole blood collected for examination of the serum T content and the testis tissues obtained from both the ischemic and healthy sides for HE and TUNEL staining. After operation, the body weight was significantly increased as compared with the baseline in groups A ([2.65±0.07] vs [2.45±0.07] kg, P<0.05) and C ([3.03±0.11] vs [2.92±0.07] kg, P<0.05), but not in group B ([3.05±0.07] vs [3.05±0.07] kg, P>0.05). The serum T level showed no statistically significant difference in group A before and after operation ([139.59±9.39] vs [140.19±9.47] ng/L, P>0.05), but was remarkably lower after operation than the baseline in groups B [148.06±3.31] vs [74.12±4.00] ng/L, P<0.01) and C ([133.75±6.48] vs[94.76±3.13] ng/L, P<0.01) as well as than the postoperative index in group A (P<0.01). In comparison with group A and the healthy side of group B, the testis tissue of the ischemic side in group B exhibited structural damage of most of the seminiferous tubules with disappearance of spermatogenic cell structures, apoptosis of spermatogenic cells, and exudation of light-eosin edema fluid in the mesenchyme and lumen, with a markedly increased apoptosis index (P<0.01) and a significantly decreased Johsen's score (P<0.01). Compared with ischemic side of group B, The testis tissue of the ischemic side in group C was restored to normal as compared with that in group B, with a dramatically decreased apoptosis index (P<0.01) and a remarkably increased Johnsen's score (P<0.01). Ischemic preconditioning can raise the decreased serum T level and reduce the apoptosis of spermatogenic cells in rabbits with testicular ischemia-reperfusion injury, which could be applied as a potential option for the clinical treatment of testicular ischemia-reperfusion injury.


Role of right gastroepiploic artery in myocardial revascularization with arterial grafts.
Between July 1990 and December 1992. 112 patients underwent myocardial revascularization with arterial grafts in the Department of Cardiac Surgery, University of Milan. Monovascular patients were excluded from the study. The right gastroepiploic artery was used in 44 patients (39.3%); mean age was 54.3 years and reoperation rate 18.2%. Of the 44 patients, previous myocardial infarction had occurred in 25 (57%). Emergency operation was performed in one case (2%). Mean left ventricular shortening fraction was 36% and mean ejection fraction 58.6%. Coronary artery disease was bivascular in 10 patients (23%) and trivascular in 34 (77%). The arterial revascularization in patients with gastroepiploic artery was performed using a left internal thoracic artery graft in all 44 patients; the right internal thoracic artery was used in 18 (41%) and the inferior epigastric artery in two (4%). The sites of gastroepiploic artery grafting were 55% posterior descending, 16% right coronary artery, 11% posterolateral branch, 14% circumflex and in 4% posterior descending and posterolateral as sequential graft. No patient died; postoperative myocardial infarction rate was 4%. No complications related to gastroepiploic artery utilization were noted. Forty-three (98%) of the gastroepiploic artery group underwent graft reinvestigation: the arteries were correctly visualized in 41 patients (95%) and were patent in 39 cases and stenotic in two. A mid-term postoperative stress test (mean 17.4 months) was performed in 91% of patients. Normal limits were found in 37 patients (92.5%) and an abnormal stress test result in three (7.5%). The contemporary follow-up showed no deaths or myocardial infarctions. Three patients (7%) had recurrent angina. The role of gastroepiploic artery in arterial revascularization has become fundamental, especially, it is believed, for the posterior or posterolateral left ventricular wall. The present data show the patients to be clinically and functionally well 1 year after operation.


Peroxisome proliferator-activated receptor gamma is induced during differentiation of colon epithelium cells.
Peroxisome proliferator-activated receptor gamma (PPARgamma), a fatty acid-activated nuclear receptor, is implicated in adipocyte differentiation and insulin sensitisation. In view of the association of dietary fat intake and bowel disease, the expression of PPARgamma in rodent and human intestine was studied. Expression of PPARgamma mRNA was examined by Northern blot hybridisation, RNase protection, and/or competitive RT-PCR assays, whereas PPARgamma protein levels were evaluated by immunoblotting and immunohistochemistry. PPARgamma mRNA and protein were abundantly expressed in colon relative to the small intestine both in rodents and in man. Interestingly, expression of PPARgamma was primarily localised in the more differentiated epithelial cells in the colon. The level of expression of PPARgamma in colon was similar to the levels seen in adipose tissue. Expression of PPARgamma increased from proximal to distal segments of the colon in man. In Caco-2 and HT-29 human adenocarcinoma cells, PPARgamma expression increased upon differentiation, consistent with PPARgamma being associated with a differentiated epithelial phenotype. High-level expression of PPARgamma was observed in the colon, but not in the small intestine, suggesting a potential role of this nuclear receptor in the colon.


Thymineless death in Bacillus subtilis.
A study has been made of the intracellular changes occurring during thymineless death in Bacillus subtilis 2337. The kinetics of death were paralleled by the rate of breakdown of DNA. During thymineless death single-strand breaks accumulated within DNA, breakdown of approximately 13% of the DNA to acid-soluble material occurred, deoxyribonuclease levels rose sharply, and yet double-strand breaks did not occur in the DNA. On restoration of thymine, however, double-strand breaks accumulated, though this could be prevented by the specific inhibition of DNA preplication on restoration of thymine. The results probably indicate that during thymineless death, single-strand gaps accumulate within the DNA of cells. On restoration of thymine both DNA replicaion and repair of gaps are simultaneously initiated, and when a replication fork reaches a gap before it is repaired, double-strand breakage of the DNA occurs. The possible relevance of these events to the lethality of the cells is discussed.


Long-term effects of cannabis on oculomotor function in humans.
Cannabis is known to affect human cognitive and visuomotor skills directly after consumption. Some studies even point to rather long-lasting effects, especially after chronic tetrahydrocannabinol (THC) abuse. However, it is still unknown whether long-term effects on basic visual and oculomotor processing may exist. In the present study, the performance of 20 healthy long-term cannabis users without acute THC intoxication and 20 control subjects were examined in four basic visuomotor paradigms to search for specific long-term impairments. Subjects were asked to perform: 1) reflexive saccades to visual targets (prosaccades), including gap and overlap conditions, 2) voluntary antisaccades, 3) memory-guided saccades and 4) double-step saccades. Spatial and temporal parameters of the saccades were subsequently analysed. THC subjects exhibited a significant increase of latency in the prosaccade and antisaccade tasks, as well as prolonged saccade amplitudes in the antisaccade and memory-guided task, compared with the control subjects. The results point to substantial and specific long-term deficits in basic temporal processing of saccades and impaired visuo-spatial working memory. We suggest that these impairments are a major contributor to degraded performance of chronic users in a vital everyday task like visual search, and they might potentially also affect spatial navigation and reading.


Immune-enhancing effects of β-lactoglobulin glycated with lactose following in vitro digestion on cyclophosphamide-induced immunosuppressed mice.
β-Lactoglobulin (β-LG) is a major milk protein, making up more than 53% of the total whey proteins, and is seen as a valuable ingredient in food processing because of its high essential amino acid content and diverse functional applications. The Maillard reaction can occur during the storage and processing of food and generate various beneficial effects, including anti-allergenicity, antioxidant, and immunomodulatory effects. The addition of an β-LG-lactose conjugate (LGL) produced by the Maillard reaction was shown to have a strong immune-enhancing effect, increasing both nitric oxide generation and cytokine expression through activation of RAW 264.7 cells, even after in vitro digestion. Furthermore, daily LGL administration resulted in the upregulation of several immune markers in a cyclophosphamide-induced immunosuppressive mouse model, indicating that this treatment stimulates multiple immune cells, including macrophages, natural killer cells, and lymphocytes, enhancing the proliferation and activation of both the innate and adaptive immune responses. Taken together, these findings indicate that consuming LGL on a regular basis can improve immunity by increasing the natural production of various immune cells.


Transglutaminase cross-linking properties of the small proline-rich 1 family of cornified cell envelope proteins. Integration with loricrin.
Small proline-rich 1 (SPR1) proteins are important for barrier function in stratified squamous epithelia. To explore their properties, we expressed in bacteria a recombinant human SPR1 protein and isolated native SPR1 proteins from cultured mouse keratinocytes. By circular dichroism, they possess no alpha or beta structure but have some organized structure associated with their central peptide repeat domain. The transglutaminase (TGase) 1 and 3 enzymes use the SPR1 proteins as complete substrates in vitro but in different ways: head domain A sequences at the amino terminus were used preferentially for cross-linking by TGase 3, whereas those in head domain B sequences were used for cross-linking by TGase 1. The TGase 2 enzyme cross-linked SPR1 proteins poorly. Together with our data base of 141 examples of in vivo cross-links between SPRs and loricrin, this means that both TGase 1 and 3 are required for cross-linking SPR1 proteins in epithelia in vivo. Double in vitro cross-linking experiments suggest that oligomerization of SPR1 into large polymers can occur only by further TGase 1 cross-linking of an initial TGase 3 reaction. Accordingly, we propose that TGase 3 first cross-links loricrin and SPRs together to form small interchain oligomers, which are then permanently affixed to the developing CE by further cross-linking by the TGase 1 enzyme. This is consistent with the known consequences of diminished barrier function in TGase 1 deficiency models.


Gi-mediated tyrosine phosphorylation of Grb2 (growth-factor-receptor-bound protein 2)-bound dynamin-II by lysophosphatidic acid.
Lysophosphatidic acid (LPA) is the prototypic G-protein-coupled receptor agonist that activates the Ras-mitogen-activated protein (MAP) kinase cascade through pertussis toxin (PTX)-sensitive Gi and enhanced tyrosine kinase activity. We recently detected a 100 kDa protein (p100) that binds to the C-terminal SH3 domain of growth-factor-receptor-bound protein 2 (Grb2) and becomes tyrosine phosphorylated in a PTX-sensitive manner in LPA-treated Rat-1 cells [Kranenburg, Verlaan, Hordijk and Moolenaar (1997) EMBO J. 16, 3097-3105]. Through glutathione S-transferase-Grb2 affinity purification and microsequencing, we have now identified p100 as dynamin-II, a GTPase that regulates clathrin-mediated endocytosis. We show that in Rat-1 cells, Grb2-bound dynamin-II is rapidly tyrosine phosphorylated in response to LPA in a PTX-sensitive manner. Thus, tyrosine phosphorylation of Grb2-bound dynamin-II may be a critical event in Gi-mediated activation of the Ras-MAP kinase cascade in fibroblasts.


Effect of a low-resource-intensive lifestyle modification program incorporating gymnasium-based and home-based resistance training on type 2 diabetes risk in Australian adults.
The purpose of this study was to assess the effectiveness of a low-resource-intensive lifestyle modification program incorporating resistance training and to compare a gymnasium-based with a home-based resistance training program on diabetes diagnosis status and risk. A quasi-experimental two-group study was undertaken with 122 participants with diabetes risk factors; 36.9% had impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) at baseline. The intervention included a 6-week group self-management education program, a gymnasium-based or home-based 12-week resistance training program, and a 34-week maintenance program. Fasting plasma glucose (FPG) and 2-h plasma glucose, blood lipids, blood pressure, body composition, physical activity, and diet were assessed at baseline and week 52. Mean 2-h plasma glucose and FPG fell by 0.34 mmol/l (95% CI -0.60 to -0.08) and 0.15 mmol/l (-0.23 to -0.07), respectively. The proportion of participants with IFG or IGT decreased from 36.9 to 23.0% (P = 0.006). Mean weight loss was 4.07 kg (-4.99 to -3.15). The only significant difference between resistance training groups was a greater reduction in systolic blood pressure for the gymnasium-based group (P = 0.008). This intervention significantly improved diabetes diagnostic status and reduced diabetes risk to a degree comparable to that of other low-resource-intensive lifestyle modification programs and more intensive interventions applied to individuals with IGT. The effects of home-based and gymnasium-based resistance training did not differ significantly.


Advanced in vitro models of vascular biology: Human induced pluripotent stem cells and organ-on-chip technology.
The vascular system is one of the first to develop during embryogenesis and is essential for all organs and tissues in our body to develop and function. It has many essential roles including controlling the absorption, distribution and excretion of compounds and therefore determines the pharmacokinetics of drugs and therapeutics. Vascular homeostasis is under tight physiological control which is essential for maintaining tissues in a healthy state. Consequently, disruption of vascular homeostasis plays an integral role in many disease processes, making cells of the vessel wall attractive targets for therapeutic intervention. Experimental models of blood vessels can therefore contribute significantly to drug development and aid in predicting the biological effects of new drug entities. The increasing availability of human induced pluripotent stem cells (hiPSC) derived from healthy individuals and patients have accelerated advances in developing experimental in vitro models of the vasculature: human endothelial cells (ECs), pericytes and vascular smooth muscle cells (VSMCs), can now be generated with high efficiency from hiPSC and used in 'microfluidic chips' (also known as 'organ-on-chip' technology) as a basis for in vitro models of blood vessels. These near physiological scaffolds allow the controlled integration of fluid flow and three-dimensional (3D) co-cultures with perivascular cells to mimic tissue- or organ-level physiology and dysfunction in vitro. Here, we review recent multidisciplinary developments in these advanced experimental models of blood vessels that combine hiPSC with microfluidic organ-on-chip technology. We provide examples of their utility in various research areas and discuss steps necessary for further integration in biomedical applications so that they can be contribute effectively to the evaluation and development of new drugs and other therapeutics as well as personalized (patient-specific) treatments.


Lipids and Alzheimer's Disease.
Lipids, as the basic component of cell membranes, play an important role in human health as well as brain function. The brain is highly enriched in lipids, and disruption of lipid homeostasis is related to neurologic disorders as well as neurodegenerative diseases such as Alzheimer's disease (AD). Aging is associated with changes in lipid composition. Alterations of fatty acids at the level of lipid rafts and cerebral lipid peroxidation were found in the early stage of AD. Genetic and environmental factors such as apolipoprotein and lipid transporter carrying status and dietary lipid content are associated with AD. Insight into the connection between lipids and AD is crucial to unraveling the metabolic aspects of this puzzling disease. Recent advances in lipid analytical methodology have led us to gain an in-depth understanding on lipids. As a result, lipidomics have becoming a hot topic of investigation in AD, in order to find biomarkers for disease prediction, diagnosis, and prevention, with the ultimate goal of discovering novel therapeutics.


ZJM-289, a novel nitric oxide donor, alleviates the cerebral ischaemic-reperfusion injury in rats.
1. Current studies indicate that nitric oxide (NO) plays a dual role as both a protective and pathogenic factor in focal cerebral ischaemia depending on the level, location, source and environment. The present study hypothesized that the NO donor ZJM-289 could inhibit cerebral ischaemia-reperfusion (I/R) injury and investigated the mechanism of the beneficial events. 2. Adult male rats were randomly divided into four groups: (i) sham operated; (ii) I/R (ischaemia for 90 min and reperfusion for 24 h) treated with vehicle; (iii) I/R treated with 0.1 mmol/kg body weight ZJM-289; and (iv) I/R treated with 0.2 mmol/kg body weight ZJM-289. We evaluated the changes in brain infarction, brain-water content, neurological deficits and histopathology. Western blot analysis was used to study the expression of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) in the brain after I/R. The levels of NO and cyclic guanosine monophosphate (cGMP) were also determined. 3. ZJM-289 reduced infarct volume and brain-water content in ischemic brains and promoted functional recovery. Western blotting showed significant inhibition of nNOS in ZJM-289 treated rats compared with untreated rats. However, eNOS expression in the ischemic brain was enhanced in the ZJM-289 groups. The cGMP and NO levels increased in the ZJM-289 groups after I/R. The study showed that ZJM-289 could alleviate cerebral injury after I/R through inhibition of nNOS and stimulation of the NO/soluble guanylate cyclase/cGMP pathway. Therefore, a suitable NO donor might be an effective candidate for the treatment of acute stroke by neuroprotection.


Hyperstable Synthetic Mini-Proteins as Effective Ligand Scaffolds.
Small, single-domain protein scaffolds are compelling sources of molecular binding ligands with the potential for efficient physiological transport, modularity, and manufacturing. Yet, mini-proteins require a balance between biophysical robustness and diversity to enable new functions. We tested the developability and evolvability of millions of variants of 43 designed libraries of synthetic 40-amino acid βαββ proteins with diversified sheet, loop, or helix paratopes. We discovered a scaffold library that yielded hundreds of binders to seven targets while exhibiting high stability and soluble expression. Binder discovery yielded 6-122 nM affinities without affinity maturation and Tms averaging ≥78 °C. Broader βαββ libraries exhibited varied developability and evolvability. Sheet paratopes were the most consistently developable, and framework 1 was the most evolvable. Paratope evolvability was dependent on target, though several libraries were evolvable across many targets while exhibiting high stability and soluble expression. Select βαββ proteins are strong starting points for engineering performant binders.


AKT1 E17K in Colorectal Carcinoma Is Associated with BRAF V600E but Not MSI-H Status: A Clinicopathologic Comparison to PIK3CA Helical and Kinase Domain Mutants.
The PI3K/AKT/mTOR pathway is activated through multiple mechanisms in colorectal carcinoma. Here, the clinicopathologic and molecular features of AKT1 E17K-mutated colorectal carcinoma in comparison with PIK3CA-mutated colorectal carcinoma are described in detail. Interestingly, in comparison with PIK3CA mutants, AKT1 E17K was significantly associated with mucinous morphology and concurrent BRAF V600E mutation. Among PIK3CA mutants, exon 21 mutations were significantly associated with BRAF V600E mutation, MSI-H status, and poor differentiation, while exon 10 mutations were associated with KRAS/NRAS mutations. Three of four AKT1 mutants with data from both primary and metastatic lesions had concordant AKT1 mutation status in both. Both AKT1- and PIK3CA-mutant colorectal carcinoma demonstrated frequent loss of PTEN expression (38% and 34%, respectively) and similar rates of p-PRAS 40 expression (63% and 50%, respectively). Both patients with AKT1 E17K alone had primary resistance to cetuximab, whereas 7 of 8 patients with PIK3CA mutation alone experienced tumor shrinkage or stability with anti-EGFR therapy. These results demonstrate that AKT1 E17K mutation in advanced colorectal carcinoma is associated with mucinous morphology, PIK3CA wild-type status, and concurrent RAS/RAF mutations with similar pattern to PIK3CA exon 21 mutants. Thus, AKT1 E17K mutations contribute to primary resistance to cetuximab and serve as an actionable alteration. This first systematic study of AKT1 and PIK3CA hotspot mutations and their association with cetuximab resistance and BRAF V600E mutation has important ramifications for the development of personalized medicine, particularly in identifying patient candidates for PI3K or AKT inhibitors.


Phenoxyaluminum(salophen) Scaffolds: Synthesis, Electrochemical Properties, and Self-Assembly at Surfaces of Multifunctional Systems.
Salophens and Salens are Schiff bases generated through the condensation of two equivalents of salicylaldehyde with either 1,2-phenylenediamines or aliphatic diamines, respectively. Both ligands have been extensively exploited as key building blocks in coordination chemistry and catalysis. In particular, their metal complexes have been widely used for various catalytical transformations with high yield and selectivity. Through the modification of the phenol unit it is possible to tune the steric hindrance and electronic properties of Salophen and Salen. The introduction of long aliphatic chains in salicylaldehydes can be used to promote their self-assembly into ordered supramolecular structures on solid surfaces. Herein, we report a novel method towards the facile synthesis of robust and air-stable [Al(Salophen)] derivatives capable of undergoing spontaneous self-assembly at the graphite/solution interface forming highly-ordered nanopatterns. The new synthetic approach relies on the use of [MeAlIII (Salophen)] as a building unit to introduce, via a simple acid/base reaction with functionalized acidic phenol derivatives, selected frameworks integrating multiple functions for efficient surface decoration. STM imaging at the solid/liquid interface made it possible to monitor the formation of ordered supramolecular structures. In addition, the redox properties of the Salophen derivatives functionalized with ferrocene units in solution and on surface were unraveled by cyclic voltammetry. The use of a five-coordinate aluminum alkyl Salophen precursor enables the tailoring of new Salophen molecules capable of undergoing controlled self-assembly on HOPG, and thereby it can be exploited to introduce multiple functionalities with subnanometer precision at surfaces, ultimately forming ordered functional patterns.


The Self-Assembled Skin Substitute History: Successes, Challenges, and Current Treatment Indications.
The self-assembled skin substitute (SASS) is an autologous bilayered skin substitute designed by our academic laboratory, the Laboratoire d'Organogenèse Expérimentale (LOEX) to offer definitive treatment for patients lacking donor sites (unwounded skin) to cover their burn wounds. This product shows skin-like attributes, such as an autologous dermal and epidermal layer, and is easily manipulable by the surgeon. Its development stems from the need for skin replacement in high total body surface area burned survivors presenting few donor sites for standard split-thickness skin grafting. This review aims to present the history, successes, challenges, and current therapeutic indications of this skin substitute. We review the product's development history, before discussing current production techniques, as well as clinical use. The progression observed since the initial SASS production technique described in 1999, up to the most recent technique expresses significant advances made in the technical aspect of our product, such as the reduction of the production time. We then explore the efficacy and benefits of SASS over existing skin substitutes and discuss the outcomes of a recent study focusing on the successful treatment of 14 patients. Moreover, an ongoing cross-Canada study is further assessing the product's safety and efficacy. The limitations and technical challenges of SASS are also discussed.


Factors Associated with Loss to Follow-up among Cervical Cancer Patients in Rwanda.
Cervical cancer is among the most common cancers affecting women globally. Where treatment is available in low- and middle-income countries, many women become lost to follow-up (LTFU) at various points of care. This study assessed predictors of LTFU among cervical cancer patients in rural Rwanda. We conducted a retrospective study of cervical cancer patients enrolled at Butaro Cancer Center of Excellence (BCCOE) between 2012 and 2017 who were either alive and in care or LTFU at 12 months after enrollment. Patients are considered early LTFU if they did not return to clinic after the first visit and late LTFU if they did not return to clinic after the second visit. We conducted two multivariable logistic regressions to determine predictors of early and late LTFU. Of 652 patients in the program, 312 women met inclusion criteria, of whom 47 (15.1%) were early LTFU, 78 (25.0%) were late LTFU and 187 (59.9%) were alive and in care. In adjusted analyses, patients with no documented disease stage at presentation were more likely to be early LTFU vs. patients with stage 1 and 2 when controlling for other factors (aOR: 14.93, 95% CI 6.12-36.43). Patients who travel long distances (aOR: 2.25, 95% CI 1.11, 4.53), with palliative care as type of treatment received (aOR: 6.65, CI 2.28, 19.40) and patients with missing treatment (aOR: 7.99, CI 3.56, 17.97) were more likely to be late LTFU when controlling for other factors. Patients with ECOG status of 2 and higher were less likely to be late LTFU (aOR: 0.26, 95% CI 0.08, 0.85). Different factors were associated with early and later LTFU. Enhanced patient education, mechanisms to facilitate diagnosis at early stages of disease, and strategies that improve patient tracking and follow-up may reduce LTFU and improve patient retention.


Copy Number Alterations with Prognostic Potential in Clear Cell Renal Cell Carcinoma.
To detect chromosomal aberrations in a genome-wide manner with potential value for prognosis in groups of patients with different histopathological grading in clear cell renal carcinoma (ccRCC). We performed a copy number alteration analysis using the Affymetrix platform and SNP 6.0 mapping arrays with samples from 48 ccRCC-patients. The data analysis was done using 3 different Software Platforms: Affymetrix Genotyping Console (version 126.96.36.1990) and 2 open-source packages for validation: PennCNV and PICNIC. Consistent changes were found to divide the tumors into 4 groups: first group showed typical losses on 3p, second group losses on 3p plus gains on 5q, third group gains on chromosome 7 plus losses on chromosome 8; fourth group did not show any major changes. We selected the affected genes with the highest consistency and identified 13 different genes mapping in the SNP 6.0 results and Kyoto Encyclopedia of Genes and Genomes. Remarkable for further consideration were the phosphatidylinositol 3-kinase pathway, BRAF, MET, EGLN1; growth factors, for example, HGF, PGF and TGFB2. A multimodal approach with a well-defined workflow for detecting genomic aberrations by using array technologies and comparing the findings with different comprehensive databases may provide insights into functional tumor processes and help to identify potential new targets for more individualized future treatment.


Culicoides-borne Orbivirus epidemiology in a changing climate.
Orbiviruses are of significant importance to the health of wildlife and domestic animals worldwide; the major orbiviruses transmitted by multiple biting midge (Culicoides) species include bluetongue virus, epizootic hemorrhagic disease virus, and African horse sickness virus. The viruses, insect vectors, and hosts are anticipated to be impacted by global climate change, altering established Orbivirus epidemiology. Changes in global climate have the potential to alter the vector competence and extrinsic incubation period of certain biting midge species, affect local and long-distance dispersal dynamics, lead to range expansion in the geographic distribution of vector species, and increase transmission period duration (earlier spring onset and later fall transmission). If transmission intensity is associated with weather anomalies such as droughts and wind speeds, there may be changes in the number of outbreaks and periods between outbreaks for some regions. Warmer temperatures and changing climates may impact the viral genome by facilitating reassortment and through the emergence of novel viral mutations. As the climate changes, Orbivirus epidemiology will be inextricably altered as has been seen with recent outbreaks of bluetongue, epizootic hemorrhagic disease, and African horse sickness outside of endemic areas, and requires interdisciplinary teams and approaches to assess and mitigate future outbreak threats.


Automated Grading of Age-Related Macular Degeneration From Color Fundus Images Using Deep Convolutional Neural Networks.
Age-related macular degeneration (AMD) affects millions of people throughout the world. The intermediate stage may go undetected, as it typically is asymptomatic. However, the preferred practice patterns for AMD recommend identifying individuals with this stage of the disease to educate how to monitor for the early detection of the choroidal neovascular stage before substantial vision loss has occurred and to consider dietary supplements that might reduce the risk of the disease progressing from the intermediate to the advanced stage. Identification, though, can be time-intensive and requires expertly trained individuals. To develop methods for automatically detecting AMD from fundus images using a novel application of deep learning methods to the automated assessment of these images and to leverage artificial intelligence advances. Deep convolutional neural networks that are explicitly trained for performing automated AMD grading were compared with an alternate deep learning method that used transfer learning and universal features and with a trained clinical grader. Age-related macular degeneration automated detection was applied to a 2-class classification problem in which the task was to distinguish the disease-free/early stages from the referable intermediate/advanced stages. Using several experiments that entailed different data partitioning, the performance of the machine algorithms and human graders in evaluating over 130 000 images that were deidentified with respect to age, sex, and race/ethnicity from 4613 patients against a gold standard included in the National Institutes of Health Age-related Eye Disease Study data set was evaluated. Accuracy, receiver operating characteristics and area under the curve, and kappa score. The deep convolutional neural network method yielded accuracy (SD) that ranged between 88.4% (0.5%) and 91.6% (0.1%), the area under the receiver operating characteristic curve was between 0.94 and 0.96, and kappa coefficient (SD) between 0.764 (0.010) and 0.829 (0.003), which indicated a substantial agreement with the gold standard Age-related Eye Disease Study data set. Applying a deep learning-based automated assessment of AMD from fundus images can produce results that are similar to human performance levels. This study demonstrates that automated algorithms could play a role that is independent of expert human graders in the current management of AMD and could address the costs of screening or monitoring, access to health care, and the assessment of novel treatments that address the development or progression of AMD.


Dentinal bonding agents versus glass-ionomer cements.
The long-term bonding of dental material to dentin remains an area of great controversy and the results of in vitro testing do not always reflect those found in vivo. The clinician is faced with a large number of dentinal bonding agents that have had limited testing in vivo and are frequently replaced before any long-term clinical testing has been completed. Glass-ionomer cements, although having a longer history of good adhesion to dentin, are not suitable for use in high-stress-bearing areas. The selection of materials for specific clinical situations has become more and more difficult. This paper gave a personal view of the history and evolution of both resin bonding agents and glass-ionomer cements and their potential in clinical use.


The Association of Thyrotropin and Autoimmune Thyroid Disease in Developing Papillary Thyroid Cancer.
Papillary thyroid carcinoma (PTC) is the most common type of malignant thyroid neoplasm. However, the incidence of PTC with autoimmune thyroid disease (AITD) varies between studies. This study aims to investigate whether patients with AITD have increased incidence of PTC. We also analyzed the relationship of serum thyroid-stimulating hormone (TSH) levels and PTC in relation to AITD based on histopathological data. A total of 533 participants who underwent thyroidectomy were enrolled in this retrospective study based on clinicohistopathological data and known thyroid autoantibodies. Patients were divided into PTC and benign groups according to histopathologic diagnosis. Age, gender, body mass index, and serum TSH level before thyroidectomy were recorded. Of the 533 enrolled patients, 159 (29.8%) were diagnosed with PTC, of which 38 (35.5%) had Hashimoto's thyroiditis (HT). More patients with HT were female, and patients with HT, Graves' disease, and thyroid nodules with higher TSH level had a higher incidence of PTC. A high proportion of the patients with PTC had HT. There was a trend that a higher serum TSH level was associated with a greater risk of thyroid cancer.


[Prognostic factors in stage Ia-IIb invasive cervix cancer after radical hysterectomy with special reference to stroma reaction].
158 cases of invasive carcinoma of the uterine cervix stages Ia to IIb were analysed with respect to the following prognostic criteria: histological stage, presence of nodal metastases, vascular space invasion and inflammatory stromal reaction at the periphery of the tumor. The assessment of these criteria was correlated to the prevalence of tumor recurrence. In cases with absent nodal metastases, a significant increase of tumor recurrence in stage IIb compared to other stages was noted. A constant increase of the recurrence rate was found, when nodal metastases were present, although the incidence of positive lymph nodes was approximately equal in stages Ic, IIa and IIb. The involvement of the parametrium therefore appears to be a significant parameter for the poor prognosis in stage IIb. Vascular space invasion proved to be a significant parameter with regard to lymph node involvement. When no vascular space invasion was obvious, 94% of the cases showed tumor-free lymph nodes. Overall, heavy inflammatory infiltration at the tumor periphery correlated with a good prognosis. In cases of heavy inflammatory stromal reaction, the risk of nodal metastases and tumor recurrence was significantly lower, independent of the histological stage. The incidence of heavy inflammatory infiltration was significantly higher in microinvasive carcinomas than in clinically invasive tumors. Therefore, the extent of inflammation appears to be an additional useful prognostic index to identify a group of patients at high risk for recurrence and reduced chance of survival.