Selective application of laparoscopy and fibrin glue in the failure of nonoperative management of blunt hepatic trauma.
Most blunt hepatic trauma patients can be managed nonoperatively. The current failure rate in adult blunt hepatic trauma is reportedly 0 to 19%. We wished to evaluate the applicability of laparoscopy and fibrin glue as a minimally invasive alternative to laparotomy in these unsuccessfully nonoperative cases. All adult patients with blunt hepatic trauma managed nonoperatively at Linkou, Chang Gung Memorial Hospital Medical Center, Taipei, Taiwan, over a 2-year period from July 1, 1994, to June 30, 1996, were eligible for the study. A laparoscopic examination was performed on those who failed conservative care before undertaking an exploratory laparotomy. Fibrin glue was sprayed over the wound surface if ongoing hemorrhage was evident from any liver laceration. The clinical data, operative and laparoscopic findings, operative methods, and outcomes of these patients were studied. Of the 61 patients, 55 patients were successfully treated without operation. Of the six failures (10%) all were liver related. After the introduction of laparoscopy, the nontherapeutic laparotomy rate would have decreased from 100% (6 of 6) to 50% (3 of 6), and with the adjunctive use of fibrin glue, the laparotomy rate went down to 0% (0 of 6). There were no deaths among the six patients receiving laparoscopy and fibrin glues; and only one developed a liver abscess, for a morbidity rate of 17% (1 of 6). The selective use of laparoscopy and fibrin glue can effectively reduce the nontherapeutic laparotomy rate among blunt hepatic trauma patients who fail nonoperative management.


Human type 2 angiotensin II receptor gene: cloned, mapped to the X chromosome, and its mRNA is expressed in the human lung.
The human type 2 angiotensin II receptor (AT2R) gene was isolated from a human genomic DNA library of adult female leukocytes. The putative coding region of the human AT2R gene is intronless. The primary structure of the human AT2R deduced from the nucleotide sequence of this putative coding region contains 363 amino acid residues and is highly homologous to the sequences of the rat and mouse AT2R. The human AT2R gene was mapped to the X chromosome using chromosomal assignment analysis with a human/rodent somatic cell hybrid panel. Northern blot analysis demonstrated a 3.0 kb mRNA in the human fetal lung and kidney and the human adult lung. These data and probes should enhance research in human AT2R biology.


A dual-magneto-optical-trap atom gravity gradiometer for determining the Newtonian gravitational constant.
As part of a program to determine the gravitational constant G using multiple independent methods in the same laboratory, an atom gravity gradiometer is being developed. The gradiometer is designed with two magneto-optical traps to ensure both the fast simultaneous launch of two atomic clouds and an optimized configuration of source masses. Here, the design of the G measurement by atom interferometry is detailed, and the experimental setup of the atom gravity gradiometer is reported. A preliminary sensitivity of 3 × 10-9 g/Hz to differential gravity acceleration is obtained, which corresponds to 99 E/Hz (1 E = 10-9 s-2) for the gradiometer with a baseline of 0.3 m. This provides access to measuring G at the level of less than 200 parts per million in the first experimental stage.


Atorvastatin protects against contrast-induced nephropathy via anti-apoptosis by the upregulation of Hsp27 in vivo and in vitro.
Contrast-induced nephropathy (CIN) is an iatrogenic acute renal failure occurring following the intravascular injection of iodinated radiographic contrast medium. However, the regulatory mechanisms for CIN remain to be fully elucidated. The present study aimed to investigate whether atorvastatin protects against CIN via anti‑apoptotic effects by the upregulation of Hsp27 in vivo and in vitro. To determine whether atorvastatin attenuated CIN, the inflammatory response and apoptosis in vivo and in vitro, a rat model of iopamidol‑induced CIN was used, and human embryonic proximal tubule (HK2) cell damage was assessed. The rats were assigned into four groups (n=10 per group), as follows: Control rats; rats+atorvastatin; rats + iopamidol; rats+iopamidol+atorvastatin. In vitro, the HK2 cells were treated with iopamidol in the presence or absence of atorvastatin, heat shock protein (Hsp)27 small interfering (si)RNA or pcDNA3.1‑Hsp27. The renal tissues were examined histopathologically and collected for western blot analysis. The results showed that atorvastatin ameliorated the apoptosis and deterioration of renal function (P<0.05). Furthermore, atorvastatin reduced the iopamidol‑induced activity of B cell lymphoma‑2 (Bcl‑2)‑associated X protein (Bax)/caspase‑3 and increased the expression of Bcl‑2 in vivo and in vitro. Notably, following treatment with Hsp27 siRNA or pcDNA3.1‑Hsp27, it was found that iopamidol enhanced or weakened the upregulation of Bax/caspase‑3 and downregulation of Bcl‑2 in the HK2 cells, respectively. The results of the present study suggested that atorvastatin protected against contrast‑induced renal tubular cell apoptosis through the upregulation of Hsp27 in vivo and in vitro.


Efficient access to alkynylated quinalizinones via the gold(i)-catalyzed aminoalkynylation of alkynes.
The gold-catalyzed aminoalkynylation of alkynes for the synthesis of quinalizinones is reported. For instance, the reaction of pyridinoalkynes with 1-[(triisopropylsilyl)-ethynyl]-1,2-benziodoxol-3(1H)-one (TIPS-EBX) in the presence of a catalytic amount of AuCl at 50 °C afforded alkynylated quinalizinones in 57-87% yields.


Shift work and inter-individual differences in sleep and sleepiness.
Inter-individual differences in tolerance for shift work have been studied primarily in terms of external factors affecting alertness on the job or the ability to rest and sleep while at home. However, there is increasing evidence that neurobiological factors play a role as well, particularly the major processes involved in the regulation of sleep and wakefulness. These include a sleep homeostatic process seeking to balance wakefulness and sleep and a circadian process seeking to promote wakefulness during the day and sleep during the night. Shift work is associated with a temporal misalignment of these two endogenous processes. During nightwork, this misalignment makes it difficult to stay awake during the nightshift and sleep during the day. However, inter-individual variability in the processes involved in sleep/wake regulation is substantial. Recent studies have demonstrated the existence of inter-individual differences in vulnerability to cognitive deficits from sleep loss. Moreover, these inter-individual differences were shown to constitute a trait. Interestingly, self-evaluations of sleepiness did not correspond well with the trait inter-individual variability in objective levels of performance impairment during sleep deprivation. Perhaps because of this discrepancy, in operational settings, the inter-individual differences in vulnerability to sleep loss do not appear to be limited due to self-selection mechanisms. Indeed, even among a highly select group of active-duty jet fighter pilots flying a series of simulated night missions, systematic inter-individual differences in performance impairment from sleep loss were still observed. There are significant personal and economic consequences to human error and accidents caused by performance deficits due to sleep loss. It is important, therefore, to study the inter-individual differences in the regulation of sleep and wakefulness in the work environment so that cognitive impairment during shift work may be better anticipated and prevented.


Quality of Pharmacist-Managed Anticoagulation Therapy in Long-Term Ambulatory Settings: A Systematic Review.
To perform a systematic review to evaluate the quality of warfarin anticoagulation control in outpatient pharmacist-managed anticoagulation services (PMAS) compared with routine medical care (RMC). MEDLINE, SCOPUS, EMBASE, IPA, CINAHL, and Cochrane CENTRAL, from inception to May 2017. Search terms employed: ("pharmacist-managed" OR "pharmacist-provided" OR "pharmacist-led" OR "pharmacist-directed") AND ("anticoagulation services" OR "anticoagulation clinic" OR "anticoagulation management" OR "anticoagulant care") AND ("quality of care" OR "outcomes" OR "bleeding" OR "thromboembolism" OR "mortality" OR "hospitalization" OR "length of stay" OR "emergency department visit" OR "cost" OR "patient satisfaction"). Criteria used to identify selected articles: English language; original studies (comments, letters, reviews, systematic reviews, meta-analyses, editorials were excluded); warfarin use; outpatient setting; comparison group present; time in therapeutic range (TTR) included as a measure of quality of anticoagulant control; study design was not a case report. Of 177 articles identified, 25 met inclusion criteria. Quality of anticoagulation control was better in the PMAS group compared with RMC in majority of the studies (N = 23 of 25, 92.0%). Clinical outcomes were also favorable in the PMAS group as evidenced by lower or equal risk of major bleeding (N = 10 of 12, 83.3%) or thromboembolic events (N = 9 of 10, 90.0%), and lower rates of hospitalization or emergency department visits (N = 9 of 9, 100%). When reported, PMAS have also resulted in cost-savings in all (N=6 of 6, 100%) of studies. Compared with routine care, pharmacist-managed outpatient-based anticoagulation services attained better quality of anticoagulation control, lower bleeding and thromboembolic events, and resulted in lower health care utilization.


Impact of pre-pregnancy body mass index, weight gain and blood lipid level during pregnancy on pregnancy outcome in patients with gestational diabetes mellitus.
To explore the effects of pre-pregnancy body mass index (BMI), weight gain and blood lipid level during pregnancy on pregnancy outcome in patients with and without gestational diabetes mellitus(GDM). A total of 12 650 singleton pregnant women without history of hypertension and diabetes who were admitted at Women's Hospital, Zhejiang University School of Medicine for delivery from January 2018 to April 2019 were enrolled in the study. There were 2381 cases complicated with gestational diabetes (GDM group) and 10 269 cases without GDM (non-GDM group). The pre-pregnancy BMI and weight gain during pregnancy were documented in two groups. The factors related to perinatal outcome were analyzed. In both GDM and non-GDM pregnant women, pre-pregnancy overweight and excessive weight gain during pregnancy were independent factors of large for gestational age infant (LGA), small for gestational age infant (SGA) and first cesarean section (<0.01 or <0.05). Excessive weight gain during pregnancy was also an independent risk factor of preeclampsia (<0.05). Triglyceride levels in the second trimester were independently associated with multiple adverse pregnancy outcomes, such as LGA, preeclampsia, initial cesarean delivery, premature delivery. Controlling excessive or insufficient weight gain during pregnancy can significantly reduce the incidence of LGA and SGA. And controlling BMI before pregnancy can effectively reduce the incidence of LGA, preeclampsia and the first cesarean section. For non-GDM pregnant women, abnormal blood lipid levels in the second trimester may be closely related to multiple adverse pregnancy outcomes, and active dietary guidance or treatment is also required.


Diffuse interstitial fibrosis in nonasbestos pneumoconiosis--a pathological study.
Pathological examinations of 233 consecutive autopsy cases with nonasbestos pneumonconiosis revealed evidence of diffuse interstitial fibrosis (DIF) in 64 (27.5%), among whom 45 (19.3%) showed bilateral involvement and 9 (3.9%) extensive disease closely resembling usual interstitial pneumonia. The patients with DIF were significantly older and had longer occupational histories as compared with those without DIF. There was no correlation between the occurrence of DIF and the type of the underlying disease (silicosis or mixed dust pneumoconiosis) except that an extensive DIF was more frequently associated with mixed dust pneumoconiosis. The extensive DIF developed an in situ malignancy much more frequently (33.3%) than the focal disease (2.6%).


Pathological effects of processed bovine pericardial scaffolds--a comparative in vivo evaluation.
The objective of the present study was to assess the biocompatibility and regenerative potential of decellularized bovine pericardial scaffold in comparison with glutaraldehyde-treated and fresh bovine pericardial implants using short-term intramuscular implantation testing in a rat model. The inflammatory and immune responses were assessed using histopathological examination, special stains for connective tissue, histomorphometric evaluation, and immunohistochemistry. The decellularized pericardium showed an active tissue remodeling response with complete cellular invasion, minimum connective tissue encapsulation, extensive fibrovascular tissue formation, and collagen deposition. On the contrary, the glutaraldehyde-treated pericardial implants showed incomplete degradation and cellular invasion, while the fresh pericardial implants elicited a severe foreign body reaction. The results of immunohistochemical staining revealed a minimum T helper (CD4+) lymphocyte response in decellularized pericardial implants compared with its glutaraldehyde-treated and fresh counterparts. The decellularized bovine pericardium was better accepted as a prosthetic scaffold, which permitted maximum collagen deposition and active tissue remodeling by invading host cells and showed good tissue integration in vivo compared with glutaraldehyde-treated and fresh/untreated pericardium.


Revealing Fungal Communities in Alpine Wetlands Through Species Diversity, Functional Diversity and Ecological Network Diversity.
The biodiversity of fungi, which are extremely important in maintaining the ecosystem balance in alpine lakeside wetlands, has not been fully studied. In this study, we investigated the fungal communities of three lakeside wetlands from different altitudes in the Qinghai-Tibet Plateau and its edge. The results showed that the fungi of the alpine lakeside wetland had higher species diversity. Functional annotation of fungi by FUNGild software showed that saprophytic fungi were the most abundant type in all three wetlands. Further analysis of the microbial phylogenetic molecular ecological network (pMEN) showed that saprophytic fungi are important species in the three wetland fungal networks, while symbiotic fungi and pathotrophic fungi have different roles in the fungal networks in different wetlands. Community diversity was high in all three lakeside wetlands, but there were significant differences in the composition, function and network structure of the fungal communities. Contemporary environmental conditions (soil properties) and historical contingencies (geographic sampling location) jointly determine fungi community diversity in this study. These results expand our knowledge of fungal biodiversity in the alpine lakeside wetlands.


MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study.
Recently, mutations of makorin RING-finger protein 3 (MKRN3) have been described in familial central precocious puberty. Serum levels of this protein decline before the pubertal onset in healthy girls and boys. The aim of the study is to investigate MKRN3 circulating levels in patients with central precocious puberty. We performed an observational cross-sectional study. We enrolled 17 patients with central precocious puberty aged 7 years (range: 2-8 years) and breast development onset <8 years; 17 prepubertal control age-matched patients aged 6.3 years (2-8.2); and 10 pubertal stage-matched control patients aged 11.4 years (9-14). Serum values of MKRN3, gonadotropins, (17)estradiol and Anti-Müllerian Hormone were evaluated and the MKRN3 genotyped in central precocious puberty patients. No MKRN3 mutation was found among central precocious puberty patients. MKRN3 levels were lower in patients with central precocious puberty compared to prepubertal age-matched ones (p: 0.0004) and comparable to those matched for pubertal stage. MKRN3 levels were inversely correlated to Body Mass Index Standard Deviations (r:-0.35; p:0.02), Luteinizing Hormone (r:-0.35; p:0.03), FSH (r:-0.37; p:0.02), and (17)estradiol (r: -0.36; p:0.02). We showed that girls with central precocious puberty had lower peripheral levels of MKRN3 compared to age-matched pairs and that they negatively correlated to gonadotropins, estrogen, and BMI. Our findings support the MKRN3 involvement in central precocious puberty also in absence of deleterious mutations, although our sample size is small. In addition our data suggest the role of MKRN3 in the complex mechanism controlling puberty onset and its interaction with other factors affecting puberty such as nutrition.


The secreted plant N-glycoproteome and associated secretory pathways.
N-Glycosylation is a common form of eukaryotic protein post-translational modification, and one that is particularly prevalent in plant cell wall proteins. Large scale and detailed characterization of N-glycoproteins therefore has considerable potential in better understanding the composition and functions of the cell wall proteome, as well as those proteins that reside in other compartments of the secretory pathway. While there have been numerous studies of mammalian and yeast N-glycoproteins, less is known about the population complexity, biosynthesis, structural variation, and trafficking of their plant counterparts. However, technical developments in the analysis of glycoproteins and the structures the glycans that they bear, as well as valuable comparative analyses with non-plant systems, are providing new insights into features that are common among eukaryotes and those that are specific to plants, some of which may reflect the unique nature of the plant cell wall. In this review we present an overview of the current knowledge of plant N-glycoprotein synthesis and trafficking, with particular reference to those that are cell wall localized.


Absolute quantification of oxygenated hemoglobin within the visual cortex with functional near infrared spectroscopy (fNIRS).
To examine absolute changes in oxygenated (HbO) and deoxygenated (Hb) hemoglobin concentrations over the visual cortex in response to visual stimulation. Before this study, only relative changes have been reported at the visual cortex. Near infrared spectroscopy (NIRS) can be used to assess changes in hemoglobin concentration in tissue. A frequency domain oximeter with a specially designed probe was placed over the visual cortex while the participant viewed a checkerboard stimulus. The stimulus was alternated at 7.5 Hz for 30 seconds before being replaced by a control gray screen. The mean HbO concentration when the stimulus was presented was 26.8+/-3.9 microM, as opposed to 25.9+/-3.9 microM for the control condition, and the mean Hb concentration was 18.8+/-2.3 microM during stimulation and 19.1+/-2.3 microM during the control condition. The greatest change in HbO concentration occurred within the first 10 seconds. It did not increase significantly (P>0.01) after that time. This study is the first to demonstrate absolute quantification of HbO and Hb concentrations in the visual cortex with functional changes in hemoglobin concentrations in response to a visual stimulus. NIRS has the potential to be a valuable clinical tool in assessing the hemodynamics of the visual system in a quantitative and localized manner.


Fast-degradable microbeads encapsulating human umbilical cord stem cells in alginate for muscle tissue engineering.
Human umbilical cord mesenchymal stem cells (hUCMSCs) are inexhaustible and can be obtained without an invasive surgery. To date, there has been no report on seeding hUCMSCs in three-dimensional scaffolds for muscle tissue engineering. The objectives of this study were to (1) investigate hUCMSC seeding in a scaffold for muscle engineering and (2) develop a novel construct consisting of hUCMSC-encapsulating and fast-degradable microbeads inside a hydrogel matrix. The rationale was that the hydrogel matrix would maintain the defect volume, while the microbeads would degrade to release the cells and concomitantly create macropores in the matrix. hUCMSCs were encapsulated in alginate-fibrin microbeads, which were packed in an Arg-Gly-Asp (RGD)-modified alginate matrix (AM). This construct is referred to as hUCMSC-microbead-AM. The control consisted of the usual cell encapsulation in AM without microbeads (referred to as hUCMSC-AM). In the hUCMSC-AM construct, the hUCMSCs showed as round dots with no spreading at 1-14 days. In contrast, cells in the hUCMSC-microbead-AM construct had a healthy spreading and elongated morphology. The microbeads successfully degraded and released the cells at 8 days. Myogenic expressions for hUCMSC-microbead-AM were more than threefold those of hUCMSC-AM (p<0.05). Immunofluorescence for myogenic markers was much stronger for hUCMSC-microbead-AM than hUCMSC-AM. Muscle creatine kinase of hUCMSC-microbead-AM at 14 days was twofold that of hUCMSC-AM (p<0.05). In conclusion, hUCMSC encapsulation in novel fast-degradable microbeads inside a hydrogel matrix was investigated for muscle engineering. Compared to the usual method of seeding cells in a hydrogel matrix, hUCMSC-microbead-AM construct had greatly improved cell viability and myogenic differentiation, and hence, is promising to enhance muscle regeneration.


Intracellular sodium determines frequency-dependent alterations in contractility in hypertrophied feline ventricular myocytes.
Hypertrophy and failure (H/F) in humans and large mammals are characterized by a change from a positive developed force-frequency relationship (+FFR) in normal myocardium to a flattened or negative developed force-frequency relationship (-FFR) in disease. Altered Ca(2+) homeostasis underlies this process, but the role of intracellular Na(+) concentration ([Na(+)](i)) in H/F and frequency-dependent contractility reserve is unclear. We hypothesized that altered [Na(+)](i) is central to the -FFR response in H/F feline myocytes. Aortic constriction caused left ventricular hypertrophy (LVH). We found that as pacing rate was increased, contraction magnitude was maintained in isolated control myocytes (CM) but decreased in LVH myocytes (LVH-M). Quiescent LVH-M had higher [Na(+)](i) than CM (LVH-M 13.3 +/- 0.3 vs. CM 8.9 +/- 0.2 mmol/l; P < 0.001) with 0.5-Hz pacing (LVH-M 14.9 +/- 0.5 vs. CM 10.8 +/- 0.4 mmol/l; P < 0.001) but were not different at 2.5 Hz (17.0 +/- 0.7 vs. control 16.0 +/- 0.7 mmol/l; not significant). [Na(+)](i) was altered by patch pipette dialysis to define the effect of [Na(+)](i) on contraction magnitude and action potential (AP) wave shape at slow and fast pacing rates. Using AP clamp, we showed that LVH-M require increased [Na(+)](i) and long diastolic intervals to maintain normal shortening. Finally, we determined the voltage dependence of contraction for Ca(2+) current (I(Ca))-triggered and Na(+)/Ca(2+) exchanger-mediated contractions and showed that there is a greater [Na(+)](i) dependence of contractility in LVH-M. These data show that increased [Na(+)](i) is essential for maintaining contractility at slow heart rates but contributes to small contractions at fast rates unless rate-dependent AP shortening is prevented, suggesting that altered [Na(+)](i) regulation is a critical contributor to abnormal contractility in disease.


Comparison of short-term outcomes between laparoscopic-assisted and open complete mesocolic excision (CME) for the treatment of transverse colon cancer.
Colorectal cancer (CRC) is the third most common cancer worldwide. Although laparoscopic-assisted complete mesocolic excision (LCME) is a superior treatment, there are few studies available on it owe to the low incidence and technical difficulty of LCME in transverse colon cancer. The clinical data of 78 patients with transverse colon cancer who were treated by LCME and open complete mesocolic excision (OCME) were retrospectively analyzed. A total of 39 cases had been treated by LCME, compared with 39 cases treated by OCME. The patient characteristics and short-term outcomes including operation time, intra-operative blood loss, length of incision, time to first flatus, first postoperative ambulation, postoperative hospitalization time, number of harvested lymph nodes, length of resected specimen and incidence of complications were evaluated. There was no case converted to OCME in LCME group. LCME had significantly shorter length of incision, shorter operation time, less intra-operative blood loss, shorter postoperative hospitalization time (P<0.05). The length of resected specimen and the numbers of harvested lymph nodes were (26.5±5.4 cm) and (16.2±3.1) in LCME group, and (24.8±4.9 cm) and (15.1±3.5) in OCME group, with no differences between two groups. The incidence of wound infection was lower while the incidence of lymphatic leakage, anastomotic leakage, urinary tract infection and wound dehiscence had no significant differences between two groups. None of patients in these two groups developed urinary retention, anastomotic bleeding and postoperative intestinal obstruction. Our findings suggested that LCME is a safe, feasible and effective treatment method for the treatment of transverse colon cancer due to it can provide superior short-term outcomes including less intra-operative blood loss, faster recovery and lower incidence of wound infection.


[Familial occurrence of pituitary adenoma (author's transl)].
The familial occurrence of brain tumors are exceedingly rare except in cases with phacomatosis. We encountered pituitary adenomas in two sisters of a family, so far presenting no evidence of multiple endocrine adenomatosis (MEA). Case 1, K. O. a 26-year-old woman was admitted to our Hospital on September 10, 1970 with visual acuity and field disturbance, irregular menstruation and acromegaly. Neurological examination: Her visual acuity was Vd 0.6 and Vs 0.3, visual field was bitemporal hemianopsia, and ther was papilledema bilaterally. She had left exophthalmos and left abducens palsy. Roentgenogram of the skull, brain scanning, cerebral angiogram, pneumoencephalogram suggested the presence of a pituitary tumor. On Sep. 17, 1970, through a left frontotemporal craniotomy the tumor was removed subtotally. The pathological diagnosis was pituitary adenoma (chromophobe). Case 2, M. T. a 31-year-old woman, sister of case 1, was admitted to the Hospital on September 19, 1973, with mild headache, left visual field disturbance and amenorrhea. She had a child, and a past history of pulmonary tbc. Neurological examination: Her visual acuity was Vd 1.2 and Vs 0.03, and visual field of the right eye was temporal lower quandrant anopsia. There was optic nerve atrophy in the left eye. Plain X-ray craniogram, brain scanning, cerebral angiogram and pheumoencephalogram suggested the presence of a pituitary tumor. On Sep. 28, 1973, a right frontal craniotomy was performed. The tumor tissue with capsule was removed subtotally. The pathological diagnosis was pituitary adenoma (mixed type). In the literatures about familial brain tumors with histological diagnosis, glioma and glioblastoma are common, meningioma is relatively rare. Pituitary adenoma with no evidence of MEA is exceedingly rare. The two sisters presented in this paper, have no evidence of hyperparathyroidism, pancreas adenoma and peptic ulcer. So, we consider, at present, these cases should not be field in MEA.


Lymph Node Stromal Cell-Intrinsic MHC Class II Expression Promotes MHC Class I-Restricted CD8 T Cell Lineage Conversion to Regulatory CD4 T Cells.
MHC class I (MHC-I)-restricted CD4+ T cells have long been discovered in the natural repertoire of healthy humans as well as patients with autoimmune diseases or cancer, but the exact origin of these cells remains to be fully characterized. In mouse models, mature peripheral CD8+ T cells have the potential to convert to CD4+ T cells in the mesenteric lymph nodes. This conversion can produce a unique population of MHC-I-restricted CD4+ T cells including Foxp3+ regulatory T cells termed MHC-I-restricted CD4+Foxp3+ T (CI-Treg) cells. In this study we examined the cellular and molecular elements that promote CD8-to-CD4 lineage conversion and the development of CI-Treg cells in mice. Using adoptive transfer and bone marrow chimera experiments, we found that the differentiation of CI-Treg cells was driven by lymph node stromal cell (LNSC)-intrinsic MHC-II expression as opposed to transcytosis of MHC-II from bone marrow-derived APCs. The lineage conversion was accompanied by Runx3 versus ThPOK transcriptional switch. This finding of a new role for LNSCs in vivo led us to develop an efficient tissue culture method using LNSCs to generate and expand CI-Treg cells in vitro. CI-Treg cells expanded in vitro with LNSCs effectively suppressed inflammatory tissue damage caused by pathogenic CD4+ T cells in mouse models of colitis. This study identified a novel role of MHC-II expressed by LNSCs in immune regulation and the potential utilization of LNSCs to generate novel subsets of immune regulatory cells for therapeutic applications.


Superficial stromal keratitis in the dog.
Superficial stromal keratitis or pannus is a syndrome of corneal, conjunctival and third eyelid inflammation. Superficial stromal keratitis mainly presents as a subepithelial corneal infiltration of vascular connective tissue, and usually arises from the lateral (temporal) limbal area. In some dogs perilimbal hyperaemia and third eyelid blepharitis can be present without corneal involvement. The most commonly affected breed of dog is the German Shepherd. Most cases of superficial stromal keratitis can be controlled with topical corticosteroids, and only rarely is cryosurgery or superficial keratectomy required to remove excessive pigment and or granulation tissue. The precise aetiology of SSK is unknown, but is likely to be multifactorial, with sunlight being a significant factor. Corneal lipidosis and keratoconjunctivitis sicca can occur secondary to superficial stromal keratitis.


N-Mannich Bases of Aromatic Heterocyclic Amides: Synthesis via Copper-Catalyzed Aerobic Cross-Dehydrogenative Coupling under Ambient Conditions.
An efficient and facile method to synthesize N-Mannich bases has been developed using an inexpensive copper(I) bromide/air catalyst system at ambient temperature. A cross-dehydrogenative coupling of N,N-dimethylarylamines occurs efficiently with aromatic heterocyclic amides (oxindoles, isatins), cyclic amides (lactams), simple amides (benzamide), as well as imides (succinimide, phthalimide) to furnish the corresponding amidated/imidated derivatives in good to excellent yields. Preliminary mechanistic and isotope-labeling studies suggest the reaction follows a radical pathway and involves an iminium ion intermediate.


Brain oxygen utilization is unchanged by hypoglycemia in normal humans: lactate, alanine, and leucine uptake are not sufficient to offset energy deficit.
During hypoglycemia, substrates other than glucose have been suggested to serve as alternate neural fuels. We evaluated brain uptake of endogenously produced lactate, alanine, and leucine at euglycemia and during insulin-induced hypoglycemia in 17 normal subjects. Cross-brain arteriovenous differences for plasma glucose, lactate, alanine, leucine, and oxygen content were quantitated. Cerebral blood flow (CBF) was measured by Fick methodology using N(2)O as the dilution indicator gas. Substrate uptake was measured as the product of CBF and the arteriovenous concentration difference. As arterial glucose concentration fell, cerebral oxygen utilization and CBF remained unchanged. Brain glucose uptake (BGU) decreased from 36.3+/-2.6 to 26.6+/-2.1 micromol.100 g of brain(-1).min(-1) (P<0.001), equivalent to a drop in ATP of 291 micromol.100 g(-1).min(-1). Arterial lactate rose (P<0.001), whereas arterial alanine and leucine fell (P<0.009 and P<0.001, respectively). Brain lactate uptake (BLU) increased from a net release of -1.8+/- 0.6 to a net uptake of 2.5+/-1.2 micromol.100 g(-1).min(-1) (P<0.001), equivalent to an increase in ATP of 74 micromol.100 g(-1).min(-1). Brain leucine uptake decreased from 7.1+/-1.2 to 2.5 +/- 0.5 micromol.100 g(-1).min(-1) (P<0.001), and brain alanine uptake trended downward (P<0.08). We conclude that the ATP generated from the physiological increase in BLU during hypoglycemia accounts for no more than 25% of the brain glucose energy deficit.


Dynamics of Bone Disease Biomarkers Dickkopf-1 and Sclerostin in Patients with Multiple Myeloma.
Dickkopf-1 (DKK-1) and sclerostin are essential Wnt/β-catenin pathway inhibitors, playing an important role in multiple myeloma bone disease (MBD). We aimed to examine the serum DKK-1 and sclerostin variations in newly diagnosed multiple myeloma (NDMM) patients at diagnosis and in the course of therapy, including autologous stem cell transplantation (ASCT). This study included 41 NDMM-patients and 33 controls. MBD was assessed by whole-body low-dose computed tomography. DKK-1 and sclerostin were assayed by commercial ELISA kits. At diagnosis, NDMM-patients revealed significantly higher DKK-1 and sclerostin values (p < 0.0001), showing dependence on disease stage (lowest in ISS-I and highest in ISS-III: p < 0.0012 and p < 0.025, respectively, for both proteins). Bone lesions revealed significant positive correlation with both DKK-1 (p < 0.05) and sclerostin (p < 0.0001). In the course of therapy, significant reduction, more prominent after ASCT, was observed for both parameters in each treatment point compared to the baseline (p < 0.0001). Markedly lower sclerostin (p < 0.01) and DKK-1 (p < 0.05) values were observed in patients with complete and very good partial response compared to those with partial response, stable, or progressive disease. Sclerostin and DKK-1 in NDMM patients reflect the MBD severity and the effect of therapy. Both proteins could represent a novel tool for better disease monitoring and effectiveness of therapy.


Single determination of plasma ACTH using an immunoradiometric assay with high detectability differentiates between ACTH-dependent and -independent Cushing's syndrome.
The purpose of this retrospective study was to elucidate the value of an ACTH assay with high detectability to differentiate between ACTH-dependent and -independent Cushing's syndrome. The study was based on the case records of 56 patients with Cushing's syndrome comprising 34 patients with ACTH-dependent Cushing's syndrome and 22 patients with ACTH-independent Cushing's syndrome. Basal morning plasma 1-39 ACTH was measured using an immunoradiometric assay (IRMA) with a normal range of 1.8-11 pmol/L. Peripheral corticotrophin-releasing hormone (CRH) tests were performed in 24 and 17 patients with ACTH-dependent and -independent Cushing's syndrome, respectively. Using a single ACTH measurement, a complete separation was observed between the two defined groups, with a cut-off value of 2.4 pmol/L. Mean ACTH concentration was 14.4 pmol L (range 2.5-47.7 pmol/L) in ACTH-dependent Cushing's syndrome and 0.6 pmol/L (range 0.2-2.2 pmol/L) in ACTH-independent Cushing's syndrome. The range of separation between the two groups was further increased by using two ACTH measurements in each patient or peripheral stimulation with CRH. It is concluded that in the majority of patients with Cushing's syndrome a single basal morning ACTH determination is sufficient to discriminate between ACTH-dependent and ACTH-independent Cushing's syndrome. In borderline cases with ACTH in the range 2-3 pmol/L, repeated measurements might be necessary. The peripheral CRH test was not superior to repeated ACTH measurements.


Interobserver agreement for the detection of atherosclerotic plaque in coronary CT angiography: comparison of two low-dose image acquisition protocols with standard retrospectively ECG-gated reconstruction.
We compared the interobserver variability concerning the detection of calcified and non-calcified plaque in two different low-dose and standard retrospectively gated protocols for coronary CTA. 150 patients with low heart rates and less than 100 kg body weight were randomised and examined by contrast-enhanced dual-source CT coronary angiography (100 kV, 320 mAs). 50 patients were examined with prospectively ECG-triggered axial acquisition, 50 patients with prospectively ECG-triggered high pitch spiral acquisition, and 50 patients using spiral acquisition with retrospective ECG gating. Two investigators independently analysed the datasets concerning the presence of calcified and non-calcified plaque on a per-segment level. Mean effective dose was 1.4 ± 0.2 mSv for axial, 0.8 ± 0.07 mSv for high-pitch spiral, and 5.3 ± 2.6 mSV for standard spiral acquisition (P < 0.0001). In axial acquisition, interobserver agreement concerning the presence of atherosclerotic plaque was achieved in 650/749 coronary segments (86.8%). In high-pitch spiral acquisition, agreement was achieved in 664/748 segments (88.8%, n.s.). In standard spiral acquisition, agreement was achieved in 672/738 segments (91.0%, P < 0.0001). Interobserver agreement was significantly higher for calcified than for non-calcified plaque in all data acquisition modes. Low-dose coronary CT angiography permits the detection of coronary atherosclerotic plaque with good interobserver agreement. • Low-dose CT protocols permit coronary plaque detection with good interobserver agreement. • Image noise is a major predictor of interobserver variability. • Interobserver agreement is significantly higher for calcified than for non-calcified plaque.


Ascorbic Acid vs Calcitriol in Influencing Monocyte Chemoattractant Protein-1, Nitric Oxide, Superoxide Dismutase, as Markers of Endothelial Dysfunction: In Vivo Study in Atherosclerosis Rat Model.
Ascorbic acid and calcitriol were frequently utilized in conjunction as therapy during the COVID-19 pandemic, and individuals with minor symptoms had notable improvements. There have been a few studies, often with conflicting findings, that examine the use of them for endothelium restoration and numerous clinical trial studies that failed to establish the efficacy. The aim of this study was to find the efficacy of ascorbic acid compared to calcitriol on the inflammatory markers monocyte chemoattractant protein-1 (MCP-1), nitric oxide (NO), and superoxide dismutase (SOD), as protective agents which play an important role in the early stages of atherosclerosis formation. This study was an experimental in vivo study. The total of 24 male Rattus norvegicus strain Wistar rats were divided into 4 groups, namely: control/normal group (N), atherosclerosis group (DL) given atherogenic diet, atherosclerosis group given atherogenic diet and ascorbic acid (DLC), and atherosclerosis group given atherogenic diet and calcitriol (DLD) treatment for 30 days. Ascorbic acid and calcitriol treatment was significantly effective (P<0.05) in lowering expression of MCP-1 and increasing NO and SOD level. Calcitriol was superior to ascorbic acid in increasing SOD (P<0.05). There was no significant difference between ascorbic acid and calcitriol in decreasing MCP-1 and increasing NO (P>0.05). Both treatments could reduce MCP-1, and increase NO and SOD by increasing antioxidants. In this study calcitriol was superior to ascorbic acid in increasing SOD, but not NO and decreasing MCP-1. According to the theory, it was found that calcitriol through nuclear factor erythroid 2-related factor 2 (Nrf2) causes a direct increase in the amount of SOD. Nrf2 is an emerging regulator of cellular resistance to oxidants. Ascorbic acid and calcitriol treatment was able to reduce MCP-1 and increase NO and SOD in atherosclerosis rat. Calcitriol was significantly superior in increasing SOD levels compared to ascorbic acid.


NMR Relaxation Experiments Probe Monomer-Fibril Interaction and Identify Critical Interacting Residues Responsible for Distinct Tau Fibril Morphologies.
Tau aggregation is governed by secondary processes, a major pathological pathway for tau protein fibril propagation, yet its molecular mechanism remains unknown. This work uses saturation transfer and lifetime line-broadening experiments to identify the critical residues involved in these secondary processes. Distinct residue-specific NMR relaxation parameters were obtained for the truncated three repeat tau construct (K19) in equilibrium with structurally different, self-aggregated (saK19) or heparin-induced (hK19) fibrils. The interacting residues are restricted to R3 repeat for hK19 and to R3, R4, and R' repeats for saK19 fibrils. Furthermore, the relaxation profiles of tau monomers in equilibrium with the structurally comparable, in vitro pathological fibrils (tauAD and tauCTE) were similar but distinct from hK19 or saK19 fibrils. Thus, residue-specific relaxation identifies the important residues involved in the binding of monomers to the fibrils. The relaxation profile of the monomers in equilibrium with the NMR invisible fibril seeds potentially distinguishes the distinct structures of tau fibrils.


Triplex profiling of functionally distinct chaperones (ERp29/PDI/BiP) reveals marked heterogeneity of the endoplasmic reticulum proteome in cancer.
The biomedical need for streamlined approaches to monitor proteome dynamics is growing rapidly. This study examined the ability of a knowledge-based triplex-profiling strategy (i.e., three functionally distinct chaperones, ERp29/PDI/BiP) to clarify uncertainties about how cancer affects the endoplasmic reticulum (ER) proteome. Investigating a wide range of samples at the tissue and cellular levels (>114 samples from 9 tissues of origin), we obtained consistent evidence that the ER proteome undergoes a major but variable expansion in cancer. Three factors having a strong influence on the ER proteome were identified (cancer-cell type, growth rate, culture mode), and the functionally enigmatic chaperone ERp29 was linked distinctively to histogenetic aspects of tumorigenesis. These findings justify pursuit of the ER-proteome as a medical target in cancer, validate ERp29/PDI/BiP profiling as a streamlined yet powerful measure of ER-proteome dynamics, and suggest that biomarker sets based on distinct functionalities could have broader biomedical utility.


Artificial Neural Processing-Driven Bioelectronic Nose for the Diagnosis of Diabetes and Its Complications.
Diabetes and its complications affect the younger population and are associated with a high mortality rate; however, early diagnosis can contribute to the selection of appropriate treatment regimens that can reduce mortality. Although diabetes diagnosis via exhaled breath has great potential for early diagnosis, research on such diagnosis is restricted to disease detection, requiring in-depth examination to diagnose and classify diseases and their complications. This study demonstrates the use of an artificial neural processing-based bioelectronic nose to accurately diagnose diabetes and classify diabetic types (type I and II) and their complications, such as heart disease. Specifically, an M13 phage-based electronic nose (e-nose) is used to explore the features of subjects with diabetes at various levels of cellular and organismal organization (cells, liver organoids, and mice). Exhaled breath samples are collected during culturing and exposed to the phage-based e-nose. Compared with cells, liver organoids cultured under conditions mimicking a diabetic environment display properties that closely resemble the characteristics of diabetic mice. Using neural pattern separation, the M13 phage-based e-nose achieves a classification success rate of over 86% for four conditions in mice, namely, type 1 diabetes, type 2 diabetes, diabetic cardiomyopathy, and cardiomyopathy.


[Conformational analysis and hemolytic activity of immunoglobulin G fragment 285-292 and its analogs].
Theoretical conformational analysis was carried out for the 285-292 fragment of human immunoglobulin G (His-Asn-Ala-Lys-Thr-Lys-Pro-Arg) and its analogues containing Arg, Glu, Gly, Lys, or Trp residue instead of the His residue in position 1. Spectropolarimetic investigation of these peptides showed the analogues to have different activities in the C1q-mediated erythrocytes hemolysis assay. Comparison of the low-energy structures sets of the compounds tested allowed to suggest a model of the "biological active" conformation for the peptide molecule in the course of the C1q complement component binding.


Brighter horizons: The necessity of concentrated sponsorship targeted toward minoritized student pharmacists.
Due to the effects of structural racism, disproportionately lower numbers of Black, Hispanic or LatinX, American Indian, and Alaska Native students pursue a career in pharmacy and successfully matriculate into the profession. Despite these disparities being present for many years, little progress has been achieved in diversifying the pharmacy profession, resulting in a persistent lack of diversity within pharmacy leadership across employers and pharmacy organizations. Consistent with recent recommendations for improving diversity in pharmacy, the PharmGradWishlist (PGWL) initiative was created as a way for practicing pharmacists and organizations to provide direct financial sponsorship to racially and ethnically minoritized trainees to offset costs incurred during training and during the transition from student to practicing pharmacist. Many of these costs, such as residency and fellowship application fees, job interview travel costs, board exam and licensing fees, and moving expenses, are not typically subsidized by federal student funding. Offsetting these costs is an important way to reduce barriers to entering the profession and postgraduate training, the latter of which may be particularly important in trainees' pursuit of academic and leadership positions in pharmacy. The initial development and advertisement of the initiative occurred through social media and the grassroots efforts of the PGWL team, a group of 10 volunteer pharmacists from across the country, and resulted in generous donations from a small proportion of practicing pharmacists nationwide. It is now time for the profession as a whole to embrace the role of direct sponsorship in improving diversity in the profession. We call upon pharmacists and pharmacy organizations to advocate for and participate in financial sponsorship of racially and ethnically minoritized trainees and pharmacists as a way to increase diversity and promote health equity.


Comparative study of two systems for detecting becteraemia and septicaemia.
Two blood culturing systems were compared in parallel-a semi-automated radiometric method, BACTEC1, and the conventional method used in our laboratory. BACTEC contains radioactive 14C labelled substrates and monitors the level of 14CO2 evolved by actively metabolizing bacteria. BACTEC was as efficient as the conventional method in detecting positive cultures and indicated that it was superior in detecting positive cultures earlier than the conventional system.


Effect of Binding Components in Complex Sample Matrices on Recovery in Direct Immersion Solid-Phase Microextraction: Friends or Foe?
The development of matrix compatible coatings for solid-phase microextraction (SPME) has enabled direct extraction of analytes from complex sample matrices. The direct immersion (DI) mode of SPME when utilized in conjunction with such extraction phases facilitates extraction of a wide range of analytes from complex matrices without the incurrence of fouling or coating saturation. In this work, mathematical models and computational simulations were employed to investigate the effect of binding components present in complex samples on the recovery of small molecules varying in logP for extractions carried out using the direct immersion approach. The presented findings corroborate that the studied approach indeed enables the extraction of both polar and nonpolar analytes from complex matrices, provided a suitable sorbent is employed. Further results indicated that, in certain cases, the kinetics of extraction of a given analyte in its free form might be dependent on the desorption kinetics of their bound form from matrix components, which might lower total recoveries of analytes with high affinity for the matrix. However, the binding of analytes to matrix components also enables SPME to extract a balanced quantity of different logP analytes, facilitated by multiphase equilibria, with a single extraction device.


Synthesis of Ge-imogolite: influence of the hydrolysis ratio on the structure of the nanotubes.
The synthesis protocol for Ge-imogolite (aluminogermanate nanotubes) consists of 3 main steps: base hydrolysis of a solution of aluminum and germanium monomers, stabilization of the suspension and heating at 95 °C. The successful synthesis of these nanotubes was found to be sensitive to the hydrolysis step. The impact of the hydrolysis ratio (from n(OH)/n(Al) = 0.5 to 3) on the final product structure was examined using a combination of characterization tools. Thus, key hydrolysis ratios were identified: n(OH)/n(Al) = 1.5 for the formation of nanotubes with structural defects, n(OH)/n(Al) = 2 for the synthesis of a well crystallized Ge imogolite and n(OH)/n(Al) > 2.5 where nanotube formation is hindered. The capability of controlling the degree of the nanotube's crystallinity opens up interesting opportunities in regard to new potential applications.


Temporal course of upregulation of Na(v)1.8 in Purkinje neurons parallels the progression of clinical deficit in experimental allergic encephalomyelitis.
Multiple sclerosis (MS) is recognized to involve demyelination and axonal atrophy but accumulating evidence suggests that dysregulated sodium channel expression may also contribute to its pathophysiology. Recent studies have demonstrated that the expression of Na(v)1.8 voltage-gated sodium channels, which are normally undetectable within the CNS, is upregulated in cerebellar Purkinje cells in experimental allergic encephalomyelitis (EAE) and MS, and suggest that the aberrant expression of these channels contributes to clinical dysfunction by distorting the firing pattern of these neurons. In this study we examined the temporal pattern of upregulation for Na(v)1.8 mRNA and protein in chronic relapsing EAE by in situ hybridization and immunocytochemistry, respectively. Our results demonstrate a positive correlation between disease duration and degree of upregulation of Na(v)1.8 mRNA and protein in Purkinje neurons in chronic-relapsing EAE. The progressive deterioration in clinical baseline scores (i.e. in clinical scores during remissions) is paralleled by a continued increase in Na(v)1.8 mRNA and protein expression, but temporary worsening during relapses is not associated with transient changes in Na(v)1.8 expression. These results provide evidence that the expression of sodium channel Na(v)1.8 contributes to the development of clinical deficits in an in vivo model of neuroinflammatory disease.


Transcortical-transventricular approach in colloid cysts of the third ventricle: surgical experience with 26 cases.
Colloid cysts of the third ventricle account for 0.5-2% of all intracranial tumors. The treatment of these benign tumors remains controversial, and the best surgical option has not yet been determined. Between 1995 and 2002, 27 patients with colloid cysts of the third ventricle presented at our clinic. Twenty-six underwent transcortical-transventricular approaches. One refused surgical treatment. There was no surgical mortality. The main morbidity was epileptic seizures in two patients. Overall outcome was good in all patients. The mean follow-up period was 3.4 years. There were no tumor recurrences. The transcortical-transventricular approach can be used safely to excise third ventricle colloid cysts with low risk of mortality and morbidity.


The amyloid interactome: Exploring protein aggregation.
Protein-protein interactions are the quintessence of physiological activities, but also participate in pathological conditions. Amyloid formation, an abnormal protein-protein interaction process, is a widespread phenomenon in divergent proteins and peptides, resulting in a variety of aggregation disorders. The complexity of the mechanisms underlying amyloid formation/amyloidogenicity is a matter of great scientific interest, since their revelation will provide important insight on principles governing protein misfolding, self-assembly and aggregation. The implication of more than one protein in the progression of different aggregation disorders, together with the cited synergistic occurrence between amyloidogenic proteins, highlights the necessity for a more universal approach, during the study of these proteins. In an attempt to address this pivotal need we constructed and analyzed the human amyloid interactome, a protein-protein interaction network of amyloidogenic proteins and their experimentally verified interactors. This network assembled known interconnections between well-characterized amyloidogenic proteins and proteins related to amyloid fibril formation. The consecutive extended computational analysis revealed significant topological characteristics and unraveled the functional roles of all constituent elements. This study introduces a detailed protein map of amyloidogenicity that will aid immensely towards separate intervention strategies, specifically targeting sub-networks of significant nodes, in an attempt to design possible novel therapeutics for aggregation disorders.


Variance estimation for epidemiologic effect estimates under misclassification.
This paper presents basic methods for construction of variance estimators for epidemiologic effect estimates when adjusting for misclassification. Methods are described for differential and non-differential misclassification, and for external and internal estimates of classification rates. The methods take account of sampling variability in both the observed data and the estimated classification rates. The methods are illustrated in a case-control analysis of the association of antibiotic use during pregnancy with sudden infant death syndrome.


Regulation of human immunodeficiency virus type 1 envelope glycoprotein fusion by a membrane-interactive domain in the gp41 cytoplasmic tail.
Truncation of the human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) gp41 cytoplasmic tail (CT) can modulate the fusogenicity of the envelope glycoprotein (Env) on infected cells and virions. However, the CT domains involved and the underlying mechanism responsible for this "inside-out" regulation of Env function are unknown. HIV and SIV CTs are remarkably long and contain amphipathic alpha-helical domains (LLP1, LLP2, and LLP3) that likely interact with cellular membranes. Using a cell-cell fusion assay and a panel of HIV Envs with stop codons at various positions in the CT, we show that truncations of gp41 proximal to the most N-terminal alpha helix, LLP2, increase fusion efficiency and expose CD4-induced epitopes in the Env ectodomain. These effects were not seen with a truncation distal to this domain and before LLP1. Using a dye transfer assay to quantitate fusion kinetics, we found that these truncations produced a two- to fourfold increase in the rate of fusion. These results were observed for X4-, R5-, and dual-tropic Envs on CXCR4- and CCR5-expressing target cells and could not be explained by differences in Env surface expression. These findings suggest that distal to the membrane-spanning domain, an interaction of the gp41 LLP2 domain with the cell membrane restricts Env fusogenicity during Env processing. As with murine leukemia viruses, where cleavage of a membrane-interactive R peptide at the C terminus is required for Env to become fusogenic, this restriction of Env function may serve to protect virus-producing cells from the membrane-disruptive effects of the Env ectodomain.


Structure and functional relationships of Hsp90.
Understanding the mode of action of Hsp90 requires that molecular detail of its interactions with client proteins and co-chaperones are known. The structure determination of the N-terminal domain of Hsp90/Hsp90beta, proof that it is an ATPase, that this activity is regulated and the identification of co-chaperones that facilitate Hsp90 function were landmarks towards understanding conformational changes in Hsp90 brought about by ATP, co-chaperones and client proteins. Sti1 and Cdc37/p50, which associate with early Hsp90 complexes, were shown to be inhibitors of Hsp90 ATPase activity and therefore promote its 'open' state, whereas Sba1/p23, which associates with mature complexes, inhibits ATPase activity and stabilises the 'closed' state. The isolation and characterisation of Aha1, the only known strong activator of Hsp90 ATPase activity, which promotes the 'closed' state of Hsp90, will also be of major importance in understanding Hsp90 function. The structure determination of the middle region of Hsp90 has shed further light on the complex ATP-cycle of Hsp90, identifying a catalytic loop, with key residues that are essential for ATP hydrolysis. These studies, together with biochemical ones, suggest that ATP hydrolysis, is dependent on a complex rate-limiting step, involving N-terminal dimerization and association of the middle region, and therefore the catalytic loop, of Hsp90 with the N-terminal domains. The structure of the middle region of Hsp90 will also accelerate our understanding of client protein interactions since this region is implicated in their recognition and in particular their active-site openings.


Submucous cleft palate.
We review 97 cases of SMCP, 79 of which were operated. The comparative results are presented. For those requiring surgery (i.e. those having hypernasality), it has been our experience that the use of a pharyngeal flap, alone or combined with a palatoplasty, is productive of better speech results than is a palatoplasty alone.


Relationship of trihalomethane in drinking water with hypertension and arrhythmia among young and middle-aged adults in Petropavlovsk, Kazakhstan.
There are no studies investigating the association of chlorinated drinking water with the risk of cardiovascular diseases (CVDs) among young and middle-aged adults. This study was aimed to assess the associations between trihalomethanes (THMs) in drinking water and the risk of CVDs in in the target group in Petropavlovsk, Kazakhstan. 448 dwellers of Petropavlovsk were asked about their demographic, socioeconomic, lifestyle, behavioural characteristics, and drinking water preferences. THMs exposure was assessed to each participant based on their residence address. We used multivariable logistic regression analysis to assess the risk of CVDs in young and middle-aged adults. The results showed that the risk of hypertension in the adjusted logistic regression model was increased by 68% and a 2.7-fold in the second and third THM tertiles, respectively. Participants in the second and third THM exposure tertiles had a 2.3-fold and a 4.8-fold increase in the risk of arrhythmia.


Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques.
Monocytes participate critically in atherosclerosis. There are 2 major subsets expressing different chemokine receptor patterns: CCR2(+)CX3CR1(+)Ly-6C(hi) and CCR2(-)CX3CR1(++)Ly-6C(lo) monocytes. Both C-C motif chemokine receptor 2 (CCR2) and C-X(3)-C motif chemokine receptor 1 (CX3CR1) are linked to progression of atherosclerotic plaques. Here, we analyzed mouse monocyte subsets in apoE-deficient mice and traced their differentiation and chemokine receptor usage as they accumulated within atherosclerotic plaques. Blood monocyte counts were elevated in apoE(-/-) mice and skewed toward an increased frequency of CCR2(+)Ly-6C(hi) monocytes in apoE(-/-) mice fed a high-fat diet. CCR2(+)Ly-6C(hi) monocytes efficiently accumulated in plaques, whereas CCR2(-)Ly-6C(lo) monocytes entered less frequently but were more prone to developing into plaque cells expressing the dendritic cell-associated marker CD11c, indicating that phagocyte heterogeneity in plaques is linked to distinct types of entering monocytes. CCR2(-) monocytes did not rely on CX3CR1 to enter plaques. Instead, they were partially dependent upon CCR5, which they selectively upregulated in apoE(-/-) mice. By comparison, CCR2(+)Ly-6C(hi) monocytes unexpectedly required CX3CR1 in addition to CCR2 and CCR5 to accumulate within plaques. In many other inflammatory settings, these monocytes utilize CCR2, but not CX3CR1, for trafficking. Thus, antagonizing CX3CR1 may be effective therapeutically in ameliorating CCR2(+) monocyte recruitment to plaques without impairing their CCR2-dependent responses to inflammation overall.


Moving forward: a qualitative research inquiry to inform the development of a resource pack for women following primary breast cancer treatment.
While the UK charity Breast Cancer Care has extensive resources for women with breast cancer, this research partnership developed the first resource driven and informed by primary research with these women, exploring their needs and developing the resource according to need. Data were collected from focus groups with breast cancer survivors and telephone interviews with health professionals and experts, which explored the needs of women after primary cancer treatment, and were analyzed using thematic analysis. As well as information, these women needed resources to help them regain control over life, adapt to a changed body, and restore lost confidence.


New metabolites from the sponge-derived fungus Aspergillus sydowii J05B-7F-4.
Two new metabolites, diorcinolic acid (1) and β-d-glucopyranosyl aspergillusene A (8), together with six diphenylethers (2-7), a diketopiperazine (9), a chromone (10) and a xanthone (11) were isolated from the fungus Aspergillus sydowii derived from the marine sponge Stelletta sp. The planar structures and their relative configurations were elucidated by analysing 1D, 2D NMR and HRESIMS data. Compound 8 is the first glycoside of phenolic bisabolane sesquiterpenes. Compounds 1 and 8 exhibited mild cytotoxicity against KB (human nasopharyngeal carcinoma cells), HepG2 (human liver cancer cells) and HCT 116 (human colon cancer cells). All compounds were evaluated for antibacterial activity and their abilities to suppress LPS-induced nitric oxide (NO) production. Compounds 2 and 4-7 showed mild antibacterial activity against human pathogen Staphylococcus aureus and fish pathogens Streptococcus iniae and Vibrio ichthyoenteri, and compounds 4 and 7 weakly suppressed NO production.


Robenidine Analogues Are Potent Antimalarials in Drug-Resistant Plasmodium falciparum.
Robenidine is a veterinary drug used in the poultry industry to treat coccidiosis caused by parasites in the Eimeria genus. Though this compound and related aminoguanidines have recently been studied in other pathogens, the chemotype has not been systematically explored to optimize antimalarial activity despite the close genetic relationship between Eimeria and Plasmodium (both are members of the Apicomplexa phylum of unicellular, spore-forming parasites). In this study, a series of aminoguanidine robenidine analogues was prepared and tested in vitro against Plasmodium falciparum, including multidrug-resistant strains. Selected compounds were further evaluated in vivo against murine Plasmodium yoelii in mice. Iterative structure-activity relationship studies led to the discovery of 1, an aminoguanidine with excellent activity against drug-resistant malaria in vitro and impressive in vivo efficacy with an ED50 value of 0.25 mg/kg/day in a standard 4-day test.


Exploration of a Swedish community-based family-oriented setting for promoting healthy food habits: professionals' experiences.
Health is created in everyday life and settings, where food literacy (FL) and health literacy (HL) are recognized as important for autonomy over one's own health. Though it is acknowledged that bridging the gap between healthcare settings and community settings may be necessary to reach those requiring extra support. Open preschool (OP) is a low threshold community setting which parents with their young children can visit voluntarily, where the various activities offered can be opportunities to address topics related to food and health. The aim of this study is to explore preschool teachers and health practitioners' thoughts and experience of OP as a setting for health promotion, with focus on food and eating. The study is localized to OP's in a multicultural district in Gothenburg, Sweden. Semi-structured interviews were conducted with three preschool teachers and seven health practitioners (one dental hygienist, three dietitians and three public health strategists). With an inductive approach, data were analysed using qualitative content analysis. From the perspective of teachers and health practitioners, the findings indicate that OP can be a setting for mutual learning in a supportive environment. OP provides various possibilities for improved FL and HL by linking health practitioners with families, providing the opportunity to socialize and by eating together. The results also reveal that language barriers can sometimes hinder communication, and that OP does not reach all families. Continuous collaboration between OP and health organizations and practitioners along with regular use of intercultural mediators is recommended by the professionals.


Comparison of the timing of initial prophylactic palivizumab dosing on hospitalization of neonates for respiratory syncytial virus.
The effects of two prophylactic palivizumab schedules on hospitalization of neonates for respiratory syncytial virus (RSV) were compared. This retrospective study was conducted in the neonatal intensive care unit (NICU) of a tertiary care, academic medical center. Patients were divided into two groups. Group 1 (hospitalized between October 2005 and April 2007) received inpatient doses of palivizumab monthly throughout the RSV season, regardless of their anticipated discharge date, followed by outpatient doses. Group 2 (hospitalized between October 2007 and April 2009) received only one dose of palivizumab before hospital discharge with subsequent outpatient doses. The primary outcome measure was the number of hospitalizations for RSV bronchiolitis. Secondary endpoints included the total number of palivizumab doses each patient received, number of inpatient doses per patient, number of hospitalizations requiring intensive care unit admission, patient need for mechanical ventilation, outcome of the RSV-related hospitalization, and cost of inpatient palivizumab doses per patient. A total of 207 neonates were included in the study (112 in group 1, 95 in group 2). The mean gestational age was 29.7 weeks in group 1 and 30.3 weeks in group 2. Seven patients were hospitalized for RSV infection (5 in group 1 versus 2 in group 2, p = 0.4564). No RSV-related deaths occurred. Significantly more inpatient doses were administered to group 1 versus group 2 (1.7 versus 1, p < 0.001). Limiting inpatient palivizumab to 1 dose before discharge resulted in an institutional cost savings of more than $60,000 annually. Hospitalization rates for RSV did not significantly differ between NICU patients who received inpatient prophylactic palivizumab monthly and those who received only one dose before discharge.


Effects of branched-chain amino acids to lysine ratios in corn distillers dried grains with solubles containing diets on growth performance, plasma nitrogen profile, carcass traits, and economic analysis in growing-finishing pigs.
A study was conducted to identify the effects of standardized ileal digestible (SID) branched-chain amino acids (BCAA):lysine (Lys) ratios on the growth performance, plasma nitrogen (N) profile, carcass traits, and economic analysis of growing-finishing pigs fed diets with high corn distillers dried grains with solubles (cDDGS) inclusions. A total of 1,140 pigs (initial body weight [BW] = 28.7 ± 2.0 kg) were housed in 45 pens of 25 or 26 pigs and fed one of five diets in a randomized complete block design. Experimental diets were fed in four phases based on BW. Dietary treatments were a corn-soybean meal (SBM) based diet (PC), a corn-SBM-cDDGS-based diet (NC) with SID BCAA:Lys ratio of PIC (2020) recommendation and NC diets with SID BCAA:Lys ratios targeted for the 73% SID Val:Lys, 60% SID Ile:Lys, and 144% SID Leu:Lys during the growing phases (25 to 80 kg, Grow), targeted for the 78% SID Val:Lys, 70% SID Ile:Lys, and 160% to 170% SID Leu:Lys during the finishing phases (80 to 120 kg, finish), and both during the growing and finishing phases (Grow-Finish). One pig from each pen was bled at the end of 7 and 13 wk. After the 11-wk-feeding trial, pigs were sent to a commercial abattoir to investigate carcass traits. Pigs fed the Finish diet had a greater overall average daily gain (P < 0.05) than pigs fed the other cDDGS diets. Dietary treatments did not affect the hot carcass weight. However, feeding the Finish diet increased (P < 0.05) the iodine value of pork belly samples and decreased (P < 0.05) carcass yield. The plasma urea nitrogen (PUN) concentration at the end of the growing phase and plasma concentrations of Leu and Val were greater (P < 0.05) in pigs fed the Finish diet compared to the other cDDGS diets. Feeding pigs the cDDGS diets with different BCAA:Lys ratios had no difference in income over feed cost and income over feed and facility costs compared to the corn-SBM diet. Therefore, feeding pigs cDDGS diets with SID BCAA:Lys ratios adjusted for the previously determined finishing phase (from 80 to 120 kg of BW) recommendations by SBM inclusion supported growth performance and economic benefits equal to the corn-SBM diet.


Detection of mRNAs of GA733 genes by RT-PCR in exfoliated cells of pleural and peritoneal effusions and its clinical values.
To evaluate the diagnostic values of the detection of mRNAs of GA733 gene family in exfoliated cells of pleural and peritoneal effusions. Sixty specimens of pleural and peritoneal fluids from 60 patients were collected. GA733-1 and GA733-2 mRNA in the exfoliated cells were detected by qualitative RT-PCR, and their diagnostic values were assessed. Patients Sixty patients with pleural or peritoneal effusions, from May 2003 and August 2004, aged 23-85 (average 56.5 years). GA733-1 and GA733-2 mRNA were positive in 5 (13.9%) and 27 (75.0%) of 36 malignant specimens, and in 1 and 7 of 11 cause-unknown specimens, respectively, but both of them were negative in all 13 benign specimens, and the difference of GA733-2 mRNA positive rates among the three groups was significant (P<0.005), but that of GA733-1 mRNA was not (P>0.05). GA733-1 and GA733-2 mRNA were positive in 4 (15.4%) and 22 (84.6%) of 26 cytological positive specimens, and in 1 and 6 of 6 suspicious specimens, and in 1 (3.5%) and 6 (21.4%) of 28 negative specimens, respectively and the difference of GA733-2 mRNA positive rates among the three groups was significant (P<0.005), but that of GA733-1 mRNA was not (P>0.05). Sensitivity, specificity and accuracy of detection for GA733-2 mRNA for diagnosis of malignant effusions were 75.0%, 100% and 81.6%, respectively. The detection of GA733-2 mRNA by qualitative RT-PCR is sensitive and highly specific for the diagnosis of malignant pleural and peritoneal effusions, while the diagnostic value of GA733-1 mRNA needs to be further investigated.


Topological insulator in the core of the superconducting vortex in graphene.
The core of the vortex in a general superconducting order parameter in graphene is argued to be ordered, with the possible local order parameters forming the algebra U(1) x Cl(3). A sufficiently strong Zeeman coupling of the magnetic field of the vortex to the electron spin breaks the degeneracy in the core in favor of the anomalous quantum Hall state. I consider a variety of superconducting condensates on the honeycomb lattice and demonstrate the surprising universality of this result. A way to experimentally determine the outcome of the possible competition between different types of orders in the core is proposed.


Association between dietary insulin index and load and psychological disorders.
The present study was carried out to determine whether the dietary insulin index (DII) and dietary insulin load (DIL) are related to psychological disorders in a cross-sectional study among adults. A total of 3172 Iranian adults (age range of 18-55 years) were included. Data on dietary intakes were collected using a validated dish-based 106-item semi-quantitative FFQ. DII and DIL were calculated using food insulin index values published earlier. To assess depression and anxiety, an Iranian validated version of the Hospital Anxiety and Depression Scale was used. Furthermore, psychological distress was examined using the General Health Questionnaire. Among women, a significant positive association was seen; such that women in the highest quartile of DIL had higher odds of depression than those in the lowest quartile (OR 1·84; 95 % CI 1·14, 2·96). In terms of DII, in the fully adjusted model, women in the top quartile of DII were more likely to be depressed compared with those in the bottom quartile (OR 1·65; 95 % CI 1·05, 2·58). In conclusion, we found a significant positive association between DIL and DII and odds of depression among women, but not in men. However, such findings were not seen for anxiety and psychological distress.


Exploring the Potential Molecular Mechanism of Scutellaria baicalensis Georgi in the Treatment of Gastric Cancer Based on Network Pharmacological Analysis and Molecular Docking Technology.
Objective: To explore the molecular mechanism of Scutellaria baicalensis Georgi in treating gastric cancer by network pharmacological analysis and molecular docking. Methods: Taking Scutellaria baicalensis Georgi as the object, the active components and corresponding potential drug targets in Scutellaria baicalensis Georgi were obtained from the database of TCM Pharmacological System Analysis Platform (TCMSP). GeneCards/OMIM/DrugBank and other databases were used to collect gastric cancer-related genes, and the obtained genes were intersected with drug targets to obtain the target genes of Scutellaria baicalensis Georgi on gastric cancer. Furthermore, the interaction network of Scutellaria baicalensis Georgi-active ingredients-target-gastric cancer-related genes was constructed. Protein-protein interaction analysis and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on target genes. The PubChem website was used to screen the compounds corresponding to the target genes, and the target protein and 3D structure pdb format files were obtained from the PDB database. Finally, the molecular docking calculation was performed by the AutoDock Vina program. The in vivo cell experiments on the effect of Scutellaria baicalensis on proliferation and migration of gastric cancer cells were used to determine the therapeutic effect of Scutellaria baicalensis on gastric cancer, and the two genes ESR1 and FOS are the key targets of Scutellaria baicalensis on gastric cancer. Results: A total of 10 gastric cancer-related target genes were screened out, and Scutellaria baicalensis Georgi contained 10 active compounds targeting 10 gene sites. There are 30 effective compounds in Scutellaria baicalensis Georgi targeted to treat gastric cancer, and there are 91 corresponding targeting gene sites, involving a total of 10 pathways. The results of molecular docking show that ESR1, FOS, and Scutellaria baicalensis Georgi have good binding free energy and docking fraction. The docking fraction of FOS is -4.200 and the binding free energy is -27.893 kcal/mol. The docking fraction of ESR1 is -5.833 and the binding free energy is -30.001 kcal/mol. The effect of Scutellaria baicalensis Georgi on gastric cancer was verified by in vitro cell experiments and Western blotting. Conclusion: Scutellaria baicalensis Georgi can target and regulate multiple signal pathways by acting on ESR1 and FOS gene loci, thus having a potential therapeutic effect on gastric cancer.


Roxadustat treatment for erythropoiesis-stimulating agent-hyporesponsive anemia in maintenance hemodialysis patients.
Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is a prevalent problem affecting hemodialysis (HD) patients. Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. We explored the ability of roxadustat to increase the hemoglobin (Hb) concentration in ESA-hyporesponsive patients undergoing HD and assessed its effect on iron metabolism and inflammation. This prospective study included 30 patients with ESA-hyporesponsive anemia who had been undergoing stable dialysis. All patients received roxadustat three times per week for 24 weeks. The primary endpoint was the mean change in Hb from baseline to the average level over weeks 20 to 24. Iron metabolism markers, C-reactive protein, interleukin (IL)-6, and safety were also assessed. At week 24, roxadustat treatment resulted in a 2.5 ± 1.3 g/dL increase in the Hb level. In total, 28 of 30 patients (93.3%) had an Hb level increase of more than 1.0 g/dL from baseline. Seventeen patients (56.7%) met the endpoint, with a mean Hb level of at least 10.0 g/dL. Iron metabolism and IL-6 levels were also improved. Oral roxadustat is effective for ESA-hyporesponsive anemia in maintenance HD patients and may also improve iron metabolism and IL-6 levels.


The Epidemiology of Hand, Foot and Mouth Disease in Asia: A Systematic Review and Analysis.
Hand, foot and mouth disease (HFMD) is a widespread pediatric disease caused primarily by human enterovirus 71 (EV-A71) and Coxsackievirus A16 (CV-A16). This study reports a systematic review of the epidemiology of HFMD in Asia. PubMed, Web of Science and Google Scholar were searched up to December 2014. Two reviewers independently assessed studies for epidemiologic and serologic information about prevalence and incidence of HFMD against predetermined inclusion/exclusion criteria. Two reviewers extracted answers for 8 specific research questions on HFMD epidemiology. The results are checked by 3 others. HFMD is found to be seasonal in temperate Asia with a summer peak and in subtropical Asia with spring and fall peaks, but not in tropical Asia; evidence of a climatic role was identified for temperate Japan. Risk factors for HFMD include hygiene, age, gender and social contacts, but most studies were underpowered to adjust rigorously for confounding variables. Both community-level and school-level transmission have been implicated, but their relative importance for HFMD is inconclusive. Epidemiologic indices are poorly understood: No supporting quantitative evidence was found for the incubation period of EV-A71; the symptomatic rate of EV-A71/Coxsackievirus A16 infection was from 10% to 71% in 4 studies; while the basic reproduction number was between 1.1 and 5.5 in 3 studies. The uncertainty in these estimates inhibits their use for further analysis. Diversity of study designs complicates attempts to identify features of HFMD epidemiology. Knowledge on HFMD remains insufficient to guide interventions such as the incorporation of an EV-A71 vaccine in pediatric vaccination schedules. Research is urgently needed to fill these gaps.


LEC1 sequentially regulates the transcription of genes involved in diverse developmental processes during seed development.
LEAFY COTYLEDON1 (LEC1), an atypical subunit of the nuclear transcription factor Y (NF-Y) CCAAT-binding transcription factor, is a central regulator that controls many aspects of seed development including the maturation phase during which seeds accumulate storage macromolecules and embryos acquire the ability to withstand desiccation. To define the gene networks and developmental processes controlled by LEC1, genes regulated directly by and downstream of LEC1 were identified. We compared the mRNA profiles of wild-type and lec1-null mutant seeds at several stages of development to define genes that are down-regulated or up-regulated by the lec1 mutation. We used ChIP and differential gene-expression analyses in Arabidopsis seedlings overexpressing LEC1 and in developing Arabidopsis and soybean seeds to identify globally the target genes that are transcriptionally regulated by LEC1 in planta Collectively, our results show that LEC1 controls distinct gene sets at different developmental stages, including those that mediate the temporal transition between photosynthesis and chloroplast biogenesis early in seed development and seed maturation late in development. Analyses of enriched DNA sequence motifs that may act as cis-regulatory elements in the promoters of LEC1 target genes suggest that LEC1 may interact with other transcription factors to regulate distinct gene sets at different stages of seed development. Moreover, our results demonstrate strong conservation in the developmental processes and gene networks regulated by LEC1 in two dicotyledonous plants that diverged ∼92 Mya.


Working across the boundaries of health professions disciplines in education, research, and service: the University of Washington experience.
The Institute of Medicine's vision for health professions education specifies working together across professions and schools to provide patient-centered care. Improvement in collaborative preparation of health professionals is seen as central to achieving substantial improvement in the quality of health care. In this article, the authors address one central question: How can medical schools work with other health-sciences schools to promote their educational, research, and service missions? The authors summarize the history of the University of Washington (UW) Health Sciences Center in promoting interprofessional collaboration in education, service and research; analyze the key strategic, structural, cultural and technical elements that have promoted success or served as barriers in the development of the UW Center for Health Sciences Interprofessional Education and Research; and suggest strategies that may be transferable to other institutions seeking to implement an interprofessional health sciences program. These include both top-down and bottom-up authority and function in key working groups, institutional policies such as interprofessional course numbers and shared indirect costs, and development of a culture of interprofessionalism among faculty and students across program boundaries.


Effect of verteporfin photodynamic therapy on endostatin and angiogenesis in human choroidal neovascular membranes.
To evaluate the effect of verteporfin photodynamic therapy (PDT) on endostatin with regard to expression of vascular endothelial growth factor (VEGF) in human choroidal neovascular membranes (CNVs) secondary to age-related macular degeneration. A retrospective review of an interventional case series of 68 patients who underwent removal of CNV. 29 patients were treated with PDT 3-655 days before surgery. 39 CNVs without previous treatment were used as controls. CNVs were stained for CD34, CD105, Ki-67, cytokeratin 18, endostatin, E-selectin and VEGF. "Predominance score of VEGF over endostatin" (mean) was defined as the difference between VEGF and endostatin staining scores. In four CNVs treated by PDT 3 days previously, PS was significantly higher in the retinal pigment epithelium (mean = 2.5, p = 0.006) and stroma (mean = 2, p = 0.015) than in the control group (mean = 0). At longer post-PDT intervals, PS was significantly decreased in the retinal pigment epithelium (mean = 0, p = 0.019) and stroma (mean = 0, p = 0.015). Proliferative activity was high (p = 0.023), but mostly related to inflammatory cells. PDT did not influence E-selectin expression significantly. VEGF predominance over endostatin early after PDT might contribute to enhanced angiogenic activity associated with recurrences. Strategies upregulating or replacing endostatin early after PDT might increase the effectiveness of PDT.


Drivers of Healthcare Costs Among the Costliest Patients With Psoriasis Over Three Years in a United States Health Plan.

OBJECTIVE: To compare patients with psoriasis by cost level over 3 years.

METHODS: Psoriasis patients in a large US health plan in 2011-2013 were identified. Four groups were created by healthcare costs excluding biologics: patients having top 10% of costs in all 3 years (Top), top 10% in 2 of 3 years (High), bottom 90% in 2 of 3 years (Medium), and bottom 90% in all 3 years (Bottom). Comorbidities, utilization, and costs between groups were compared.

RESULTS: The study included 18,653 patients: 514 (3%), 805 (4%), 2,443 (13%), and 14,891 (80%) patients in the Top, High, Medium, and Bottom groups, respectively. Significantly more patients in the Top vs Bottom group had diabetes (31.1% vs 9.4%), cardiovascular disease (26.5% vs 4.3%), psoriatic arthritis (25.7% vs 10.7%), depression (27.8% vs 6.9%), and anxiety (22.0% vs 7.9%) in 2011 (all P less than 0.05). Patients in the Top group had more unique 2011 prescriptions (17.7 vs 6.6; P less than 0.001) than the Bottom group, but similar biologic use (22.4% vs 21.6%). Patients in the Top, High, Medium, and Bottom groups had mean 2011 total costs of $68,913, $40,575, $24,292, and $8,815, and contributed to 14%, 13%, 23%, and 51% of the overall costs, respectively. Mean total costs increased 14-18% over time for all groups. Although mean 2011 total costs for patients in the Top group were 7.8 times of those in the Bottom group, psoriasis-related costs were less disparate ($8,716 vs $4,541). Compared with patients in the Bottom group, those in the Top group were more likely to have any 2011 hospitalization (36.8% vs 2.6%; psoriasis-related: 11.1% vs 0.7%) or emergency visit (50.8% vs 20.8%; psoriasis-related: 3.9% vs 1.0%).

CONCLUSION: The costliest patients with psoriasis had significantly higher prevalence of comorbidities, prescription fills, inpatient and emergency utilization, but not biologic medication use or biologic costs.

J Drugs Dermatol. 2017;16(7):651-658.
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Patient Perceptions on Data Sharing and Applying Artificial Intelligence to Health Care Data: Cross-sectional Survey.
Considerable research is being conducted as to how artificial intelligence (AI) can be effectively applied to health care. However, for the successful implementation of AI, large amounts of health data are required for training and testing algorithms. As such, there is a need to understand the perspectives and viewpoints of patients regarding the use of their health data in AI research. We surveyed a large sample of patients for identifying current awareness regarding health data research, and for obtaining their opinions and views on data sharing for AI research purposes, and on the use of AI technology on health care data. A cross-sectional survey with patients was conducted at a large multisite teaching hospital in the United Kingdom. Data were collected on patient and public views about sharing health data for research and the use of AI on health data. A total of 408 participants completed the survey. The respondents had generally low levels of prior knowledge about AI. Most were comfortable with sharing health data with the National Health Service (NHS) (318/408, 77.9%) or universities (268/408, 65.7%), but far fewer with commercial organizations such as technology companies (108/408, 26.4%). The majority endorsed AI research on health care data (357/408, 87.4%) and health care imaging (353/408, 86.4%) in a university setting, provided that concerns about privacy, reidentification of anonymized health care data, and consent processes were addressed. There were significant variations in the patient perceptions, levels of support, and understanding of health data research and AI. Greater public engagement levels and debates are necessary to ensure the acceptability of AI research and its successful integration into clinical practice in future.


Substitution of H Atoms in Unsaturated (Vinyl-Type) Carbocations by Cl or O Atoms.
Introduction of Cl and O atoms into C4-vinyl carbocations was studied by X-ray diffraction analysis and IR spectroscopy. Chlorine atoms are weak electron acceptors in ordinary molecules but, within vinyl carbocations, manifest themselves as strong electron donors that accept a positive charge. The attachment of a Cl atom directly to a C=C bond leads to an increase in the e-density on it, exceeding that of the common double bond. The positive charge should be concentrated on the Cl atom, and weak δ- may appear on the C=C bond. More distant attachment of the Cl atom, e.g., to a C atom adjacent to the C=C bond, has a weaker effect on it. If two Cl atoms are attached to the Cγ atom of the vinyl cation, as in Cl2CγCδHCαHCH3, then the cation switches to the allyl type with two practically equivalent and almost uncharged CγCδCα bonds. When such a strong nucleophile as the O atom is introduced into the carbocation, a protonated ester molecule with a C-O(H+)-C group and a C=C bond forms. Nonetheless, in the future, there is still a possibility of obtaining carbocations with a non-protonated C-O-C group.


Role of Global Longitudinal Strain in Predicting Outcomes in Hypertrophic Cardiomyopathy.
Global longitudinal strain (GLS) is a sensitive indicator of global left ventricular function particularly in those with normal ejection fraction. We examined the potential value of GLS in predicting outcomes in hypertrophic cardiomyopathy (HC). Conventional and strain echocardiography was performed in 400 patients with HC followed for a median 3.1 years (interquartile range 1.2 to 5.6). Peak systolic strain from 3 apical views was averaged to calculate GLS. Patients were divided based on a previously published cutoff value of -16%. Additionally, we identified 4 HC subgroups based on GLS: GLS ≤ -20%, -20% < GLS ≤ -16%, -16% < GLS ≤ -10%, and GLS > -10%. The primary end point was a composite of new-onset sustained ventricular tachycardia/fibrillation, heart failure, cardiac transplantation, and all-cause death. Patients with GLS > -16% had significantly more events (17% vs 7%, p = 0.002). In the 4-group analysis, event rates increased with worsening GLS (5%, 7%, 14%, and 33%, respectively, p = 0.001). Event-free survival was significantly superior in those with GLS ≤ -16% versus GLS > -16% (p = 0.004); similarly, GLS > -10% portended a significantly worse event-free survival compared with each of the other 3 groups (p <0.01 for all pairwise comparisons). By univariate and multivariate Cox regression analysis, GLS remained significantly associated with the composite end point. GLS > -10% had 4 times the risk of events compared with GLS ≤ -16% (p = 0.006). In conclusion, echo-based GLS is independently associated with outcomes in HC. Patients with GLS > -10% have significantly higher event rates.


Electrophysiology and metallosis: support for an oxidative (free radical) mechanism in the human eye.
Nine cases of metal intraocular foreign body are presented. This study investigates the use of electrodiagnostic techniques in the diagnosis of metallosis and as a prognostic indicator. The electro-oculogram (EOG) and the electoretinogram (ERG) indicate that there are two mechanisms of metallosis, one of which involves cytotoxic damage by siderosomes, and the other lipid peroxidation of photoreceptor outer segments and retinal pigment epithelium. The evidence suggests that the location of the foreign body in the eye determines whether either or both of these mechanisms occur. We propose that these tests can help the ophthalmologist decide when a foreign body has to be removed and give information as to the mechanism of the pathological process.


Electron interaction with phosphate cytidine oligomer dCpdC: base-centered radical anions and their electronic spectra.
Computational chemistry approach was applied to explore the nature of electron attachment to cytosine-rich DNA single strands. An oligomer dinucleoside phosphate deoxycytidylyl-3',5'-deoxycytidine (dCpdC) was selected as a model system for investigations by density functional theory. Electron distribution patterns for the radical anions of dCpdC in aqueous solution were explored. The excess electron may reside on the nucleobase at the 5' position (dC(•-)pdC) or at the 3' position (dCpdC(•-)). From comparison with electron attachment to the cytosine related DNA fragments, the electron affinity for the formation of the cytosine-centered radical anion in DNA is estimated to be around 2.2 eV. Electron attachment to cytosine sites in DNA single strands might cause perturbations of local structural characteristics. Visible absorption spectroscopy may be applied to validate computational results and determine experimentally the existence of the base-centered radical anion. The time-dependent DFT study shows the absorption around 550-600 nm for the cytosine-centered radical anions of DNA oligomers. This indicates that if such species are detected experimentally they would be characterized by a distinctive color.


Extracapsular spread in ipsilateral neck and contralateral neck metastases in laryngeal cancer.
We investigated the incidence of extracapsular spread (ECS) and the impact of ECS on contralateral neck metastasis in 67 patients with ipsilateral nodal metastasis (IpN+) whose records were extracted retrospectively from those of 155 laryngeal cancer patients. The incidence of ECS in association with variables was determined: T stage, N stage, tumor location, tumor extension, number of positive nodes, and contralateral neck status. The variables were evaluated to identify their impact on the rates of contralateral neck metastasis (CNM) and 3-year survival. Of the 67 patients, 30 (44.7%) had ECS. A significant relationship was found between ECS positivity and increased N stage, tumor extension up to the midline, number of positive nodes, and CNM (p = .04, p = .0001, p = .018, p = .0001, respectively). Multivariate analysis revealed that N stage (p = .002; odds ratio, 3.5517) and the presence of ECS (p = .0036; odds ratio, 7.7840) in IpN+ were associated with the greatest risk of CNM. The 3-year survival rate of patients with ipsilateral ECS was significantly lower than that of patients without ECS (43% versus 81%, p = .0002). Both CNM and presence of ECS in IpN+ emerged as significant independent predictors for survival with Cox multivariate analysis (p = .0086 and p = .0234, respectively). This result indicates the necessity of treating the contralateral N0 neck in cases of IpN+ with ECS.


Sylvatic rabies epidemic in Italy: implementation of a data management system to assess the level of application of preventive dog vaccination.
After 20 years of absence, rabies re-emerged in wild animals in north-eastern Italy in October 2008. Besides measures undertaken to fight the spread of infection in wildlife, vaccination against rabies was made compulsory for dogs living in the risk area. In the last 15 years, the veterinary authorities have focused on implementing computerized data collection systems in animal health, to serve as working tools for epidemiological surveillance activities and emergencies management. The prerequisite for implementing any data collection system is knowledge of the animal population. This also applies to the Canine Registry Data Bank, in which data on dogs and their movements, together with personal data on each owner and keeper, have been stored since 2003. The management information system has been updated and specific functions have been integrated in order to support the activity of both the veterinary services and the veterinary practitioners involved in the dog vaccination program. Vaccination became voluntary in February 2013. This paper describes implementation of the software and organization of data gathering, highlighting the benefits of computerized data compared to previously used paper-based data collection systems. The new functions, designed to centralize collection of uniform, updated vaccination data, have led to more efficient organization and better control of the vaccination plan. Automated information processing allowed vaccination operations to be supervised, incurred costs to be calculated, and vaccination coverage of the dog population to be monitored during the 3 years of compulsory vaccination.