Impact of the Herbal Breviscapine on the Pharmacokinetics of Simvastatin in Rats: The Involvement of CYP3A4.
The effect of breviscapine injection on the pharmacokinetics of simvastatin and the mRNA expression of hepatic cytochrome P450 (CYP) enzyme was investigated with rats. The rats were pretreated for 8 consecutive days with breviscapine injection (20 mg/kg/day, i. v.), followed by administration of simvastatin through gavage (40 mg/kg). The control rats received the corresponding volume of saline solution for the pretreatment. Blood samples were collected at varied time points after simvastatin administration and the liver was harvested after the last collection of the blood sample for measurement of the CYP3A4 mRNA expression. Pre-treatment with breviscapine injection led to increased plasma concentration of simvastatin, showing 57% increase for AUC0-∞ (P<0.01), 31% increase for C max (P<0.01), and 36% decrease for the total plasma clearance, compared with the control. Pre-treatment with breviscapine injection also inhibited the mRNA expression of the hepatic CYP3A4. These findings indicate that pre-treatment with breviscapine injection could increase the plasma concentration of simvastatin, possibly by inhibiting the expression of the hepatic CYP3A4, and combined use of breviscapine with simvastatin may improve the simvastatin efficacy and reduce its adverse reactions through reduced its dosage.


The effect of eflornithine 13.9% cream on the bother and discomfort due to hirsutism.
Although unwanted facial hair often leads to anxiety and avoidance of social situations, evaluation of treatment outcomes in clinical trials has relied largely on measures external to the patient such as the extent of hair growth or an expert physician's assessment, neglecting to include patient reported outcomes (PRO). To assess the level of bother caused by a dermatological condition (hirsutism) and changes brought on by treatment, the instrument ESTEEM was developed by expanding the Bother Assessment in Skin Conditions (BASC) scale to six questions to cover the discomfort felt in four social situations and bother due to removing facial hair. Each question elicits responses on a visual analog scale. Women participating in two randomized clinical trials evaluated a new treatment (eflornithine 13.9% cream). Analyses examined the level of bother at each visit, the changes with treatment, the correlations with the Physician's Global Assessment, and the effect size. Hirsutism bothers patients considerably. The mean for overall bother was 89% and the mean discomfort in social situations exceeded 80% in nearly all cases. Treatment led to significant reductions in bother on all six items with effect sizes ranging from 0.46 to 1.62. Eflornithine is an effective treatment for unwanted facial hair in women, as reported by the patients. ESTEEM addresses the specific concerns of women with hirsutism.


Functional correlates of compensatory renal hypertrophy.
The functional correlates of compensatory renal hypertrophy were studied by micropuncture techniques in rats after the removal of one kidney. The glomerular filtration rate increased to roughly the same extent in the whole kidney and in individual surface nephrons, resulting in a greater amount of sodium delivered to the tubules for reabsorption. The fraction of the glomerular filtrate absorbed [determined from the tubular fluid-to-plasma ratio (TF/P) for inulin] remained unchanged in both proximal and distal portions of the nephron. The way in which the tubules adjusted to nephrectomy, however, differed in proximal and distal convolutions. After nephrectomy, the reabsorptive half-time, indicated by the rate of shrinkage of a droplet of saline in a tubule blocked with oil, was unchanged in the proximal tubule but significantly shortened in the distal convoluted tubule. Nevertheless, steady-state concentrations of sodium in an isolated raffinose droplet in the distal as well as the proximal tubule were the same in hypertrophied kidneys as in control animals. Possible reasons for this paradox are discussed. Transit time through the proximal tubules was unchanged by compensatory hypertrophy, but transit time to the distal tubules was prolonged. Changes in renal structure resulting from compensatory hypertrophy were also found to differ in the proximal and the distal protions of the nephron. Although tubular volume increased in both protions, the volume increase was twice as great in the proximal tubule as in the distal. In order, therefore, for net reabsorption to increase in the distal tubule, where the changes in tubular volume are not so marked, an increase in reabsorptive capacity per unit length of tubule is required. This increase is reflected in the shortening of reabsorptive half-time in the oil-blocked distal tubule that was actually observed.


Synergism of diethylstilbestrol and other carcinogens in concurrent development of hepatic, mammary, and pituitary tumors in castrated male rats.
Castrated male WF rats, given implants of pellets containing 5.0 mg diethylstilbestrol (DES), were given N-butyl-N-nitrosourea (NBU) in small amounts, which alone produced no mammary tumors in intact female rats. Treatment resulted in the high yield of hepatic tumors (HT), mammary tumors (MT), and pituitary tumors (PT) concurrently in each rat. If animals were further treated with prolactin, the development of HT and MT was accelerated, whereas that of PT was suppressed. None of the intact or castrated rats receiving NBU and/or prolactin developed tumors in any tissues if DES treatment was omitted. Exposure of male rats, preconditioned similarly to NBU treatment, to 200 rads of 14.1-MeV fast-neutron radiation also elicited HT, MT, and PT with an efficiency comparable to that of NBU-treated rats. These findings indicate that DES played an essential role in the whole carcinogenic process in each tissue and that castrated male rats, if conditioned properly with estrogens, are useful for the study of the carcinogenesis mechanism in these tissues.


Laypeople's perceptions of the effects of event repetition, reporting delay, and emotion on children's and adults' memory.
For crimes such as child abuse and family violence, jurors' assessments of memory reports from key witnesses are vital to case outcomes in court. Since jurors are not experts on memory, the present research measured laypeople's (i.e., non-experts') beliefs about how three key factors affect witnesses' memory reports for an experienced event: how frequently an event was experienced (repeated, single), the delay between experiencing and reporting the event, and the emotional valence of the event. Across two studies, lay participants completed an online survey that measured their beliefs about each factor. In Study 1, 51 participants completed a survey about how the three factors affect children's memory. In Study 2, another 51 participants completed a survey about how the three factors affect adult's memory. Across both studies, delays were believed to worsen memory, and emotion was believed to improve memory. Beliefs about single and repeated events showed different patterns across the studies. In Study 1, participants' beliefs about children's memory for repeated experience were variable. In Study 2, participants believed that adults' memory was worse for repeated events than single events. Overall, laypeople demonstrated many accurate beliefs about memory, but showed some confusion about children's memory for repeated events.


The accuracy of restoration of femoral head centre of rotation in the anteroposterior plane after uncemented total hip arthroplasty : a CT-based study.
Hip arthroplasty aims to accurately recreate joint biomechanics. Considerable attention has been paid to vertical and horizontal offset, but femoral head centre in the anteroposterior (AP) plane has received little attention. This study investigates the accuracy of restoration of joint centre of rotation in the AP plane. Postoperative CT scans of 40 patients who underwent unilateral uncemented total hip arthroplasty were analyzed. Anteroposterior offset (APO) and femoral anteversion were measured on both the operated and non-operated sides. Sagittal tilt of the femoral stem was also measured. APO measured on axial slices was defined as the perpendicular distance between a line drawn from the anterior most point of the proximal femur (anterior reference line) to the centre of the femoral head. The anterior reference line was made parallel to the posterior condylar axis of the knee to correct for rotation. Overall, 26/40 hips had a centre of rotation displaced posteriorly compared to the contralateral hip, increasing to 33/40 once corrected for sagittal tilt, with a mean posterior displacement of 7 mm. Linear regression analysis indicated that stem anteversion needed to be increased by 10.8° to recreate the head centre in the AP plane. Merely matching the native version would result in a 12 mm posterior displacement. This study demonstrates the significant incidence of posterior displacement of the head centre in uncemented hip arthroplasty. Effects of such displacement include a reduction in impingement free range of motion, potential alterations in muscle force vectors and lever arms, and impaired proprioception due to muscle fibre reorientation. Cite this article: Bone Joint Res 2022;11(3):180-188.


Identification of morin as an agonist of imidazoline I-3 receptor for insulin secretion in diabetic rats.
Morin is a flavonoid contained in guava that is known to reduce hyperglycemia in diabetics. Morin has been demonstrated to increase plasma insulin. However, the mechanism(s) remains unknown. The present study is designed to investigate the effect of morin on the imidazoline receptor (I-R) that regulates insulin secretion. We used Chinese hamster ovary (CHO) cells transfected with an I-R expression construct (NISCH-CHO-K1 cells) to identify the direct effect of morin on the I-R. Moreover, the imidazoline I3 receptor (I-3R) is known to be present in pancreatic β cells and involved in insulin secretion. Therefore, we applied a specific antagonist (KU14R) to block I-3R in diabetic rats. Additionally, the effect of morin on insulin secretion was characterized in isolated pancreatic islets. Morin decreased blood glucose levels by increasing plasma insulin levels in diabetic rats. In CHO cells expressing an I-R, morin increased calcium influx in a dose-dependent manner. Additionally, KU14R dose-dependently inhibited the morin-induced effects, including hypoglycemia and the increase in insulin secretion and plasma C-peptide levels, in diabetic rats. Furthermore, morin enhanced insulin secretion from isolated pancreatic islets, and this effect was also dose-dependently inhibited by KU14R. Phospholipase C (PLC) is known to couple with the I-R, and a PLC inhibitor dose-dependently attenuated the insulin secretion induced by morin in isolated pancreatic islets. Taken together, these data suggest that morin can activate I-3R to enhance insulin secretion. Therefore, it would be useful to develop morin into a treatment for diabetic disorders.


Big Data Analytics in Chemical Engineering.
Big data analytics is the journey to turn data into insights for more informed business and operational decisions. As the chemical engineering community is collecting more data (volume) from different sources (variety), this journey becomes more challenging in terms of using the right data and the right tools (analytics) to make the right decisions in real time (velocity). This article highlights recent big data advancements in five industries, including chemicals, energy, semiconductors, pharmaceuticals, and food, and then discusses technical, platform, and culture challenges. To reach the next milestone in multiplying successes to the enterprise level, government, academia, and industry need to collaboratively focus on workforce development and innovation.


High hydrostatic pressure-induced cell death in human chondrocytes and chondrosarcoma cells.
In orthopedic surgery, sterilization of bone used for reconstruction of osteoarticular defects caused by malignant tumors is carried out in different ways. At present, to devitalize tumor-bearing osteochondral segments, extracorporal irradiation or autoclaving is mainly used, although both methods have substantial disadvantages, e.g. loss of biomechanical and/or biological integrity of the bone and destabilization of the articular surface. In this regard, high hydrostatic pressure (HHP) treatment of bone is a new, advancing technology, now being used in preclinical testing to inactivate tumor cells. To find out if this technique is also suited for extracorporal inactivation of chondrocytes and chondral tumor cells, the effect of HHP on cell viability and morphology of human chondrocytes / chondrosarcoma cells was investigated in the present study. SW1353 chondrosarcoma cells and chondrocytes were subjected to HHP in the range of 50 to 350 MPa (10 min, 37 degrees C) and, subsequently, cell viability and cell morphology assessed. After exposure at 350 MPa, all HHP-treated chondral cells showed explicit morphological changes, evident by membrane ruffling and bleb formation; chondrosarcoma cells treated this way were irreversibly damaged and not alive. We anticipate that, in orthopedic surgery, HHP eventually can serve as a novel, promising technical approach for cell inactivation (including tumor cells) and allow subsequent reimplantation of the osteoarticular autograft.


Nanoimprint-Transfer-Patterned Solids Enhance Light Absorption in Colloidal Quantum Dot Solar Cells.
Colloidal quantum dot (CQD) materials are of interest in thin-film solar cells due to their size-tunable bandgap and low-cost solution-processing. However, CQD solar cells suffer from inefficient charge extraction over the film thicknesses required for complete absorption of solar light. Here we show a new strategy to enhance light absorption in CQD solar cells by nanostructuring the CQD film itself at the back interface. We use two-dimensional finite-difference time-domain (FDTD) simulations to study quantitatively the light absorption enhancement in nanostructured back interfaces in CQD solar cells. We implement this experimentally by demonstrating a nanoimprint-transfer-patterning (NTP) process for the fabrication of nanostructured CQD solids with highly ordered patterns. We show that this approach enables a boost in the power conversion efficiency in CQD solar cells primarily due to an increase in short-circuit current density as a result of enhanced absorption through light-trapping.


Induction of pulmonary edema and emphysema in goats by intraruminal administration of 3-methylindole.
The effects of intraruminal administration of 3-methylindole (3MI; skatole) were determined in goats. The 3MI was given to 4 goats at the dose level of 0.3 g/kg of body weight, to 2 goats at 0.2 g/kg, and to 2 goats at 0.1 g/kg; 3 nontreated goats were used as controls. Clinical signs of acute progressive respiratory tract disease were seen in all treated goats. Goats given the largest dose of 3MI (0.3 g/kg) died between 5 and 11 hours after treatment; those given smaller doses (0.2 and 0.1 g/kg) died between 79 and 92 hours. Increased plasma concentrations of 3MI were detected in goats give 0.1 or 0.2 g/kg within 3 hours after administration. By 24 and 36 hours, the concentrations of 3MI in the plasma decreased to low or nondetectable amounts and remained low for the duration of the experiment. Clinical signs of respiratory distress in the goats progressed after 3MI had been cleared from the plasma. Diffuse pulmonary edema and hydrothorax were extensive in goats which died early in the course of the experimentally induced disease. In goats which died at later stages, the lungs were firm and had less watery transudate. Temporal variations in the nature of pulmonic changes were even more obvious by microscopic examination. Diffuse pulmonary edema was the predominant early change. Small foci of emphysema were apparently caused by overdistention of some clusters of alveoli. Marked septal thickening and proliferation of alveolar cells were the prominent changes in goats which died between 79 and 92 hours after treatment. Incubation of L-tryptophan with caprine ruminal fluid resulted in formation of indoleacetic acid, indole, and 3MI. Similar incubations did not convert indoleacetic acid to 3MI. Control incubations showed 3MI as a fermentation metabolite, indicating it exists in caprine ruminal fluid in vivo. Results demonstrated that goats are susceptible to intraruminal administration of 3MI. The transitory appearance of 3MI in the plasma associated with progressive respiratory tract disease was similar to observations in cattle give 3MI. Clinical signs and lesions seen at necropsy were qualitatively similar to those reported in cattle given tryptophan and indoleacetic acid.


Validation of the influence of biosignals on performance of machine learning algorithms for sleep stage classification.
Sleep stage identification is critical in multiple areas (e.g. medicine or psychology) to diagnose sleep-related disorders. Previous studies have reported that the performance of machine learning algorithms can be changed depending on the biosignals and feature-extraction processes in sleep stage classification. To compare as many conditions as possible, 414 experimental conditions were applied, considering the combination of different biosignals, biosignal length, and window length. Five biosignals in polysomnography (i.e. electrocardiogram (ECG), electroencephalogram (EEG), electromyogram (EMG), electrooculogram left, and electrooculogram right) were used to identify optimal signal combinations for classification. In addition, three different signal-length conditions and six different window-length conditions were applied. The validity of each condition was examined via classification performance from the XGBoost classifiers trained using 10-fold cross-validation. Furthermore, results considering feature importance were examined to validate the experimental results in terms of model explanation. The combination of EEG + EMG + ECG with a 40 s window and 120 s signal length resulted in the best classification performance (precision: 0.853, recall: 0.855, F1-score: 0.853, and accuracy: 0.853). Compared to other conditions and feature importance results, EEG signals showed a relatively higher importance for classification in the present study. We determined the optimal biosignal and window conditions for the feature-extraction process in machine learning algorithm-based sleep stage classification. Our experimental results inform researchers in the future conduct of related studies. To generalize our results, more diverse methodologies and conditions should be applied in future studies.


Experiential acceptance and trait-mindfulness as predictors of analogue post-traumatic stress.
Experiential acceptance and trait-mindfulness are associated with post-traumatic stress disorder (PTSD) after traumatic events. This study was a preliminary attempt to examine (1) associations of experiential acceptance and trait-mindfulness with post-traumatic stress (PTS) associated with negative, but not necessarily traumatizing, life events ('analogue' PTS), (2) the role of these variables in the context of neuroticism as well as worry and rumination - two other regulatory strategies associated with PTS, and (3) the impact of pre-trauma tendencies towards experiential acceptance and mindfulness on analogue PTS. Data were obtained from two distinct student samples. A first sample provided cross-sectional data. In a second sample, indices of acceptance, mindfulness, neuroticism, worry, and rumination were tapped at inclusion into the study, and analogue PTS and confrontation with stressful life events were subsequently assessed 1 year later. In the cross-sectional sample, higher acceptance and mindfulness were associated with lower analogue PTS, even when controlling for neuroticism, worry, and rumination. In the prospective sample, pre-trauma mindfulness (but not experiential acceptance, neuroticism, worry, and rumination) assessed at baseline predicted levels of analogue PTS 1 year later. Findings suggest that experiential acceptance and trait-mindfulness are incrementally related to PTS beyond neuroticism, worry, and rumination and that pre-trauma trait-mindfulness may be a resilience factor protecting against severe PTS. We examined associations of experiential acceptance and trait-mindfulness with post-traumatic stress (PTS) associated with negative life events ('analogue' PTS). Experiential acceptance and trait-mindfulness were associated with concurrent analogue PTS, over and above neuroticism, worry, and rumination. Pre-trauma trait-mindfulness (but not pre-trauma experiential acceptance) significantly predicted analogue PTS in prospective analyses. Enhancing mindfulness skills could be a useful tool to reduce the risk of PTS in trauma-exposed samples.


Duplex-Doppler ultrasonography in monitoring clinical pancreas transplantation.
The findings are reported that were obtained with duplex-Doppler ultrasonography (US) in seven diabetic patients who underwent pancreatic grafting with pancreaticocystostomy. Five normal functioning grafts showed homogenous echostructure and pulsed Doppler spectrum characteristics of low impedance vascular beds. Four of these patients developed graft rejection (five episodes). The remaining two grafts had pulsed Doppler evidence of venous thrombosis. It was not possible to differentiate graft rejection from venous thrombosis using real-time US. In both circumstances a heterogeneous pancreatic echostructure with a small amount of peripancreatic fluid and an increase in pancreas size were observed. Pulsed Doppler, however, showed absence of venous flow in both cases of venous thrombosis whereas all rejection episodes were characterized by an increase in arterial impedance. We conclude that duplex-Doppler US is a promising noninvasive method of detecting surgical complications and graft rejection in pancreatic transplant recipients.


Role of MRI in Evaluation of Malignant Lesions of Tongue and Oral Cavity.
Aim of the present study was to evaluate the role of MRI in staging of malignant lesions of the oral cavity and to correlate MRI findings with clinical/surgical and anatomical-pathological findings, wherever possible. The study included 50 patients who presented with malignant lesions of the oral cavity and were referred to radiology departments for MRI. All patients included were subjected to a detailed physical examination following which MRI was carried out on Philips Gyroscan Achieva 1.5 Tesla unit. In the study, the highest number of patients were found to have tongue malignancy (82%) followed by buccal mucosa and gingivobuccal sulcus malignancy (18%). The highest number of patients was in the age group of 51-60 years (32%). The incidence was higher in males (96%). There was moderate agreement (k=0.537) for T stage between the clinical and MRI staging assessments. The agreement for N stage between clinical and MRI staging assessments was fair (k=0.328). The final diagnosis was made by histopathology in 22 patients. The agreement for T stage was good/substantial (k=0.790) and for N stage was moderate (k=0.458) between MRI and histopathology staging assessments. MRI provides satisfactory accuracy for preoperative estimation of tumor thickness and predicting occult cervical nodal metastasis. MRI is the preferred modality in evaluation and staging of oral cavity malignancy which helps a clinician for planning of treatment.


[Armed conflict and access to emergency treatment in the occupied West Bank of Palestine--secondary publication].
Research on the health consequences of armed conflicts is still in its infancy. Systematic medical data collection among emergency department contacts at three hospitals in the occupied West Bank of Palestine showed that patients delayed by the Israeli occupation were more likely to be admitted to hospital than other patients. The occupation of Palestine has resulted in severe restriction to the civil population's freedom of movement that influences access to health care, among a number of other serious problems. This presents a serious violation of the Geneva Conventions.


Expression, purification and catalytic activity of Lupinus luteus asparagine beta-amidohydrolase and its Escherichia coli homolog.
We describe the expression, purification, and biochemical characterization of two homologous enzymes, with amidohydrolase activities, of plant (Lupinus luteus potassium-independent asparaginase, LlA) and bacterial (Escherichia coli, ybiK/spt/iaaA gene product, EcAIII) origin. Both enzymes were expressed in E. coli cells, with (LlA) or without (EcAIII) a His-tag sequence. The proteins were purified, yielding 6 or 30 mg.L(-1) of culture, respectively. The enzymes are heat-stable up to 60 degrees C and show both isoaspartyl dipeptidase and l-asparaginase activities. Kinetic parameters for both enzymatic reactions have been determined, showing that the isoaspartyl peptidase activity is the dominating one. Despite sequence similarity to aspartylglucosaminidases, no aspartylglucosaminidase activity could be detected. Phylogenetic analysis demonstrated the relationship of these proteins to other asparaginases and aspartylglucosaminidases and suggested their classification as N-terminal nucleophile hydrolases. This is consistent with the observed autocatalytic breakdown of the immature proteins into two subunits, with liberation of an N-terminal threonine as a potential catalytic residue.


Exposure to Phlebotomus perniciosus sandfly vectors is positively associated with Toscana virus and Leishmania infantum infection in human blood donors in Murcia Region, southeast Spain.
Antibodies against Phlebotomus perniciosus sandfly salivary gland homogenate (SGH) and recombinant protein rSP03B, sandfly-borne Toscana virus (TOSV), Sandfly Fever Sicilian virus (SFSV) and Leishmania, as well as DNA of the latter parasite, were investigated in 670 blood samples from 575 human donors in Murcia Region, southeast Spain, in 2017 and 2018. The estimated SGH and rSP03B seroprevalences were 69% and 88%, respectively, although correlation between test results was relatively low (ρ = 0.39). Similarly, TOSV, SFSV and Leishmania seroprevalences were 26%, 0% and 1%, respectively, and Leishmania PCR prevalence was 2%. Prevalences were significantly greater in 2017, overdispersed and not spatially related to each other although both were positively associated with SGH but not to rSP03B antibody optical densities, questioning the value of the latter as a diagnostic marker for these infections in humans.


STM imaging of electronic waves on the surface of Bi2Te3: topologically protected surface states and hexagonal warping effects.
Scanning tunneling spectroscopy studies on high-quality Bi2Te3 crystals exhibit perfect correspondence to angle-resolved photoemission spectroscopy data, hence enabling identification of different regimes measured in the local density of states (LDOS). Oscillations of LDOS near a step are analyzed. Within the main part of the surface band oscillations are strongly damped, supporting the hypothesis of topological protection. At higher energies, as the surface band becomes concave, oscillations appear, dispersing with a wave vector that may result from a hexagonal warping term.


[Numerical and structural anomalies of chromosome no. 18 (author's transl)].
Two newborn babies with trisomy 18 and one with a deletion of the short arm of chromosome 18 (Syndrome 18p-) were admitted within 3 months to the Westfälische Landeskinderklinik Bochum. Under this aspect the clinical appearance of numerical and structural anomalies of chromosome 18 is described. Clinical symptomatiology which is rather typical for Trisomy 18 (Edwards syndrome) so that a diagnosis may be made in many instances even before the result of chromosomal analysis is available is compared with the facts given in the literature. The 83 cases of syndrome 18p- published so far are presented in a table. The absolute frequency compared with conceptional age of the mother gives a 2 peak distribution curve with one maximum between 25 and 29 years and one between 40 and 45 years. Similar patterns indicating two different ways of pathogenesis were described for trisomy 18 and 21. Furthermore patients suffering from syndrome 18p- show an increased incidence of IgA deficiency, which is 1:2 compared to 1:500 to 1:700 in an unselected population.


[Diabetes mellitus].
Diabetes mellitus is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Diabetes is a serious health concern. The number of cases of diabetes mellitus is estimated to grow at a rate of 50% between 2000 and 2010. There are several types of diabetes: type 1 diabetes, type 2 diabetes, gestational diabetes, and other specific types of diabetes. Beta cell dysfunction plays a key role in the physiopathology of diabetes, even when insulin resistance, which is often present in several diabetes-related diseases, is considered among the causes of hyperglycemic type 2 diabetes. The prolonged hyperglycemia that is peculiar to all kind of diabetes has long term complications on several organs and systems. The diagnosis of diabetes is based on the evaluation of glucose plasma levels performed under fasting conditions or two hours after the oral ingestion of 75 grams of glucose. Currently, achieving and maintaining normal plasma levels of glucose are the aims of therapy for both type 1 and type 2 diabetes. Particularly, the therapy for type 1 diabetes is based on the administration of insulin, whereas that of type 2 diabetes changes over the time: diet and physical activity are the first treatments; oral hypoglycemic drugs are used as a second therapeutic step; and the administration of insulin is the last therapeutic option. The principal therapeutic innovation of the past ten years is represented by the tight and flexible control of glucose plasma level obtained by using the insulin analogues produced by recombinant DNA technology.


Applying cultural safety beyond Indigenous contexts: Insights from health research with Amish and Low German Mennonites.
People who identify as members of religious communities, such as the Amish and Low German Mennonites, face challenges obtaining quality health care and engagement in research due in part to stereotypes that are conveyed through media and popular discourses. There is also a growing concern that even when these groups are engaged in research, the guiding frameworks of the research fail to consider the sociocultural or historical relations of power, further skewing power imbalances inherent in the research relationship. This paper aims at discussing the uses of cultural safety in the context of health research and knowledge translation with groups of people that are associated with a specific religion. Research with the Amish and Low German Mennonites is provided as examples to illustrate the use of cultural safety in this context. From these examples, we discuss how the use of cultural safety, grounded in critical theoretical perspectives, offers new insight into health research with populations that are traditionally labeled as minority, vulnerable, or marginalized, especially when a dominant characteristic is a unique religious perspective.


Treatment goals for moderate to severe psoriasis: an Australian consensus.
The high incidence of comorbidities in patients with psoriasis, significant impact on quality of life and patients' dissatisfaction with treatment led a European group to develop a consensus position on psoriasis treatment goals. There is an evident need for similar treatment goals in Australia. The aim of this project was to develop Australian treatment goals that reflect the local environment. A panel of 12 representatives was drawn from across Australia consisting of nine dermatologists and a rheumatologist, a dermatology nurse and a general practitioner (GP)/dermatology trainee. The group met on three occasions between September 2011 and March 2012. The panel undertook a literature review and critically examined available evidence-based treatment goals. A questionnaire relating to psoriasis assessment and specific treatment outcomes was developed. Following discussion and debate, recommended treatment goals for psoriasis patients in Australia were determined. The panel agreed by consensus on recommended psoriasis treatment goals in the Australian environment. There was recognition that in addition to psoriasis area severity index (PASI) assessment, a quality of life assessment was highly relevant in determining psoriasis severity and treatment outcome. Mild psoriasis was defined as PASI ≤ 10 and a dermatology life quality index (DLQI) ≤ 10, with moderate to severe psoriasis defined as PASI > 10 and/or DLQI > 10. The presence of certain definedclinical features would elevate a patient's classification from mild to moderate/severe. The target for treatment was defined as a maintained change in PASI ≥ 75% improvement and DLQI ≤ 5. These largely concurred with the European treatment goals. A flow chart for psoriasis management in Australia based on outcome measures was developed. There is a need to identify and articulate treatment goals for psoriasis. Assessment of psoriasis severity requires both physical scoring (PASI) and consideration of quality of life measures (DLQI). Identification of treatment goals will guide clinicians in treatment decision-making, enhance the availability and appropriate use of therapies and increase patient satisfaction with their care.


Evolution of regorafenib from bench to bedside in colorectal cancer: Is it an attractive option or merely a "me too" drug?
Colorectal cancer (CRC) is a major public health problem in the United States with an estimated 50,260 deaths in 2017. Over the past two decades, several agents have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with metastatic CRC (mCRC). Regorafenib (BAY 73-4506) is a small-molecule multikinase inhibitor that was approved for the treatment of mCRC in 2012. This agent is a novel oral diphenylurea-based multikinase inhibitor that is active against several angiogenic receptor tyrosine kinases (RTKs; VEGFR-1, VEGFR-2, VEGFR-3, TIE-2), oncogenic RTKs (c-KIT, RET), stromal RTKs (PDGFR-B, FGFR-1), and intracellular signaling kinases (c-RAF/RAF-1, BRAF, BRAFV600E). Preclinical studies have documented its broad-spectrum activity against different solid tumor types including CRC. Phase I studies showed that it had an acceptable safety profile in advanced refractory mCRC. A subsequent Phase III trial (CORRECT) demonstrated significant clinical efficacy of regorafenib in patients with refractory or advanced mCRC, which eventually led to its FDA approval for the treatment of mCRC in September 2012. However, the drug was associated with significant toxicity in clinical practice when administered at the approved doses, which necessitated a thorough reassessment of its dosing schedule and toxicity profile. This review summarizes the development of regorafenib from the initial preclinical studies to the Phase III trials and critically examines the current clinical space occupied by regorafenib in the treatment of mCRC, at 5 years after its initial FDA approval.


VAMP8-3xHA Uptake Assay in HeLa Cells.
Transmembrane proteins are rarely exclusively localized to a specific vesicle or an organelle. Most transmembrane proteins undergo complicated trafficking routes. Thus, transmembrane proteins are under constant flux, and at steady state, found on a variety of vesicles or organelles. This characteristic makes the study of their trafficking routes complex, since at any given moment, different molecules are often being trafficked in opposing directions. Pulse-chase experiments can temporally track a specific pool of a transmembrane protein of interest, allowing for the kinetic description of its trafficking route. This type of technique has been used extensively to follow a large array of plasma membrane localized proteins (Diril et al., 2006; Jean et al., 2010). Here, we describe a method that allows the study of VAMP8 trafficking from the plasma membrane to endolysosomal compartments. This method was used to describe a role for MTMR13 and RAB21 in the regulation of VAMP8 trafficking to endolysosomes (Jean et al., 2015).


[Imported acute hepatitis in Spanish travelers to tropical countries].
Among the immunizable diseases, viral hepatitis is the most frequently diagnosed in travellers. The epidemiology and the clinical presentation of the imported viral hepatitis among patients in the Tropical Medicine Unit of Hospital Clínic (Barcelona) are studied in this article. A retrospective review of 47 viral hepatitis in Spanish travellers seen during the period 1988-1991 is presented, representing 2.47% of all diagnosis. Only a third of the patients were hepatitis A cases. The duration of the trip was significantly shorter in those who acquired hepatitis of the A and non-A--non-B types. Africa (60% cases), India and South East Asia (17%) and Central America (16%) were considered areas of risk. The B, C and non-A--non-B hepatitis types had a more silent clinical and biological presentation. Gathered data confirm the importance of hepatitis as an imported disease, the partial protection of the Spanish population against hepatitis A and the need to introduce this infection among the advice to be given in a travellers clinic.


Standardized one-day evaluation before urinary reconstructive surgery for neurogenic lower urinary tract dysfunction: Feasibility and impact on surgical strategy and care pathway.
To describe a concept of standardized preoperative one-day evaluation before urinary reconstructive or diversion surgery for the treatment of neurogenic lower urinary tract (LUT) dysfunction, and to evaluate its feasibility and its impact on the care pathway. All patients who underwent a one-day standardized evaluation before a urinary reconstructive or derivation surgery for the treatment of neurogenic LUT dysfunction between January 2017 and December 2021 in our institution were included. Data were collected retrospectively from standardized reports. The main outcome was the rate of completion of the tests and consultations planned during this evaluation. Secondary outcomes included the findings from the one-day evaluation and changes in the urological surgical strategy at different time points within one year. One hundred and thirty-one patients benefited from this one-day standardized evaluation. The overall completeness rate of the data collected was 77.5%, increasing from 62.3% in 2017 to 89.3% in 2021. The urological surgical plan was modified for 19.1% of patients following this preoperative evaluation. The indication was then confirmed for 114 patients (87.0%) by the multidisciplinary meeting and was carried out unchanged during the following year for 89 patients (67.9%). An associated colostomy procedure was proposed for 18.3% of patients and was finally performed in 11.5%. A standardized multidisciplinary preoperative one-day evaluation before performing reconstructive or diversion surgery for the treatment of neurogenic LUT dysfunction seems feasible and makes it possible to optimize the surgical plan and adapt the course of care.


Calcium absorption and acceptance of low-lactose milk among children with primary lactase deficiency.
A calcium absorption investigation was carried out with the purpose of determining whether lactose-hydrolyzed milk facilitates calcium absorption in subjects with lactose malabsorption. Nine children participated in the study, which was divided into two investigation periods separated by at least 1 week. During the first period the children were given a lactose-free diet, whereas during the second period their diet contained lactose-hydrolyzed milk. The amount of calcium, number of calories, and rotation of specifically defined meals in the diet during the two periods were identical, and the children functioned as their own controls. We found calcium absorption to be significantly higher with the diet containing hydrolyzed milk than with the lactose-free diet supplemented with extra calcium (p less than 0.05). During the study a double-blind lactose intolerance test was performed. The children had significantly fewer clinical symptoms and signs, such as abdominal pain, borborygmus, meteorism, and defecations, within 24 h after drinking 0.5 L of lactose-hydrolyzed milk as compared with drinking ordinary milk (25 g of lactose). None of the children experienced any unpleasant side effects when consuming the lactose-hydrolyzed milk (approximately 94% degree of hydrolysis) during the study period. All the children liked the hydrolyzed milk because it had a pleasant, sweet flavor as a result of the increased content of glucose.


Is standard percutaneous nephrolithotomy still the standard treatment modality for renal stones less than three centimeters?
The aim of study was to compare the efficiency and safety of standard percutaneous nephrolithotomy (sPNL) and miniaturized percutaneous nephrolithotomy (mPNL) in lower calyx and/or pelvic stones smaller than three centimeters. From October 2010 to August 2015, 108 mPNL and 176 sPNL procedures were performed for renal stones smaller than three cm and located in the lower calyx and/or renal pelvis. All patients were evaluated preoperatively with intravenous pyelography and/or computed tomography. Intraoperative parameters, post-operative results and complications were recorded. Postoperative success was defined as complete stone clearance and/or clinically insignificant residual fragments at 3rd month. Preoperative characteristics were similar between sPNL and mPNL groups except previous renal stone operation history and gender. The mean operation time was significantly shorter in the sPNL group (p<0.001). The mean hemoglobin drop was significantly less in the mPNL group (p=0.001), we found a 1.27±1.4 and 0.5±1.3 decrease in mean hemoglobin levels (mg/dL) in the sPNL and mPNL groups, respectively. Transfusion rate was 1.9% in mPNL and 5.6% in sPNL groups, and the difference was statistically significant (p=0.048). Only one patient in the sPNL group needed angiography and embolization. Postoperative JJ stent insertion rate was significantly higher in the mPNL group (p=0.03). Both sPNL and mPNL are safe and effective surgical procedures for lower calyx and/or pelvis stones smaller than 3 cm. However, use of smaller caliber instruments was associated with a lesser hemoglobin drop and need for transfusion.


[IMPROVING THE ORGANIZATION OF LABOR AND THE QUALITY OF MEDICAL CARE AT PARAMEDIC AND OBSTETRIC STATIONS].
In the provision of primary health care to the rural population, the role of paramedic and obstetric stations (FAP) is great. The purpose of the study is to develop a system of measures aimed at improving the quality of medical care provided at paramedic and obstetric stations. The study was conducted in 2019-2020 on the basis of 26 FAP of 12 central district hospitals (CRH) of the Republic of Dagestan. The organization of labor of 26 paramedics and 26 midwives during 1740 hours was studied by the method of time-lapse observation. The content of 16511 visits by the FAP population was analyzed. The expert evaluation method studied the quality of medical care to 445 patients on 7 FAP. The main work of FAP paramedics accounts for 74.5%, and for midwives - 76.3% of all labor costs. A significant share in the cost structure is occupied by preventive (22.9% for paramedics and 27.8% for midwives) and diagnostic and therapeutic activities (17% and 15.6%). There are high costs for transitions and relocations (17.3% and 14.1%) and for working with documentation (13.7% and 14.5%). In the structure of visits by the population of paramedics and midwives of FAP, for reasons of the greatest proportion are visits with therapeutic and diagnostic purposes (37%), followed by visits for medical appointments (32.8%) and preventive (23.9%). The quality of medical care provided by paramedics to patients with therapeutic diseases was inadequate in 23.8% of cases. Every third (35.7%) patient was treated with FAP unreasonably. Out of the total number of patients who were treated unreasonably on FAP, according to experts, 62.5% had to be treated in the CRH, 34.8% - in the district hospital (outpatient clinic).


Risk of SARS-CoV-2 in a car cabin assessed through 3D CFD simulations.
In this study, the risk of infection from SARS-CoV-2 Delta variant of passengers sharing a car cabin with an infected subject for a 30-min journey is estimated through an integrated approach combining a recently developed predictive emission-to-risk approach and a validated CFD numerical model numerically solved using the open-source OpenFOAM software. Different scenarios were investigated to evaluate the effect of the infected subject position within the car cabin, the airflow rate of the HVAC system, the HVAC ventilation mode, and the expiratory activity (breathing vs. speaking). The numerical simulations here performed reveal that the risk of infection is strongly influenced by several key parameters: As an example, under the same ventilation mode and emitting scenario, the risk of infection ranges from zero to roughly 50% as a function of the HVAC flow rate. The results obtained also demonstrate that (i) simplified zero-dimensional approaches limit proper evaluation of the risk in such confined spaces, conversely, (ii) CFD approaches are needed to investigate the complex fluid dynamics in similar indoor environments, and, thus, (iii) the risk of infection in indoor environments characterized by fixed seats can be in principle controlled by properly designing the flow patterns of the environment.


Improved in vitro fertilization outcomes after treatment of subclinical hypothyroidism in infertile women.
To assess the effect of treatment of maternal subclinical hypothyroidism on infertility outcome. Between April 1, 2006, and April 22, 2007, we conducted a prospective, randomized trial in infertile women with subclinical hypothyroidism who elected to undergo in vitro at the Shatby University Hospital for Women in Alexandria, Egypt. Patients were randomly assigned to 2 groups: treatment group (group A) and placebo group (group B). Male-factor infertility was ruled out. One month before the assisted reproduction technology procedure, group A underwent levothyroxine treatment with a dosage of 50 to 100 mcg daily, while group B started placebo. All patients underwent controlled ovarian stimulation. Patients who achieved pregnancy were followed up throughout their pregnancy until delivery. Levothyroxine treatment and placebo were maintained throughout pregnancy in group A and group B, respectively. Mean thyrotropin value was significantly lower in group A than in group B (1.1 ± 0.3 mIU/L vs 4.9 ± 0.7 mIU/mL, respectively). Mean number of retrieved oocytes was similar in both groups (6.19 ± 0.74 [group A] vs 6.08 ± 0.79 [group B]). Miscarriage rate was significantly lower in group A than in group B (9% vs 13%, respectively), and the clinical pregnancy rate and delivery rate were significantly higher in group A than in group B (35% and 10% vs 26% and 3%, respectively), indicating that the quality, not the quantity, of retrieved oocytes was more important. These preliminary data suggest that levothyroxine supplementation should be recommended to achieve clinical pregnancies in women with subclinical hypothyroidism who are undergoing in vitro fertilization-intracytoplasmic sperm injection.


[Daily Life Style and Psoriasis].
Skin is an important organ that is located on the outermost layer of the human body, and serves as a defense barrier against external stimulation. Daily life style, including diet, exercise, and sleep, is a fundamental behavior of humans, and it has recently been reported that daily life style has a strong relationship with the inflammatory condition of skin diseases. This relationship has been examined by various approaches, including epidemiological investigations. Psoriasis is one inflammatory skin disease and is especially closely related with daily life style, such as diet, sleep, smoking and alcohol consumption. The interleukin (IL)-23/IL-17 axis plays an important role in the pathogenesis of psoriasis, and daily life style is considered to affect this cascade, leading to exacerbation of the inflammatory condition. In this review article, we report how daily life style affects psoriasis.


Genomic Investigation of Balanced Chromosomal Rearrangements in Patients with Abnormal Phenotypes.
Balanced chromosomal rearrangements (BCR) are associated with abnormal phenotypes in approximately 6% of balanced translocations and 9.4% of balanced inversions. Abnormal phenotypes can be caused by disruption of genes at the breakpoints, deletions, or positional effects. Conventional cytogenetic techniques have a limited resolution and do not enable a thorough genetic investigation. Molecular techniques applied to BCR carriers can contribute to the characterization of this type of chromosomal rearrangement and to the phenotype-genotype correlation. Fifteen individuals among 35 with abnormal phenotypes and BCR were selected for further investigation by molecular techniques. Chromosomal rearrangements involved 11 reciprocal translocations, 3 inversions, and 1 balanced insertion. Array genomic hybridization (AGH) was performed and genomic imbalances were detected in 20% of the cases, 1 at a rearrangement breakpoint and 2 further breakpoints in other chromosomes. Alterations were further confirmed by FISH and associated with the phenotype of the carriers. In the analyzed cases not showing genomic imbalances by AGH, next-generation sequencing (NGS), using whole genome libraries, prepared following the Illumina TruSeq DNA PCR-Free protocol (Illumina®) and then sequenced on an Illumina HiSEQ 2000 as 150-bp paired-end reads, was done. The NGS results suggested breakpoints in 7 cases that were similar or near those estimated by karyotyping. The genes overlapping 6 breakpoint regions were analyzed. Follow-up of BCR carriers would improve the knowledge about these chromosomal rearrangements and their consequences.


Endoplasmic Reticulum Stress in Hepatic Stellate Cells Promotes Liver Fibrosis via PERK-Mediated Degradation of HNRNPA1 and Up-regulation of SMAD2.
Endoplasmic reticulum (ER) stress has been implicated in a variety of diseases. Hepatic stellate cells (HSCs) contribute to the development of liver fibrosis. Information on the link between ER stress and HSC activation is scarce. We investigated the effects of ER stress in HSCs on the progression of liver fibrosis and the regulation of this process in cells and mice. Proteins and messenger RNAs were measured in 2 sets of liver samples (n = 25 and n = 44) collected from patients with chronic hepatitis C virus infection and/or fibrosis. ER stress was induced in cells and mice using chemical agents. Lentiviral vectors were constructed to express glucose-regulated protein 78 (GRP78; also known as HSPA5) or heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) from the α-smooth muscle actin promoter and injected into C57BL/6 mice for HSC-specific gene expression. Liver tissues and HSCs were collected from mice or rats and analyzed using immunoblottings and quantitative reverse-transcription polymerase chain reaction. LX-2 cells were transfected with small interfering RNAs, microRNA mimics, or overexpression vectors. Hepatic ER stress was much higher in liver tissues from patients with severe vs mild fibrosis. ER stress induced fibrogenic genes in HSCs. Targeted lentiviral delivery of glucose-regulated protein 78 to HSCs in mice reduced fiber accumulation in liver. Levels of SMAD2, but not SMAD3, were increased in fibrotic liver tissues from patients or mice exposed to ER stress; small interfering RNA-mediated knockdown of SMAD2 reduced ER stress-mediated activation of HSCs. In rat HSCs, ER stress increased levels of SMAD2 messenger RNA by decreasing levels of microRNA 18a (MIR18A), an inhibitor of SMAD2 expression, rather than transactivating the SMAD2 gene. ER stress-activated PKR-like endoplasmic reticulum kinase, also known as EIF2AK3 (PERK) phosphorylated HNRNPA1, a protein required for the maturational processing of primary MIR18A, at Thr51, accelerating its degradation. Overexpression of HNRNPA1 (or its T51A mutant) in HSCs of mice inhibited liver fibrosis. Severe fibrotic liver tissues from patients had increased levels of phosphorylated PERK and reduced levels of HNRNPA1 in HSCs, compared with mild fibrotic liver tissues. ER stress in HSCs promotes liver fibrosis by inducing overexpression of SMAD2, via dysregulation of MIR18A; this dysregulation is mediated by PERK phosphorylation and destabilization of HNRNPA1.


Treadmill exercise-dependent tumor growth retardation in T-cell lymphoma-bearing host displays gender dimorphism.
A number of previous investigations have reported that physical exercise renders immunopotentiating and antitumor therapeutic benefits to the tumor-bearing host. As these effects of physical exercise are mainly mediated through the modulation of hormonal and cytokine repertoire, it remains unclear if male and female tumor-bearing hosts show a gender-dependent differential response to the therapeutic action of physical exercise in tumor growth retardation. In the present investigation tumor growth retardation, following physical exercise was investigated in a gender-specific manner in a murine tumor model of a T-cell lymphoma designated as Dalton's lymphoma (DL). The results of the present investigation show that physical exercise of a tumor-bearing host on a treadmill results in a better retardation of tumor progression along with prolongation of survival time in male compared to female tumor-bearing host. Such gender dimorphism of the therapeutic benefits of physical exercise in tumor-bearing host was found to be associated with a gender-dependent variation in cell survival and induction of apoptosis in tumor cells. Moreover, expression of cell growth regulatory proteins-selectin, Hsp70, p53, CAD, SOCS, and IL-2 receptor-was found to vary in a gender-specific manner following physical exercise. The investigation also indicates the role of cytokines and macrophages in manifestation of gender dimorphism in the response of tumor-bearing mice to physical exercise. Thus, the observations of the present investigation suggest for the first time that the beneficial effects of physical exercise in a tumor-bearing host may be variable depending on the gender of the host.


Precision structural engineering of self-rolled-up 3D nanomembranes guided by transient quasi-static FEM modeling.
Micro- and nanoscale tubular structures can be formed by strain-induced self-rolled-up nanomembranes. Precision engineering of the shape and dimension determines the performance of devices based on this platform for electronic, optical, and biological applications. A transient quasi-static finite element method (FEM) with moving boundary conditions is proposed as a general approach to design diverse types of three-dimensional (3D) rolled-up geometries. This method captures the dynamic release process of membranes through etching driven by mismatch strain and accurately predicts the final dimensions of rolled-up structures. Guided by the FEM modeling, experimental demonstration using silicon nitride membranes was achieved with unprecedented precision including controlling fractional turns of a rolled-up membrane, anisotropic rolling to form helical structures, and local stress control for 3D hierarchical architectures.


Current trends and controversies over pre-operative chemotherapy for women with operable breast cancer.
The multi-disciplinary approach, including surgery, chemotherapy, endocrine therapy and radiation therapy, has become the standard treatment for primary breast cancer patients. The indication of pre-operative chemotherapy has been extended to women with potentially operable breast cancer based on the results of large randomized studies and has become an attractive option that extends the chance of breast conservation. The clinical and pathological responses to pre-operative chemotherapy correlates with long-term outcome. The anthracycline-containing regimen is now considered the standard. Sequential administration of non-cross-resistant drugs, namely taxanes, improves local tumor response but its long-term benefit has been controversial. Prediction of response to pre-operative chemotherapy still remains a challenge. Identification of useful predictive markers and development of molecular-targeted drugs is the key to individualized therapy in the future.


Reinduced expression of developmental proteins (nestin, small heat shock protein) in and around cerebral arteriovenous malformations.
Intermediate filament (IF) nestin and small heat shock protein (sHSP) are developmentally regulated proteins. Nestin is highly expressed on proliferating neuroepithelial stem cells of the developing central nervous system (CNS). During the developmental neurulation stage, nestin is replaced by mature neuronal (neurofilament) or glial cell-specific IFs (glial fibrillary acidic protein, GFAP). Several pathologic states induce astrocytes to synthesize nestin transiently in the mature brain. However, the exact nature of the embryonic conversion from nestin to mature cytoskelton is unclear. In an attempt to define the effect of ischemic hemodynamic stress caused by cerebral arteriovenous malformation (AVM) on the brain parenchyma, we examined the synthesis and cellular distribution of sHSP and nestin in vascular elements of AVMs and in the gliotic area surrounding AVMs. Ten consecutively collected surgical specimens meeting the histological criteria for AVM were immunohistochemically stained using primary antibodies for nestin, HSP27 and alphaB-crystallin. Nestin, HSP27 and alphaB-crystallin mRNA expressions were examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Nestin expression is reinduced not only in reactive astrocytes, but also in endothelial cells in the surrounding gliotic tissue of the cerebral AVM. These cells also expressed sHSP (HSP27, alphaB-crystallin) that maintain the integrity of the IF network and prevent unfolding of cellular proteins induced by various stresses. RT-PCR showed the increased expression of sHSP and nestin mRNA in the AVM specimens. These results indicate that embryonic reversion of the mature cytoskeleton to nestin and the increased expression of sHSP in response to cerebral injury are associated with increased wall tension caused by dilating AVM vessels and with the hemodynamic stress that surrounds AVMs.


Effect of adiponectin on macrophage reverse cholesterol transport in adiponectin-/- mice and its mechanism.
The objective of the present study was to investigate the effect of adiponectin (APN) on macrophage reverse cholesterol transport (RCT) in adiponectin-/- knockout mice (APN-/-mice) and its possible anti-atherosclerotic mechanism. A total of 30 male APN-/-mice were randomly divided into the control group and four intervention groups. The intervention groups were treated with intraperitoneal injections of APN, at doses of 50, 150, 200 and 250 µg/(kg/day), respectively, for 4 weeks. The control group received normal saline. After 4 weeks, serum lipid levels were measured, the degree of severity of atherosclerotic lesions was observed by light microscopy, the 3H-TC (APN-/-mice treated with intraperitoneal injections of 3H-TC-labeled macrophages) radioactivity in serum, liver, and feces, and the expression of ABCA1 mRNA and protein in liver were determined. Compared with the control group, serum triglycerides, total cholesterol, and low-density lipoproteins levels in the intervention groups were significantly decreased, while high-density lipoprotein was increased. The severity of aortic atherosclerotic lesions in the intervention groups was milder than in the control group, which had obvious aortic atherosclerotic lesions, large lipid deposition on vessel walls, and the formation of atheromatous plaques. In the intervention groups, serum 3H-TC content was significantly decreased (P<0.05), but the 3H-TC content in liver and feces was significantly increased (P<0.05). The levels of ABCA1 mRNA in liver of the intervention groups were significantly increased in a dose-dependent manner. In conclusion, APN can promote RCT and intracellular cholesterol efflux by upregulating the expression of ABCA1, to delay the occurrence and development of atherosclerosis.


Effects of prescription restrictive interventions on antibiotic procurement in primary care settings: a controlled interrupted time series study in China.
The overuse of antibiotics has been identified as a major challenge in regard to the rational prescription of medicines in low and middle income countries. Extensive studies on the effectiveness of persuasive interventions, such as guidelines have been undertaken. There is a dearth of research pertaining to the effects of restrictive interventions. This study aimed to evaluate the impacts of prescription restrictions in relation to types and administration routes of antibiotics on antibiotic procurement in primary care settings in China. Data were drawn from the monthly procurement records of medicines for primary care institutions in Hubei province over a 31-month period from May 2011 to November 2013. We analyzed the monthly procurement volume and costs of antibiotics. Interrupted time series analyses with a difference-in-difference approach were performed to evaluate the effect of the restrictive intervention (started in August 2012) on antibiotic procurement in comparison with those for cardiovascular conditions. Sensitivity tests were performed by replacing outliers using a simple linear interpolation technique. Over the entire study period, antibiotics accounted for 33.65% of the total costs of medicines procured for primary care institutions: mostly non-restricted antibiotics (86.03%) and antibiotics administered through parenteral routes (79.59%). On average, 17.14 million defined daily doses (DDDs) of antibiotics were procured per month, with the majority (93.09%) for non-restricted antibiotics and over half (52.38%) for parenteral administered antibiotics. The restrictive intervention was associated with a decline in the secular trend of costs for non-restricted oral antibiotics (- 0.36 million Yuan per month, p = 0.029), and for parenteral administered restricted antibiotics (- 0.28 million Yuan per month, p = 0.019), as well as a decline in the secular trend of procurement volume for parenteral administered non-restricted antibiotics (- 0.038 million DDDs per month, p = 0.05). Restrictive interventions are effective in reducing the procurement of antibiotics. However, the effect size is relatively small and antibiotic consumptions remain high, especially parenteral administered antibiotics.


Roles of the RON3 C-terminal fragment in erythrocyte invasion and blood-stage parasite proliferation in Plasmodium falciparum.
Plasmodium species cause malaria, and in the instance of Plasmodium falciparum is responsible for a societal burden of over 600,000 deaths annually. The symptoms and pathology of malaria are due to intraerythocytic parasites. Erythrocyte invasion is mediated by the parasite merozoite stage, and is accompanied by the formation of a parasitophorous vacuolar membrane (PVM), within which the parasite develops. The merozoite apical rhoptry organelle contains various proteins that contribute to erythrocyte attachment and invasion. RON3, a rhoptry bulb membrane protein, undergoes protein processing and is discharged into the PVM during invasion. RON3-deficient parasites fail to develop beyond the intraerythrocytic ring stage, and protein export into erythrocytes by the Plasmodium translocon of exported proteins (PTEX) apparatus is abrogated, as well as glucose uptake into parasites. It is known that truncated N- and C-terminal RON3 fragments are present in rhoptries, but it is unclear which RON3 fragments contribute to protein export by PTEX and glucose uptake through the PVM. To investigate and distinguish the roles of the RON3 C-terminal fragment at distinct developmental stages, we used a C-terminus tag for conditional and post-translational control. We demonstrated that RON3 is essential for blood-stage parasite survival, and knockdown of RON3 C-terminal fragment expression from the early schizont stage induces a defect in erythrocyte invasion and the subsequent development of ring stage parasites. Protein processing of full-length RON3 was partially inhibited in the schizont stage, and the RON3 C-terminal fragment was abolished in subsequent ring-stage parasites compared to the RON3 N-terminal fragment. Protein export and glucose uptake were abrogated specifically in the late ring stage. Plasmodial surface anion channel (PSAC) activity was partially retained, facilitating small molecule traffic across the erythrocyte membrane. The knockdown of the RON3 C-terminal fragment after erythrocyte invasion did not alter parasite growth. These data suggest that the RON3 C-terminal fragment participates in erythrocyte invasion and serves an essential role in the progression of ring-stage parasite growth by the establishment of the nutrient-permeable channel in the PVM, accompanying the transport of ring-stage parasite protein from the plasma membrane to the PVM.


Regional Proteomic Quantification of Clinically Relevant Non-Cytochrome P450 Enzymes along the Human Small Intestine.
Current challenges in accurately predicting intestinal metabolism arise from the complex nature of the intestine, leading to limited applicability of available in vitro tools as well as knowledge deficits in intestinal physiology, including enzyme abundance. In particular, information on regional enzyme abundance along the small intestine is lacking, especially for non-cytochrome P450 enzymes such as carboxylesterases (CESs), UDP-glucuronosyltransferases (UGTs), and sulfotransferases (SULTs). We used cryopreserved human intestinal mucosa samples from nine donors as an in vitro surrogate model for the small intestine and performed liquid chromatography tandem mass spectrometry-based quantitative proteomics for 17 non-cytochrome P450 enzymes using stable isotope-labeled peptides. Relative protein quantification was done by normalization with enterocyte marker proteins, i.e., villin-1, sucrase isomaltase, and fatty acid binding protein 2, and absolute protein quantification is reported as picomoles per milligram of protein. Activity assays in glucuronidations and sequential metabolisms were conducted to validate the proteomics findings. Relative or absolute quantifications are reported for CES1, CES2, five UGTs, and four SULTs along the small intestine: duodenum, jejunum, and ileum for six donors and in 10 segments along the entire small intestine (A-J) for three donors. Relative quantification using marker proteins may be beneficial in further controlling for technical variabilities. Absolute quantification data will allow for scaling factor generation and in vivo extrapolation of intestinal clearance using physiologically based pharmacokinetic modeling. SIGNIFICANCE STATEMENT: Current knowledge gaps exist in intestinal protein abundance of non-cytochrome P450 enzymes. Here, we employ quantitative proteomics to measure non-cytochrome P450 enzymes along the human small intestine in nine donors using cryopreserved human intestinal mucosa samples. Absolute and relative abundances reported here will allow better scaling of intestinal clearance.


A new strategy for antidepressant prescription.
From our research and literature search we propose an understanding of the mechanism of action of antidepressants treatments (ADTs) that should lead to increase efficacy and tolerance. We understand that ADTs promote synaptic plasticity and neurogenesis. This promotion is linked with stimulation of dopaminergic receptors. Previous evidence shows that all ADTs (chemical, electroconvulsive therapy, repetitive transcranial magnetic stimulation, sleep deprivation) increase at least one monoamine neurotransmitter serotonin (5-HT), noradrenaline (NA) or dopamine (DA); this article focuses on DA release or turn-over in the frontal cortex. DA increased dopaminergic activation promotes synaptic plasticity with an inverted U shape dose-response curve. Specific interaction between DA and glutamate is mediated by D1 receptor subtypes and Glutamate (NMDA) receptors with neurotrophic factors likely to play a modulatory role. With the understanding that all ADTs have a common, final, DA-ergic stimulation that promotes synaptic plasticity we can predict that (1) AD efficiency is related to the compound strength for inducing DA-ergic stimulation. (2) ADT efficiency presents a therapeutic window that coincides with the inverted U shape DA response curve. (3) ADT delay of action is related to a "synaptogenesis and neurogenesis delay of action." (4) The minimum efficient dose can be found by starting at a low dosage and increasing up to the patient response. (5) An increased tolerance requires a concomitant prescription of a few ADTs, with different or opposite adverse effects, at a very low dose. (6) ADTs could improve all diseases with cognitive impairments and synaptic depression by increasing synaptic plasticity and neurogenesis.


Hitting probability for anomalous diffusion processes.
We present the universal features of the hitting probability Q(x,L), the probability that a generic stochastic process starting at x and evolving in a box [0, L] hits the upper boundary L before hitting the lower boundary at 0. For a generic self-affine process, we show that Q(x,L)=Q(z=x/L) has a scaling Q(z) approximately z;{phi} as z-->0, where phi=theta/H, H, and theta being the Hurst and persistence exponent of the process, respectively. This result is verified in several exact calculations, including when the process represents the position of a particle diffusing in a disordered potential. We also provide numerical support for our analytical results.


Deficiency of apoptosis-stimulating protein two of p53 ameliorates acute kidney injury induced by ischemia reperfusion in mice through upregulation of autophagy.
Acute kidney injury (AKI) has become a common disorder with a high risk of morbidity and mortality, which remains major medical problem without reliable and effective therapeutic intervention. Apoptosis-stimulating protein two of p53 (ASPP2) is a proapoptotic member that belongs to p53 binding protein family, which plays a key role in regulating apoptosis and cell growth. However, the role of ASPP2 in AKI has not been reported. To explore the role of ASPP2 in the progression of AKI, we prepared an AKI mouse model induced by ischaemia reperfusion (I/R) in wild-type (ASPP2+/+ ) mice and ASPP2 haploinsufficient (ASPP2+/- ) mice. The expression profile of ASPP2 were examined in wild-type mice. The renal injury, inflammation response, cellular apoptosis and autophagic pathway was assessed in ASPP2+/+ and ASPP2+/- mice. The renal injury, inflammation response and cellular apoptosis was analysed in ASPP2+/+ and ASPP2+/- mice treated with 3-methyladenine or vehicle. The expression profile of ASPP2 showed an increase at the early stage while a decrease at the late stage during renal injury. Compared with ASPP2+/+ mice, ASPP2 deficiency protected mice against renal injury induced by I/R, which mainly exhibited in slighter histologic changes, lower levels of blood urea nitrogen and serum creatinine, and less apoptosis as well as inflammatory response. Furthermore, ASPP2 deficiency enhanced autophagic activity reflecting in the light chain 3-II conversion and p62 degradation, while the inhibition of autophagy reversed the protective effect of ASPP2 deficiency on AKI. These data suggest that downregulation of ASPP2 can ameliorate AKI induced by I/R through activating autophagy, which may provide a novel therapeutic strage for AKI.


Fertilization following mixed insemination with 'cervix-selected' and 'unselected' spermatozoa in the rabbit.
The possible selection of spermatozoa for fertilization by the female genital tract was investigated using genetically homogeneous, numerically adjusted 'cervix-selected' and 'unselected' rabbit spermatozoa. Samples of spermatozoa were marked by 15 min exposure to 1.3 mg TEPA/ml and then washed for 15 min. TEPA-treated and control samples were inseminated alternately into the vagina (= 'cervix-selected') or uterine horns (= 'unselected') of prospective donors. After 6 h spermatozoa were recovered from the uterine horns of the donors. Equal numbers of 'selected' and 'unselected' spermatozoa were inseminated either into the uterine horns (24 does) or oviducts (25 does) of recipients. The fertilization rates were 48 and 72%, respectively. Significantly more eggs were fertilized by untreated than by TEPA-treated spermatozoa. Almost identical fertilization rates, however, were observed between 'cervix-selected' and 'unselected' spermatozoa. It is concluded, therefore, that in the rabbit no selection of (preincubated) spermatozoa for fertilization takes place at the cervical level.


A potent polymer/pyridoxamine enzyme mimic.
An enzyme mimic consisting of pyridoxamines covalently linked to polyethyleneimine carrying long-chain alkyl groups converts pyruvic acid to dl-alanine with as much as an 8000-fold acceleration relative to the reaction with simple pyridoxamine at the same pyridoxamine concentration. The acceleration by polymer is a strong function of the length of the alkyl chains that are appended. The polymer furnishes acid and base groups to catalyze the proton transfers that are involved in transamination.


Reasons for medical evacuations of soldiers serving in International Security Assistance Force (ISAF) operation in Afghanistan.
The article presents the results of a research study into the reasons for medical evacuations of Polish military personnel taking part in the International Security Assistance Force (ISAF) operation in Afghanistan from 2007 to 2013. The authors have analysed medical records of 485 soldiers who were medically evacuated out of a combat zone in Afghanistan for battle injuries, non-battle injuries and diseases. Each medically evacuated Polish soldier was subjected to statistical analysis. The study population comprised 25,974 soldiers assigned to the Polish Military Contingent Afghanistan in the given period. From 2007 to 2013, 1.9% of the Polish military personnel (n = 485) participating in the ISAF operation in Afghanistan were evacuated for medical reasons before the scheduled termination of their contract. 40.6% of all medical evacuations were due to battle injuries, 32.4% due to non-battle injuries, and 27.0% due to diseases. ISAF is an example of a combat operation, in which battle injuries remain the leading health problem in mission participants. 3 of 4 Polish soldiers who were medically evacuated from Afghanistan were no longer fit for military service in the area of operations due to the traumas they had suffered.


Performance Comparison of the artus HBV QS-RGQ and the CAP/CTM HBV v2.0 Assays regarding Hepatitis B Virus DNA Quantification.
Over 240 million people are chronically infected with hepatitis B virus (HBV), the leading cause of liver cancer worldwide. The quantification of the HBV DNA level is critical for monitoring the efficacy of antiviral treatment of chronic HBV patients. In our study, we compared the performance of the artus HBV QS-RGQ assay to the CAP/CTM v2.0 test, as a reference method, on 142 Moroccan patients. The analytical performance of the artus HBV QS-RGQ assay, such as the limit of detection, quantification, precision, reproducibility, and linearity, was determined using dilution series from 10 to 0.1 log10 IU/mL. Detection rates and viral loads quantified by the artus HBV QS-RGQ assay were significantly lower than those from the CAP/CTM v2.0 assay (73.94% vs. 82.39%; 3.34 ± 1.94 log10 IU/mL vs. 3.91 ± 2.45 log10 IU/mL; p < 0.01). A Bland-Altman plot found a mean difference of (CAP/CTM v2.0 - artus HBV QS - RGQ) = 0.5717 log10 IU/mL, with an average range of -1.13 to 2.31 log10 IU/mL. The two methods demonstrated a high correlation (r = 0.88) for 100 positive samples, a moderate correlation for samples below 2000 IU/mL (r = 0.76), and a very high correlation for the samples above 2000 IU/mL (r = 0.95). Linearity of the artus QS-RGQ test ranged from 1.07 to 7.51 log10 IU/mL. The artus HBV QS-RGQ assay showed a strong correlation, precision, and linearity in comparison with the CAP/CTM v2.0. However, viral loads determined by the artus HBV QS-RGQ assay were lower than those determined by the CAP/CTM v2.0 assay.


Monitoring Theileria parva infection in adult Rhipicephalus appendiculatus ticks.
A rapid method is described for preparing and staining salivary glands of Rhipicephalus appendiculatus ticks infected with Theileria parva. The technique, involving the use of a modified methyl green pyronin stained minimizes the risk of losing material and allows examination of stained glands within minutes of preparation. The technique was applied in a series of studies in which ticks were either infected with T. parva under different conditions, or maturation of parasites in adult ticks was stimulated by different means. When nymphal ticks were fed on the ears of cattle the subsequent infection rate of the adult ticks showed no correlation with the parasitaemia of the cattle at the time of nymphal engorgement. There was no difference in infection rates between adult ticks in which parasite maturation had been stimulated either by incubation at 37 degree C or by feeding on rabbits. However, parasite maturation took about 1 day longer in incubated ticks than in rabbit-fed ticks. Female ticks were consistently more highly infected than males, both in terms of the percentage of ticks infected and the mean number of infected acini/tick. Ticks were infected with T. parva by injection of nymphs with parasitaemic bovine blood, but the resultant adult infection was lower than that in ticks which had been infected naturally by feeding on cattle.


Review article: drug-induced liver injury in clinical practice.
Drug-induced liver injury (DILI) is an important differential diagnosis in many patients in clinical hepatology. DILI is the leading cause of acute liver failure and is an important safety issue when new drugs are developed. To provide a review of the recent data on DILI with particular focus on the most common and relevant issues seen in clinical practice. A Medline search was undertaken to identify relevant literature using search terms including 'drug-induced liver injury' and 'hepatotoxicity'. The true incidence of DILI remains unknown but incidence up to 14 cases per 100 000 inhabitants and year has been reported. Antibiotics, analgesics and NSAIDs are the most common drugs causing liver injury. Idiosyncratic DILI has been shown to have a dose-dependent component and drugs without significant hepatic metabolism rarely cause DILI. Chronic elevation in liver enzymes can develop after DILI but this is rarely associated with clinical morbidity or mortality. Drug-induced liver injury remains a diagnostic challenge. Multicentre studies and international collaborative work with well-characterized patients will increase our understanding of liver injury associated with drugs. New therapies for acute liver failure resulting from drugs are needed.


Microglial contribution to the pathology of neurodevelopmental disorders in humans.
Microglia are the brain's resident macrophages, which guide various developmental processes crucial for brain maturation, activity, and plasticity. Microglial progenitors enter the telencephalic wall by the 4th postconceptional week and colonise the fetal brain in a manner that spatiotemporally tracks key neurodevelopmental processes in humans. However, much of what we know about how microglia shape neurodevelopment comes from rodent studies. Multiple differences exist between human and rodent microglia warranting further focus on the human condition, particularly as microglia are emerging as critically involved in the pathological signature of various cognitive and neurodevelopmental disorders. In this article, we review the evidence supporting microglial involvement in basic neurodevelopmental processes by focusing on the human species. We next concur on the neuropathological evidence demonstrating whether and how microglia contribute to the aetiology of two neurodevelopmental disorders: autism spectrum conditions and schizophrenia. Next, we highlight how recent technologies have revolutionised our understanding of microglial biology with a focus on how these tools can help us elucidate at unprecedented resolution the links between microglia and neurodevelopmental disorders. We conclude by reviewing which current treatment approaches have shown most promise towards targeting microglia in neurodevelopmental disorders and suggest novel avenues for future consideration.


Population differences in haplotype structure within a human olfactory receptor gene cluster.
We investigated the population differences in patterns of single nucleotide polymorphisms (SNPs) for a 400 kb olfactory receptor (OR) gene cluster on human chromosome 17p13.3. Samples were drawn from 35 individuals, of four different ethnogeographical origins: Pygmies, Bedouins, Yemenite Jews and Ashkenazi Jews. Of the 74 SNPs identified, two segregated between pseudogenized and intact ORs, while a third involved a change in a highly conserved motif proposed to mediate ligand-induced signal transduction. Linkage disequilibrium (LD) was computed based on phase inference across the cluster using Clark's haplotype subtraction algorithm. We also calculated LD directly from the genotypes using the expectation-maximization (EM) algorithm. Both methods yielded very similar results. Our analyses revealed substantial differences in nucleotide diversity, haplotype distribution and LD patterns among the different human populations. In particular, the two Jewish populations had low haplotype diversity and negligible decay of LD across the entire genomic region. Intriguingly, the three functional SNPs segregated at different frequencies in the different ethnogeographical groups, with the Pygmies having higher frequencies of the intact OR genes. Our data suggests that OR genes may have evolved to create different functional repertoires in distinct human populations.


Gram-Scale Total Synthesis of TAB with Cardioprotective Activity and the Structure-Activity Relationship of Its Analogs.
Traditional Chinese medicine has been proven to be of great significance in cardioprotective effects. Clinopodium chinense (Lamiaceae) has unique advantages in the treatment and prevention of cardiovascular diseases. Tournefolic acid B (TAB) was proven to be a potent component against myocardial ischemia reperfusion injury (MIRI) from Clinopodium chinense (Lamiaceae). This article will attempt to establish a gram-scale synthesis method of TAB and discuss the structure-activity relationship of its analogs. The total synthesis of TAB was completed in 10 steps with an overall yield of 13%. In addition, analogs were synthesized, and their cardioprotective activity was evaluated on the hypoxia/reoxygenation of H9c2 cells. Amidation of the acid position is helpful to the activity, while methylation of phenolic hydroxyl groups greatly decreased the cardioprotective activity. The easily prepared azxepin analogs also showed cardioprotective activity. Most of the clogP values calculated by Molinspiration ranged from 2.5 to 5, which is in accordance with Lipinski's rule of 5. These findings represent a novel kind of cardioprotective agent that is worthy of further study.


Electron spin decoherence in quantum dots due to interaction with nuclei.
We study the decoherence of a single electron spin in an isolated quantum dot induced by hyperfine interaction with nuclei. The decay is caused by the spatial variation of the electron wave function within the dot, leading to a nonuniform hyperfine coupling A. We evaluate the spin correlation function and find that the decay is not exponential but rather power (inverse logarithm) lawlike. For polarized nuclei we find an exact solution and show that the precession amplitude and the decay behavior can be tuned by the magnetic field. The decay time is given by (planck)N/A, where N is the number of nuclei inside the dot, and the amplitude of precession decays to a finite value. We show that there is a striking difference between the decoherence time for a single dot and the dephasing time for an ensemble of dots.


Effect of yoga practices on micronutrient absorption in urban residential school children.
[Purpose] This study was conducted with a view to find out the effect of yoga practices on micronutrient absorption in urban residential school children. [Subjects and Methods] The study population comprised 66 urban school children aged 11-15 years staying in a residential school in Pune City, Maharashtra, India. A stratified random sampling method was used to divide the students into experimental and control groups. There were 33 students in experimental group and 33 students in control group. Both experimental and control groups were assessed for the status of zinc, copper, iron and magnesium at the baseline and at the end of 12 weeks of yoga training. The study participants of experimental group underwent yoga training for 12 weeks, for one hour in the morning for six days a week. The control group did not undergo any yoga training during this time period. [Results] The experimental group participants showed significant improvement in micronutrient absorption as compared to control group. [Conclusion] The findings of this study indicate that yoga practices could improve micronutrient absorption in urban residential school children.


Systematic reviews of bladder training and voiding programmes in adults: a synopsis of findings from data analysis and outcomes using metastudy techniques.
This paper reports a comparison of the data analysis and outcomes from four Cochrane systematic reviews on bladder training and voiding programmes for the management of urinary incontinence using metastudy descriptive techniques to inform clinical practice, generate new ideas and identify future research directions. Bladder training is used for cognitively and physically able adults to regain continence by increasing the time interval between voids. Prompted voiding, habit retraining and timed voiding, collectively known as voiding programmes, are generally used for people with cognitive and physical impairments in institutional settings. Bladder training and voiding programmes feature as common clinical practice for the management of urinary incontinence. A synopsis of four Cochrane systematic reviews that included randomized controlled trials on bladder training, prompted voiding, habit retraining and timed voiding was undertaken using metastudy techniques for the synthesis of qualitative research, and has provided a discursive comparison and contrast of the meta-data analysis and outcomes of these reviews. Frequency of incontinence was the most common and constant outcome measure of effectiveness in the reviews. Limited data were available on other health outcomes, change in dependency status, quality of life and cost-effectiveness. The systematic review on bladder training included different types of urinary incontinence, whereas those on voiding programmes did not differentiate the type of incontinence. There is evidence on the effectiveness of bladder training but long-term follow up studies are needed. Evidence on the effectiveness of voiding programmes is limited and not available for many outcomes. Future research needs to consider the theory underpinning interventions for bladder training and voiding programmes for urinary incontinence and should incorporate recognized 'quality' research designs, established outcomes and long-term follow up. It is unclear whether health outcomes for people with comorbidities, cognitive and physical impairments will improve if extensive diagnostic and assessment investigations are undertaken.


Effect of Standardized Reminder Calls on Trauma Patient No-Show Rate.
Most patients who sustain a traumatic injury require outpatient follow-up. A common barrier to outpatient post-admission care is patient failure to follow-up. One of the most significant factors resulting in failure to follow-up is age greater than 35 years old. Recent work has shown that follow-up phone calls reduce readmission rates. Our aim was to decrease no-show appointments by 10% in 12 months. The electronic medical records at our level I and level II trauma centers were queried for all outpatient appointments for trauma between July 1, 2020 and June 9, 2021 and whether the patient attended their follow-up appointment. Patients with visits scheduled after Aug 1, 2021 received 24- and 48-hour pre-visit reminder calls. Patients scheduled between July 1, 2020 and Aug 1, 2021 did not receive pre-visit calls. Both groups were compared using multivariable direct logistic regression models. A total of n = 1822 follow-up opportunities were included in the study. During the pre-implementation phase, there was a no-show rate of 30.9% (329 of 1064 visits). Post-intervention, a 12.2% reduction in overall no-show rate occurred. A statistically significant 11.2% decrease (p < 0.001) was seen in elderly patients. Multivariate analysis showed standardized calls resulted in significantly decreased odds of failing to keep an appointment (AOR = 0.610, p < 0.001). Reminder calls led to a 12.2% reduction in no-show rate and were an independent predictor of a patient's likelihood of attending their appointment. Other predictors of attendance included insurance status and abdominal injury.


Smoking history, knowledge, and attitudes among older residents of a long-term care facility.
In the absence of empirical literature from the resident perspective, this study provided a first assessment of smoking history, knowledge of the risks of smoking, the risks of environmental tobacco exposure, and the benefits of quitting among older (age 50+) nursing home unit residents, as well as readiness to quit, barriers to quitting, frequency of cessation advice by healthcare givers, and quit-attempt history of residents who smoke. Subjects were 25 smokers and 70 non-smokers housed on long-term nursing home units in a county hospital. Results indicated that smoking status for the majority of residents was similar to when they were admitted, although smokers smoked fewer cigarettes (M = 11.6, SD = 9.2) than prior to admission (M = 18.6, SD = 11.8). Smokers were less likely than non-smokers to agree that smoking is harmful to their health. Both smokers and non-smokers were not well informed of the dangers of passive smoke exposure. The majority of smokers were in precontemplation (no interest in quitting within the next 6 months). Fewer than half of residents who smoked reported receiving cessation advice from physicians (40%) or nurses (36%), and no in-house cessation programs were available. These results suggest gaps in knowledge and resources for smoking cessation in this setting and an opportunity for intervention. This study begins to build an evidence base from the residents' perspective that can be used by healthcare providers, administrators, and policy makers in addressing smoking in the nursing home.


Indole-derived arynes and their Diels-Alder reactivity with furans.
Arynes derived from any position of the ubiquitous indole nucleus are unknown. We have now provided the first evidence for the formation and trapping of the 4,5-, 5,6-, and 6,7-indolynes. A series of o-dihalo indoles (Cl, Br, F) were synthesized and reacted under metal-halogen exchange conditions to give Diels-Alder cycloadducts in high yield with furan. The use of an excess of tert-butyllithium resulted in the rearrangement of the initially formed cycloadduct; however, employing only a slight excess of n-butyllithium cleanly gave cycloadducts with furan.


Identification of specific prognostic markers for lung squamous cell carcinoma based on tumor progression, immune infiltration, and stem index.
Lung squamous cell carcinoma (LUSC) is a unique subform of nonsmall cell lung cancer (NSCLC). The lack of specific driver genes as therapeutic targets leads to worse prognoses in patients with LUSC, even with chemotherapy, radiotherapy, or immune checkpoint inhibitors. Furthermore, research on the LUSC-specific prognosis genes is lacking. This study aimed to develop a comprehensive LUSC-specific differentially expressed genes (DEGs) signature for prognosis correlated with tumor progression, immune infiltration,and stem index. RNA sequencing data for LUSC and lung adenocarcinoma (LUAD) were extracted from The Cancer Genome Atlas (TCGA) data portal, and DEGs analyses were conducted in TCGA-LUSC and TCGA-LUAD cohorts to identify specific DEGs associated with LUSC. Functional analysis and protein-protein interaction network were performed to annotate the roles of LUSC-specific DEGs and select the top 100 LUSC-specific DEGs. Univariate Cox regression and least absolute shrinkage and selection operator regression analyses were performed to select prognosis-related DEGs. Overall, 1,604 LUSC-specific DEGs were obtained, and a validated seven-gene signature was constructed comprising FGG, C3, FGA, JUN, CST3, CPSF4, and HIST1H2BH. FGG, C3, FGA, JUN, and CST3 were correlated with poor LUSC prognosis, whereas CPSF4 and HIST1H2BH were potential positive prognosis markers in patients with LUSC. Receiver operating characteristic analysis further confirmed that the genetic profile could accurately estimate the overall survival of LUSC patients. Analysis of immune infiltration demonstrated that the high risk (HR) LUSC patients exhibited accelerated tumor infiltration, relative to low risk (LR) LUSC patients. Molecular expressions of immune checkpoint genes differed significantly between the HR and LR cohorts. A ceRNA network containing 19 lncRNAs, 50 miRNAs, and 7 prognostic DEGs was constructed to demonstrate the prognostic value of novel biomarkers of LUSC-specific DEGs based on tumor progression, stemindex, and immune infiltration. In vitro experimental models confirmed that LUSC-specific DEG FGG expression was significantly higher in tumor cells and correlated with immune tumor progression, immune infiltration, and stem index. In vitro experimental models confirmed that LUSC-specific DEG FGG expression was significantly higher in tumor cells and correlated with immune tumor progression, immune infiltration, and stem index. Our study demonstrated the potential clinical implication of the 7- DEGs signature for prognosis prediction of LUSC patients based on tumor progression, immune infiltration, and stem index. And the FGG could be an independent prognostic biomarker of LUSC promoting cell proliferation, migration, invasion, THP-1 cell infiltration, and stem cell maintenance.


Multimarker assessment for the prediction of renal function improvement after percutaneous revascularization for renal artery stenosis.
Identifying patients likely to have improved renal function after percutaneous transluminal renal angioplasty and stenting (PTRA) for renal artery stenosis (RAS) is challenging. The purpose of this study was to use a comprehensive multimarker assessment to identify those patients who would benefit most from correction of RAS. In 127 patients with RAS and decreased renal function and/or hypertension referred for PTRA, quantification of hemodynamic cardiac stress using B-type natriuretic peptide (BNP), renal function using estimated glomerular filtration rate (eGFR), parenchymal renal damage using resistance index (RI), and systemic inflammation using C-reactive protein (CRP) were performed before intervention. Predefined renal function improvement (increase in eGFR ≥10%) at 6 months occurred in 37% of patients. Prognostic accuracy as quantified by the area under the receiver-operating characteristics curve for the ability of BNP, eGFR, RI and CRP to predict renal function improvement were 0.59 (95% CI, 0.48-0.70), 0.71 (95% CI, 0.61-0.81), 0.52 (95% CI, 0.41-0.65), and 0.56 (95% CI, 0.44-0.68), respectively. None of the possible combinations increased the accuracy provided by eGFR (lower eGFR indicated a higher likelihood for eGFR improvement after PTRA, P=ns for all). In the subgroup of 56 patients with pre-interventional eGFR <60 mL/min/1.73 m(2), similar findings were obtained. Quantification of renal function, but not any other pathophysiologic signal, provides at least moderate accuracy in the identification of patients with RAS in whom PTRA will improve renal function.


THB1, a truncated hemoglobin, modulates nitric oxide levels and nitrate reductase activity.
Hemoglobins are ubiquitous proteins that sense, store and transport oxygen, but the physiological processes in which they are implicated is currently expanding. Recent examples of previously unknown hemoglobin functions, which include scavenging of the signaling molecule nitric oxide (NO), illustrate how the implication of hemoglobins in different cell signaling processes is only starting to be unraveled. The extent and diversity of the hemoglobin protein family suggest that hemoglobins have diverged and have potentially evolved specialized functions in certain organisms. A unique model organism to study this functional diversity at the cellular level is the green alga Chlamydomonas reinhardtii because, among other reasons, it contains an unusually high number of a particular type of hemoglobins known as truncated hemoglobins (THB1-THB12). Here, we reveal a cell signaling function for a truncated hemoglobin of Chlamydomonas that affects the nitrogen assimilation pathway by simultaneously modulating NO levels and nitrate reductase (NR) activity. First, we found that THB1 and THB2 expression is modulated by the nitrogen source and depends on NIT2, a transcription factor required for nitrate assimilation genes expression. Furthermore, THB1 is highly expressed in the presence of NO and is able to convert NO into nitrate in vitro. Finally, THB1 is maintained on its active and reduced form by NR, and in vivo lower expression of THB1 results in increased NR activity. Thus, THB1 plays a dual role in NO detoxification and in the modulation of NR activity. This mechanism can partly explain how NO inhibits NR post-translationally.