Hypersensitivity pneumonitis in nonhuman primates. I. Studies on the relationship of immunoregulation and disease activity.
We investigated the relationship of immunoregulation to disease activity in a nonhuman primate model of pigeon breeder's disease. Two Macaca arctoides monkeys developed classical symptoms of hypersensitivity pneumonitis after sensitization and prolonged bronchial challenge, whereas 2 other monkeys remained asymptomatic after in vivo challenge. There were no differences in the percentages of T cells, B cells, monocytes, or FC gamma-bearing T cells between symptomatic and asymptomatic animals. Nonetheless, we found a population of concanavalin A-induced, pigeon serum- (PS) induced, and spontaneous T cells that functioned as suppressor cells in autologous in vitro co-cultures in asymptomatic animals that were missing or nonfunctional in symptomatic animals. Monocyte suppressors functioned in both groups. We used low-dose total body irradiation (TBI) to inactivate T suppressor cells. Fifteen radiation units of TBI caused no change in the physical activity, routine chemistries, or blood counts of the 4 animals. After TBI, however, the previously asymptomatic animals developed fever, tachypnea, and signs of pulmonary congestion after in vivo challenge with PS. There was no change in the response to challenge in the symptomatic group. This altered response to in vivo challenge in the previously asymptomatic group persisted for 2 wk after TBI. During this period the difference in vitro immunoregulatory activity between Con A-induced, PS-induced, and spontaneous T cells in symptomatic and asymptomatic animals disappeared. Monocyte suppressors, however, continued to function in both groups after TBI. These data suggest that the monkey is an appropriate model for studies of human HP and that T cell immunoregulation may be an important element in the pathogenesis and disease activity of HP.


Marinobufagenin extraction from Rhinella marina toad glands: Alternative approaches for a systematized strategy.
Marinobufagenin is a bufadienolide compound detected mainly in skin and parotoid gland secretions of Rhinella marina (L.) toad. Bufadienolides regulate the Na+ /K+ -ATPase pump by inhibiting the cardiotonic steroid dependent-site and act as cardiac inotropes with vasoconstrictive properties. Marinobufagenin and other bufadienolides, such as telocinobufagin and bufalin, are thought to be found endogenously in mammals in salt-sensitive hypertensive states such as essential hypertension, congestive heart-failure, and preeclampsia. The role of marinobufagenin as antimicrobial agent and its cytotoxic potential have also been recognized. The particular interest around marinobufagenin prompts us to consider the Rhinella marina toad venom as a possible source for molecules with pharmacological and/or diagnostic potential. In this article, two different approaches of extraction and purification of marinobufagenin from Rhinella marina (L.) venom are studied: (i) Preparative thin-layer chromatography combined to mass spectrometry and/or ultraviolet detection and (ii) solid-phase extraction coupled with fractionation on high-performance liquid chromatography. Different chromatographic conditions are tested for each approach. The solid-phase extraction combined with high-performance liquid chromatography fractionation approach was preferred as it offered a greater yield, was less time-consuming and allowed us to selectively isolate marinobufagenin. Both protocols aim to provide efficient and convenient methods for toad venom extraction, based on an easily automatable and systematized strategy.


Intramuscular pH and energy changes in muscle.
Intracellular pH (pHi) and buffering power of unstimulated sartorius muscle (frog) were measured with pH-sensitive microelectrodes. The mean pHi for muscle was about 0.3 units more acid than the extracellular pH in the range 7.0 to 7.2. The buffer power was 44.0 +/- SE 7.1 mM/pH unit for 19 fibres with pHi 6.83 +/- SE 0.05.


Current status and future directions of liver transplantation for metabolic liver disease in children.
Orthotopic liver transplantation (OLT) in the care of children with inborn errors of metabolism (IEM) is well established and represent the second most common indication for pediatric liver transplantation in most centers worldwide, behind biliary atresia. OLT offers cure of disease when a metabolic defect is confined to the liver, but may still be transformative on a patient's quality of life reducing the chance of metabolic crises causing neurological damage in children be with extrahepatic involvement and no "functional cure." Outcomes post-OLT for inborn errors of metabolism are generally excellent. However, this benefit must be balanced with consideration of a composite risk of morbidity, and commitment to a lifetime of post-transplant chronic disease management. An increasing number of transplant referrals for children with IEM has contributed to strain on graft access in many parts of the world. Pragmatic evaluation of IEM referrals is essential, particularly pertinent in cases where progression of extra-hepatic disease is anticipated, with long-term outcome expected to be poor. Decision to proceed with liver transplantation is highly individualized based on the child's dynamic risk-benefit profile, their family unit, and their treating multidisciplinary team. Also to be considered is the chance of future treatments, such as gene therapies, emerging in the medium term.


Motor imagery: effects of age, task complexity, and task setting.
BACKGROUND/STUDY CONTEXT: Mental training may potentially enhance motor performance and self-efficacy in older adults. However, several studies revealed an age-related decay of motor imagery (MI), which suggests that mental training might be too challenging for older adults. Recognizing that laboratory results are often not transferable to real-life situations, the purpose of the present study was to evaluate imagery performance in the elderly with a more real-life-like approach. MI performance of 21 older (70.28 ± 4.65 years) and 19 younger adults (24.89 ± 3.16 years) was estimated by mental chronometry from the first-person perspective. Subjects were asked to walk in a supermarket scenario straight ahead (A), or with two changes of direction (B), or with two changes of direction while retrieving products (C). The three tasks were completed first in the subjects' imagination and then in reality, with time required as the dependent measure. MI ability was also assessed by the Controllability of Motor Imagery (CMI) test, in which subjects are required to mentally assume a sequence of body postures. Age-related alterations of MI were observed for walking only in Tasks B and C, and only in terms of intersubject variability, not in terms of across-subject means. This is in contrast to earlier studies that used a less realistic walking scenario and found an age-related decay even for MI means. Age-related alterations of CMI were observed as well, but they correlated little with those of walking. These findings suggest that MI is not a global phenomenon, as it decays in old age independently in the temporal and in the spatial domain, decays less with simple than with complex tasks, and less in an everyday-like than in a typical laboratory setting. These characteristics of MI should be taken into account when assessing its decay in old age, and when designing mental training for the elderly.


Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events and restenosis in patients undergoing coronary stent implantation: a prospective study.
Endothelial dysfunction plays a key role in atherosclerosis and predicts future cardiovascular events in individuals with or without coronary artery disease and improves with risk reduction therapy. We sought to determine the predictive value of endothelial dysfunction for long-term cardiovascular events and in-stent restenosis in patients undergoing percutaneous coronary intervention (PCI). Using high-resolution ultrasound, we assessed endothelial function by using the brachial artery flow-mediated dilation (FMD) method in 135 patients with coronary artery disease before elective coronary stenting. Patients were prospectively followed up for an average of 12 months after PCI. Thirty patients had an event during follow-up including cardiac death (four patients), myocardial infarction (nine patients), unstable angina/non-ST elevation myocardial infarction (15 patients), and stroke (two patients) and in-stent restenosis was determined in 16 of these patients. Endothelium-dependent FMD was significantly lower in patients who had an event compared with those without an event (4.7+/-1.9 vs. 6.0+/-2.0%, P=0.007), whereas endothelium-independent vasodilation to nitroglycerin was similar in both groups. FMD was the only predictor of cardiovascular events (P=0.03). Impaired endothelial function was associated with a significantly higher incidence of cardiovascular events and in-stent restenosis by Kaplan-Meier analysis. When a cutoff point of 7.5% was used, flow-mediated dilation had a sensitivity of 93%, specificity of 37%, and negative predictive value of 95% for cardiovascular events. Impaired brachial artery FMD is associated with long-term cardiovascular events and in-stent restenosis in patients undergoing PCI. Noninvasive assessment of endothelial function may serve as a surrogate marker for the estimation of future cardiovascular event risk and long-term follow-up in these patients.


Effect of methotrexate on the mandibular development of arthritic rabbits.
Juvenile idiopathic arthritis affecting the temporomandibular joint (TMJ) can cause severe disturbances of the mandibular development. Methotrexate (MTX) is often administered as a common used remission-inducing agent to treat this disease. The aim of this study was to investigate the effect of low dose MTX on the mandibular growth in arthritic rabbits. Eighteen 10-week-old female New Zealand white rabbits were randomly assigned to three groups with six animals in each group. After being sensitized to ovalbumin (OA), the first and the second group received intra-articular injections with OA. The first group remained untreated, the second was treated by weekly injections of MTX. Cephalograms were taken from each animal at 10, 13, 16, 19, and 22 weeks of age and six mandibular distances measured. All distances showed an increase between 10 and 20 per cent, whereas growth was more accentuated in the sagittal dimension. Significant differences in the overall growth could be observed between the arthritic and the control animals and less accentuated between the arthritic and the MTX animals. In contrast, existing differences between the groups were not significant during the intervals, but time had the greatest influence on mandibular growth. MTX seems to have a positive impact on growth in rabbits suffering from experimental arthritis of the TMJ.


Midterm results for endovascular stent grafts via median sternotomy for distal aortic arch aneurysm.
Dislocation or perigraft leakage is a major problem during the follow-up period for endovascular stent graft (EVG) implantation via median sternotomy for distal aortic arch aneurysm. Anchoring sutures have been applied for the prevention of these complications. Here, we evaluate the midterm results and the efficacy of anchoring sutures. There were 21 male and 2 female patients enrolled in the study with an average age of 70 years (59-83). Aneurysm types were 21 true aneurysms (13 fusiform, 8 saccular), 1 chronic dissection, and 1 penetrating aortic ulcer. Total arch replacement was performed in two patients and aortocoronary bypass grafting was combined in four patients. Anchoring sutures to fix the EVG via median sternotomy were applied for 11 recent patients. The average follow-up period was 44 (22-79) months. There were no operative mortalities, but one case of paraplegia, one of stroke, and two of temporary spinal cord dysfunction. Complications related to EVG via median sternotomy occurred in five patients who had not received anchoring sutures, but the 11 patients with anchoring sutures showed no EVG-related complications. A chronic type B dissection revealed impending rupture due to false lumen infection 1 year after operation and repeat surgery was performed. Stent dislocation occurred in four patients, two of whom required repeat surgery via left thoracotomy due to endoleakage 3 and 4 years after surgery. One died from aneurismal rupture 5 years after surgery. One required emergency graft replacement because of graft perforation 5 years after surgery. The proportion of patients free from EVG-related events at 5 years after surgery was 75%. Anchoring sutures (P = 0.0155) and a large aneurysm of more than 80 mm (P = 0.0190) were predictors of late EVG-related complications. There were five late deaths: two were from stroke, one from rupture, one from cancer, and one from multiple organ failure after repeat surgery. EVG shortens postoperative recovery with relatively lower mortality, but spinal cord injury is a complication occurring with a relatively high rate. Patients with large aneurysms are not good candidates for EVG implantation via median sternotomy Anchoring sutures to fix the EVG to the aortic wall should help prevent EVG-related events and improve the durability of EVG.


Radiopacity of Portland Cement and Calcium Silicate-Based Cement with Different Mixed Ratios of Radiopacifiers.
The present study aimed to compare the radiopacity of Portland cement (PC) or calcium silicate-based cement (CSC) with different mixed radiopacifiers [bismuth oxide (BO)/ tantalum oxide (TO) and zirconium oxide (ZO)/barium sulfate (BS)] in a ratio of 1: 1 or 1: 2, with the 3 mm aluminium thickness (mmAl) acceptable value of ISO 6876: 2012. PC and CSC mixed with different ratios of radiopacifiers were evaluated. One of high radiopacity radiopacifiers, BO or TO, was mixed with one of low radiopacity radiopacifiers, ZO or BS, in ratio of 1: 1 and 1: 2. PC or CSC powder, 1.6 g, was added into 0.4 g mixed radiopacifiers. Disc-shaped specimens of 1-mm thickness were prepared by mixing PC or CSC powder containing radiopacifiers with distilled water; the radiopacity was measured according to ISO 6876: 2012. One-way ANOVA/Tukey's test and Welch ANOVA/Games-Howell test were used to compare the radiopacity among the groups. The significance level was set at 0.05. PC groups had a higher radiopacity than CSC groups with the same radiopacifiers and ratio. BO groups showed higher radiopacity than TO groups. The groups with 1: 1 ratio provided a higher radiopacity than 1: 2 ratio groups (P>0.05). All tested radiopacifiers revealed adequate radiopacity ranging from 3.05-4.25 mmAl, except CSC with TO/BS in ratio of 1: 2.


Sensitized airway smooth muscle plasticity and hyperreactivity: a review.
To help elucidate the mechanisms underlying asthmatic bronchospasm, the goal of our research has been to determine whether airway smooth muscle (ASM) hyperreactivity was the responsible factor. We reported that in a canine model of asthma, the shortening capacity (DeltaLmax) and velocity (Vo) of in vitro sensitized muscle were significantly increased. This increase was of sufficient magnitude to account for 75% narrowing of the in vivo airway, but maximal isometric force was unchanged. This last feature has been reported by others. Under lightly loaded conditions, ASM completes 75% of its isotonic shortening within the first 2 s. Furthermore, 90% of the increased shortening of ragweed pollen-sensitized ASM (SASM), compared with control (CASM), is complete within the first 2 s. The study of shortening beyond this period will apparently not yield much useful information, and studies of isotonic shortening should be focused on this interval. Although both CASM and SASM showed plasticity and adaptation with respect to isometric force, neither muscle type showed a difference in the force developed in these phases. During isotonic shortening, no evidence of plasticity was seen, but the equilibrated SASM showed increased DeltaLmax and Vo of shortening. Molecular mechanisms of changes in Vo could result from changes in the kinetics of the myosin heavy chain ATPase. Motility assay, however, showed no changes between CASM and SASM in the ability of the purified myosin molecule (SF1) to translocate a marker actin filament. On the other hand, we found that the state of activation of the ATPase by phosphorylation of smooth muscle myosin light chain (molecular mass 20,000 Da) was greater in the SASM. This would account for the increased Vo. Investigating the signalling pathway, we found that whereas [Ca2+]i increased in both isometric and isotonic contraction, there was no significant difference between CASM and SASM. The content and activity of calmodulin were also not different between the 2 muscles. Nevertheless, we did find that content and total activity of smooth muscle myosin light chain kinase (smMLCK) and the abundance of its message were greater; this would explain the increased MLC20 phosphorylation. The binding affinity between Ca2+ and calmodulin and between 4 Ca2+ calmodulin and smMLCK remains to be studied. We conclude that SASM shows increased isotonic shortening capacity and velocity. It also shows increased content and total activity of smMLCK, which is consistent with the increased shortening. Plasticity produced by oscillation is not seen in the shortening muscle, although it is seen with respect to force development. It did not modulate the behaviour of the sensitized muscle.


Structural organization of a viral IRES depends on the integrity of the GNRA motif.
Little is known about the tertiary structure of internal ribosome entry site (IRES) elements. The central domain of foot-and-mouth disease (FMDV) IRES, named 3 or I, contains a conserved GNRA motif, essential for IRES activity. We have combined functional analysis with RNA probing to define its structural organization. We have found that a UNCG motif does not functionally substitute the GNRA motif; moreover, binding of synthetic GNRA stem-loops to domain 3 was significantly reduced in RNAs bearing UCCG or GUAG substitutions. The apical region of domain 3 consists of a four-way junction where residues of the GNRA tetraloop are responsible for the organization of the adjacent stem-loops, as deduced from ribonucleases and dimethyl sulfate accessibility. A single A-to-G substitution in the fourth position of this motif led to a strong RNA reorganization, affecting several nucleotides away in the secondary structure of domain 3. The study of mutants bearing UNCG or GUAG tetraloops revealed lack of protection to chemical attack in native RNA at specific nucleotides relative to the parental GUAA, suggesting that the GNRA motif dictates the organization and stability of domain 3. This effect is likely mediated by the interaction with distant residues. Therefore, the GNRA motif plays a crucial role in the organization of IRES structure with important consequences on activity.


Overexpression of grainyhead-like transcription factor 2 is associated with poor prognosis in human pancreatic carcinoma.
Recent studies have demonstrated that the abnormal expression of the grainyhead-like transcription factor 2 (GRHL2) gene contributes to the progression and poor prognosis of cancer through multiple mechanisms, but little is known about its expression status and prognostic value in pancreatic carcinoma (PC). The aim of the present study was to investigate the expression of GRHL2 in PC and to evaluate its clinicopathological and prognostic significance. Immunohistochemistry and western blotting were used to detect the expression of GRHL2 in PC tissues and cell lines, respectively. The expression of GRHL2 was investigated in 92 PC tissue samples by immunohistochemistry. High expression of GRHL2 was significantly associated with histological differentiation (P=0.018) and lymphatic metastasis (P=0.024). A Kaplan-Meier analysis revealed that high expression of GRHL2 was associated with worsened overall survival time (P<0.001). Multivariate analysis indicated that GRHL2 may be an independent prognostic factor for poor overall survival time (P=0.001). Additionally, western blot analysis demonstrated that the GRHL2 protein was highly expressed in PC cell lines. GRHL2 may serve an important role in the tumourigenesis of PC and serve as a potential therapeutic target for the prevention of PC progression.


FAMILIAL COMBINED HYPERLIPIDEMIA: CURRENT KNOWLEDGE, PERSPECTIVES, AND CONTROVERSIES.
Familial combined hyperlipidemia (FCHL) is the most prevalent primary dyslipidemia; however, it frequently remains undiagnosed and its precise definition is a subject of controversy. FCHL is characterized by fluctuations in serum lipid concentrations and may present as mixed hyperlipidemia, isolated hypercholesterolemia, hypertriglyceridemia, or as a normal serum lipid profile in combination with abnormally elevated levels of apolipoprotein B. FCHL is an oligogenic primary lipid disorder, which can occur due to the interaction of several contributing variants and mutations along with environmental triggers. Controversies surrounding the relevance of identifying FCHL as a cause of isolated hypertriglyceridemia and a differential diagnosis of familial hypertriglyceridemia are offset by the description of associations with USF1 and other genetic traits that are unique for FCHL and that are shared with other conditions with similar pathophysiological mechanisms. Patients with FCHL are at an increased risk of cardiovascular disease and mortality and have a high frequency of comorbidity with other metabolic conditions such as type 2 diabetes, non-alcoholic fatty liver disease, steatohepatitis, and the metabolic syndrome. Management usually requires lipid-lowering therapy directed toward reducing cholesterol and triglyceride concentrations along with cardiovascular risk protection. In recent years, the number of research studies on FCHL has been decreasing, mainly due to a lack of recognition of its impact on disease burden and comorbidity and the complexity in identifying probands for studies. This creates areas of opportunity to develop research for FCHL in epidemiology, genetics, pathophysiology, therapeutics, and cardiovascular risk management, which are discussed in depth in this review. (REV INVEST CLIN. 2018;70:224-36).


Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma.
Copper (Cu) is an essential element of organisms, which can affect the survival of cells. However, the role of copper metabolism and cuproptosis on hepatic carcinoma is still unclear. In this study, the TCGA database was used as the test set, and the ICGC database and self-built database were used as the validation set. We screened out a class of copper metabolism and cuproptosis-related genes (CMCRGs) that could influence hepatic carcinoma prognosis by survival analysis and differential comparison. Based on CMCRGs, patients were divided into two subtypes by cluster analysis. The C2 subtype was defined as the high copper related subtype, while the C1 subtype was defied as the low copper related subtype. At the clinical level, compared with the C1 subtype, the C2 subtype had higher grade pathological features, risk scores, and worse survival. In addition, the immune response and metabolic status also differed between C1 and C2. Specifically, C2 subtype had a higher proportion of immune cell composition and highly expressed immune checkpoint genes. C2 subtype had a higher TIDE score with a higher proportion of tumor immune dysfunction and exclusion. At the molecular level, the C2 subtype had a higher frequency of driver gene mutations (TP53 and OBSCN). Mechanistically, the single nucleotide polymorphisms of C2 subtype had a very strong transcriptional strand bias for C>A mutations. Copy number variations in the C2 subtype were characterized by LOXL3 CNV gain, which also showed high association with PDCD1/CTLA4. Finally, drug sensitivity responsiveness was assessed in both subtypes. C2 subtype had lower IC50 values for targeted and chemotherapeutic agents (sorafenib, imatinib and methotrexate, etc.). Thus, CMCRGs related subtypes showed poor response to immunotherapy and better responsiveness to targeted agents, and the results might provide a reference for precision treatment of hepatic carcinoma.


First Report of Citrus tristeza virus Infecting Citrus Trees in Georgia, USA.
Citrus tristeza virus (CTV) [genus Closterovirus; family Closteroviridae] is one of the most important, economically devastating viruses of citrus worldwide. On citrus trees grafted onto sour orange rootstock, typical CTV symptoms include dieback and defoliation, stunting, curling and chlorotic leaves, stem-pitting, and pinholes below the bud union on the inner face of the bark (Moreno et al. 2008). This single-stranded, positive-sense RNA virus is most efficiently transmitted by the brown citrus aphid (Toxoptera citricida), but it can also be transmitted by other aphid species and through grafting of infected plant material onto healthy plants (Moreno et al 2008; Herron et al. 2006). In Fall 2020, leaf material for virus testing was collected from 13 navel orange trees (Citrus × sinensis) grafted onto Poncirus trifoliata rootstocks (including 'Flying Dragon') located in a citrus research orchard in Tifton, GA. Trees ranged in age from 2 to 10 years, with the younger trees having been grafted from cuttings taken from the older trees. The oldest of these trees was derived from cuttings taken in 2009 from an orange tree growing locally in a residential yard in Tifton; this parent tree was more than 15 years old when these cuttings were obtained and was no longer available for sampling as of 2020. Symptoms or other visible signs of disease had not been noted on any of the tested trees, and trees were chosen for testing prior to the further dissemination of this plant material. The presence of CTV was verified via molecular and serological testing. CTV infection was initially confirmed in 8 of 13 tested samples using the ImmunoStrip® for CTV assay (Agdia® Inc., Elkhart, IN, cat no: ISK 78900/0025) according to the manufacturer's instructions. RNA was extracted from leaf material collected from the 13 sampled trees using the RNeasy Plant Mini Kit (Qiagen, Valencia, CA). Following cDNA synthesis, samples were tested for the presence of CTV by reverse-transcription PCR using primer pair AR18F (5'-ATGTCAGGCAGCTTGGGAAATT-3') and AR18R (5'-TTCGTGTCTAAGTCRCGCTAAACA-3') which produces a 511 bp amplicon (Roy et al., 2005). PCR reactions confirmed the presence of CTV, with the same eight samples that had previously tested positive via Immunostrip® producing PCR fragments of the expected size. Amplified products from two of these samples were then sequenced using Sanger sequencing (Retrogen Inc, San Diego, CA, USA) and subjected to BLAST analysis (https://blast.ncbi.nlm.nih.gov/Blast.cgi) for further identification. Sequence analysis revealed that the obtained partial sequences (MW540805) from the p18 gene of both isolates were 100% identical to one another and shared 100% identity to corresponding sequences from CTV strain N4 (MK779711.1). To the best of our knowledge, this is the first report of CTV infecting citrus plants in Georgia. CTV could pose an imminent threat to the emerging citrus industry in Georgia if it were to become established in commercial citrus plantings either via the dissemination of infected plant material or via vector transfer of the virus under field conditions. While the brown citrus aphid is not known to be widespread in Georgia at this time, other CTV vectors are prevalent including the cotton aphid (Aphis gossypii) and the black citrus aphid (T. aurantia). Georgia citrus growers and plant propagators should be aware of this virus and take appropriate control measures to prevent the spread of this viral diseas.


Megabase-scale presence-absence variation with Tripsacum origin was under selection during maize domestication and adaptation.
Structural variants (SVs) significantly drive genome diversity and environmental adaptation for diverse species. Unlike the prevalent small SVs (< kilobase-scale) in higher eukaryotes, large-size SVs rarely exist in the genome, but they function as one of the key evolutionary forces for speciation and adaptation. In this study, we discover and characterize several megabase-scale presence-absence variations (PAVs) in the maize genome. Surprisingly, we identify a 3.2 Mb PAV fragment that shows high integrity and is present as complete presence or absence in the natural diversity panel. This PAV is embedded within the nucleolus organizer region (NOR), where the suppressed recombination is found to maintain the PAV against the evolutionary variation. Interestingly, by analyzing the sequence of this PAV, we not only reveal the domestication trace from teosinte to modern maize, but also the footprints of its origin from Tripsacum, shedding light on a previously unknown contribution from Tripsacum to the speciation of Zea species. The functional consequence of the Tripsacum segment migration is also investigated, and environmental fitness conferred by the PAV may explain the whole segment as a selection target during maize domestication and improvement. These findings provide a novel perspective that Tripsacum contributes to Zea speciation, and also instantiate a strategy for evolutionary and functional analysis of the "fossil" structure variations during genome evolution and speciation.


Multiple and interconnected pathways for L-lysine catabolism in Pseudomonas putida KT2440.
L-lysine catabolism in Pseudomonas putida KT2440 was generally thought to occur via the aminovalerate pathway. In this study we demonstrate the operation of the alternative aminoadipate pathway with the intermediates D-lysine, L-pipecolate, and aminoadipate. The simultaneous operation of both pathways for the use of L-lysine as the sole carbon and nitrogen source was confirmed genetically. Mutants with mutations in either pathway failed to use L-lysine as the sole carbon and nitrogen source, although they still used L-lysine as the nitrogen source, albeit at reduced growth rates. New genes were identified in both pathways, including the davB and davA genes that encode the enzymes involved in the oxidation of L-lysine to delta-aminovaleramide and the hydrolysis of the latter to delta-aminovalerate, respectively. The amaA, dkpA, and amaB genes, in contrast, encode proteins involved in the transformation of Delta1-piperidine-2-carboxylate into aminoadipate. Based on L-[U-13C, U-15N]lysine experiments, we quantified the relative use of pathways in the wild type and its isogenic mutants. The fate of 13C label of L-lysine indicates that in addition to the existing connection between the D- and L-lysine pathways at the early steps of the catabolism of L-lysine mediated by a lysine racemase, there is yet another interconnection at the lower end of the pathways in which aminoadipate is channeled to yield glutarate. This study establishes an unequivocal relationship between gene and pathway enzymes in the metabolism of L-lysine, which is of crucial importance for the successful colonization of the rhizosphere of plants by this microorganism.


Effects of algerian nettle (Urtica dioica L.) on benign prostatic hyperplasia and their mechanism of action elucidation: in vivo and in silico approaches.
This study investigated the effect of Urtica dioica roots etheric extract (UDEE) on oxidative stress, and urine obstruction with histopathological examinations of prostatic and renal tissues,and suggests computational methods as a complementary method, to make a hypothesis on the overall effect of UDEE in the treatment of benign prostatic hyperplasia (BPH).Gas chromatography/mass spectrometry was utilised to characterise UDEE.BPH was induced in rats through daily subcutaneous injections of testosterone propionate. Rats were also orally administered UDEE or a vehicle. After four weeks, prostate weight, urine output, and biochemical markers were evaluated. UDEE treatment demonstrated significant regression of prostatic enlargement, improved biochemical and histopathological characteristics, and regulation of antioxidant activity levels. Phytosteroids stand out, act by inhibiting 5α-reductase and aromatase. This study provides an insight into treatment of BPH, demonstrating safety of this compound towards the kidney compared to finasteride without severe side effects.


Preconditioning Enhances the Therapeutic Effects of Mesenchymal Stem Cells on Colitis Through PGE2-Mediated T-Cell Modulation.
Mesenchymal stem cell (MSC)-based cell therapy has been demonstrated as a promising strategy in the treatment of inflammatory bowel disease (IBD), which is considered an immune disease. While the exact mechanisms underlying the therapeutic effect of MSCs are still unclear, MSCs display anti-inflammatory and immunomodulatory effects by interacting with various immunoregulatory cells. Our previous studies have shown that MSCs can be preconditioned and deconditioned with enhanced cell survival, differentiation and migration. In this study, we evaluated the effect of preconditioning on the immunoregulatory function of human umbilical cord-derived MSCs (hUCMSCs) and their therapeutic effect on treating IBD. Our results show that intraperitoneal administration of deconditioned hUCMSCs (De-hUCMSCs) reduces the disease activity index (DAI), histological colitis score and destruction of the epithelial barrier, and increases the body weight recovery more intensively than that of un-manipulated hUCMSCs. In addition, De-hUCMSCs but not hUCMSCs elicit anti-apoptotic effects via induction of the ERK pathway during the early stage of IBD development. In vitro co-culture studies indicate that De-hUCMSCs suppress T-cell proliferation and activation more markedly than hUCMSCs. Moreover, De-hUCMSCs block the induction of inflammatory cytokines such as tumor necrosis factor (TNF)α and interleukin (IL)-2, while promoting the secretion of the anti-inflammatory cytokine IL-10 in T-cells. Mechanically, we find that prostaglandin E2 (PGE2) secretion is significantly increased in De-hUCMSCs, the suppression of which dramatically abrogates the inhibitory effect of De-hUCMSCs on T-cell activation, implying that the crosstalk between De-hUCMSCs and T-cells is mediated by PGE2. Together, we have demonstrated that preconditioning enhances the immunosuppressive and therapeutic effects of hUCMSCs on treating IBD via increased secretion of PGE2.


Goblet cells segmentation from confocal laser endomicroscopy with an improved U-Net.
Gastric intestinal metaplasia (GIM) is regarded as a remarkable precursor for the development of intestinal-type stomach cancer. Goblet cell (GC) segmentation is the crucial step for assessing the degree of GIM by confocal laser endomicroscopy (CLE). However, GC segmentation by hand is difficult, unreliable, and time-consuming. Meanwhile, due to the high resolution and noise interference of CLE images, existing segmentation approaches perform poorly on this task. To tackle those issues, we collected 343 confocal laser endomicroscopy images of 62 patients from a Grade-A tertiary hospital. Each CLE image is manually annotated and then verified three times by skilled medical specialists. Then, U-Net is improved by incorporating the pixel gradient attention mechanism, which focuses on color gradient information around GC and captures color gradient features to direct feature maps in the skip connection layer. At last, the model output vector is used to calculate the possibility map and generate the final segmentation area. Compared with mainstream models, our proposed GC segmentation method from CLE with an improved U-Net (GCSCLE) performs the better segmentation result when tested on our CLE dataset and achieved an IOU of 87.95% and a DICE of 86.64%. Our result shows, the performance of the GCSCLE can be compared with the manual CLE image processing in clinical settings, and it can improve segmentation accuracy and save time and costs.


An extension of the pressure-test technique for immobilized biocatalyst preparations.
Based on an analysis of variables in the Ergun equation for pressure drop in granular beds, the technique of pressure-testing of immobilized biocatalyst preparations is reexamined from the point of view of evaluation of biocatalyst mechanical properties in packed bed reactors. The variation of biocatalyst particle size in the course of bioreactor performance was found to be a convenient estimate of mechanical strength for the biocatalyst particles. Based on this finding, an extension of the pressure-test technique with particle size analysis was proposed as an opportunity to carry out differential analysis of biocatalyst structure, regardless of time and position. An example of bed destruction is given to support the suggested characterization analysis.


Determination of total and unbound ribociclib in human plasma and brain tumor tissues using liquid chromatography coupled with tandem mass spectrometry.
Ribociclib is a selective, orally bioavailable inhibitor of cyclin-dependent kinase (CDK) 4/6, which has therapeutic potential for a variety of cancer types. This study was to develop and validate a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for determining total and unbound concentrations of ribociclib in human plasma and brain tumor tissue samples. Plasma and tumor homogenate samples were extracted using protein precipitation with acetonitrile. Unbound fraction in plasma or tumor homogenate was determined by equilibrium dialysis method. Chromatographic separation was achieved based on aqueous normal-phase chromatography mechanism on a Waters XBridge™ Amide column under isocratic elution with acetonitrile-ammonium formate (10 mM, pH 3) (75:25, v/v) at a flow rate of 0.8 mL/min. Ribociclib and the internal standard ([13C6]ribociclib) were monitored at the mass transitions m/z, 435.3 > 367.2 and 441.3 > 373.2, respectively, using positive electrospray ionization mode. The lower limit of quantitation (LLOQ) was 0.5 nM of ribociclib in plasma. Linear calibration curve was established at the concentration range of 0.5-1000 nM in plasma. Intra- and inter-day precision and accuracy were within the generally accepted criteria for bioanalytical method. The developed method was successfully applied to determine the plasma pharmacokinetics and central nervous system penetration of ribociclib in patients with malignant primary brain cancer.


Responses of pokeweed mitogen-stimulated peripheral mononuclear cells to human recombinant interleukins 3 and 4.
Peripheral blood mononuclear cells (PBMC) that had been stimulated with a polyclonal B cell activator, pokeweed mitogen (PWM), were examined for mitogenic responsiveness to interleukins (IL) and colony stimulating factors (CSF) or other cytokines using recombinant preparations from E. coli or Cos cells expressing their cloned cDNAs. PWM-stimulated PBMC (PWM-blasts) were found to be responsive to IL-3 depending upon the concentrations of the agent. Mitogenic response of PWM-blasts in the reaction to IL-3 was suppressed by the addition of a specific monoclonal antibody against IL-3 but not by anti-IL-2 serum, excluding the possibility that the DNA replication induced by IL-3 is a result of the proliferative response of IL-2 responder cells to IL-2, which might be produced during the culture of PWM-blasts in the presence of IL-3. The PWM-blasts were also responsive to IL-2 and IL-4 but not to other interleukins, namely, IL-1, IL-5 and IL-6, nor to granulocyte/macrophage (GM)-, granulocyte (G)- nor macrophage (M)-CSFs. They were also not responsive to interferon gamma. Similar responsiveness to IL-3 and IL-4 was found in the PBMC stimulated with a B-cell mitogen, Staphylococcus aureus Cowan 1 (Sac-1), but not in the PBMC stimulated with T cell mitogens, PHA or ConA. These results suggest that the human PBMC stimulated with B cell mitogens such as PWM or Sac-1 contain activated IL-3- and IL-4- responsive cells in sufficient number to detect these lymphokine activities.(ABSTRACT TRUNCATED AT 250 WORDS)


Estrogen depletion and drug treatment alter the microstructure of type I collagen in bone.
The impact of estrogen depletion and drug treatment on type I collagen fibril nanomorphology and collagen fibril packing (microstructure) was evaluated by atomic force microscopy (AFM) using an ovariectomized (OVX) rabbit model of estrogen deficiency induced bone loss. Nine month-old New Zealand white female rabbits were treated as follows: sham-operated (Sham; n = 11), OVX + vehicle (OVX + Veh; n = 12), OVX + alendronate (ALN, 600 μg/kg/wk., s.c.; n = 12), and OVX + cathepsin-K inhibitor L-235 (CatKI, 10 mg/kg, daily, p.o.; n = 13) in prevention mode for 27 weeks. Samples from the cortical femur and trabecular lumbar vertebrae were polished, demineralized, and imaged using AFM. Auto-correlation of image patches was used to generate a vector field for each image that mathematically approximated the collagen fibril alignment. This vector field was used to compute an information-theoretic entropy that was employed as a quantitative fibril alignment parameter (FAP) to allow image-to-image and sample-to-sample comparison. For all samples, no change was observed in the average FAP values; however significant differences in the distribution of FAP values were observed. In particular, OVX + Veh lumbar vertebrae samples contained a tail of lower FAP values representing regions of greater fibril alignment. OVX + ALN treatment resulted in a FAP distribution with a tail indicating greater alignment for cortical femur and less alignment for trabecular lumbar vertebrae. OVX + CatKI treatment gave a distribution of FAP values with a tail indicating less alignment for cortical femur and no change for trabecular lumbar vertebrae. Fibril alignment was also evaluated by considering when a fibril was part of discrete bundles or sheets (classified as parallel) or not (classified as oblique). For this analysis, the percentage of parallel fibrils in cortical femur for the OVX group was 17% lower than the Sham group. OVX + ALN treatment partially prevented the proportion of parallel fibrils from decreasing and OVX + CatKI treatment completely prevented a change. In trabecular lumbar vertebrae, there was no difference in the percentage of parallel fibrils between Sham and any of the other treatment groups.


[Sister chromatid exchange and cellular kinetics in lymphocytes of patients with adenoma and colonic cancer].
In this paper we describe the sister chromatid exchange (SCE) frequency and the cell-cycle kinetics in lymphocytes of peripheral blood from 51 untreated patients with colonic tumors: 30 with adenomas (A) (17 tubular, 6 tubulovillous and 7 villous) and 21 with carcinomas (C) (4 in situ and 17 invasive). SCE frequencies expressed as M +/- SD were 7.1 +/- 0.2 in A, 6.9 +/- 0.3 in C and 8.7 +/- 0.2 in controls. No differences were seen between the A and C frequencies and both values were significantly less than the control SCE frequencies (p less than 0.01). A lower SCE was observed in these patients especially in chromosomes 1 and 2 and groups B and D with respect to controls (p less than 0.01). The cell cycle kinetics of adenomas and carcinomas presented an elongation of the cell cycle time with reference to the controls (p less than 0.01). Replication indexes (RI) showed the following values: 1.8 +/- 0.06 in A, 1.8 +/- 0.08 in C and 2.1 +/- 0.05 in controls. The patients' values were significantly different from the controls (p less than 0.01). From the cytogenetic viewpoint, the similar behavior in SCE frequencies and cytokinetics found in adenoma and colon carcinoma suggest that adenoma is a preneoplastic lesion.


Crown construction to the lingual margin of a partial denture.
A technique is described which ensures that the interface between a newly constructed crown and an existing partial denture is accurate and neither crown nor denture need adjustment. At no time does the patient have to be without the denture. A silver plated die with a double dowelling technique is used.


Cluster-randomised trial to evaluate the 'Change for Life' mass media/ social marketing campaign in the UK.
Social marketing campaigns offer a promising approach to the prevention of childhood obesity. Change4Life (C4L) is a national obesity prevention campaign in England. It included mass media coverage aiming to reframe obesity into a health issue relevant to all and provided the opportunity for parents to complete a brief questionnaire ('How are the Kids') and receive personalised feedback about their children's eating and activity. Print and online C4L resources were available with guidance about healthy eating and physical activity. The study aims were to examine the impact of personalised feedback and print material from the C4L campaign on parents' attitudes and behaviours about their children's eating and activity in a community-based cluster-randomised controlled trial. Parents of 5-11 year old children were recruited from 40 primary schools across England. Schools were randomised to intervention or control ('usual care'). Basic demographic data and brief information about their attitudes to their children's health were collected. Families in intervention schools were mailed the C4L print materials and the 'How are the Kids' questionnaire; those returning the questionnaire were sent personalised feedback and others received generic materials. Outcomes included awareness of C4L, attitudes to the behaviours recommended in C4L, parenting behaviours (monitoring and modelling), and child health behaviours (diet, physical activity and television viewing). Follow-up data were collected from parents by postal questionnaire after six months. Qualitative interviews were carried out with a subset of parents (n = 12). 3,774 families completed baseline questionnaires and follow-up data were obtained from 1,419 families (37.6%). Awareness was high in both groups at baseline (75%), but increased significantly in the intervention group by follow-up (96% vs. 87%). Few parents (5.2% of the intervention group) returned the questionnaire to get personalised feedback. There were few significant group differences in parental attitudes or parenting and child health behaviours at follow-up. Physical activity was rated as less important in the intervention group, but a significant group-by-socioeconomic status (SES) interaction indicated that this effect was confined to higher SES families. Similar interactions were also seen for physical activity monitoring and child television time; with adverse effects in higher SES families and no change in the lower SES families. Effects were little better in families that completed the questionnaire and received personalised feedback. At interview, acceptability of the intervention was modest, although higher in lower SES families. The C4L campaign materials achieved increases in awareness of the campaign, but in this sample had little impact on attitudes or behaviour. Low engagement with the intervention appeared a key issue. Current Controlled Trials ISRCTN00791709.


Comparison of effects of 1 alpha-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin D3 in man.
The effects of short-term treatment with 1,25-dihydroxy-vitamin D3 [1,25(0H)2D3] or 1 alpha-hydroxy-vitamin D3 [1 alpha(OH)D3] on intestinal absorption of 47Ca were compared in 41 experiments in normals and 72 experiments in patients with chronic renal failure. 11 patients were studied a second time after treatment for 2-5 mo. Doses varied from 0.14 to 5.4 mug/day to establish dose-response relationships. Urinary calcium was monitored in normal subjects, nine of whom received a constant calcium intake on a metabolic unit. There was an increase in intestinal absorption of 47Ca and urinary calcium in normals receiving 1,25 (OH)2D3, 0.14 mug/day or greater, and 0.28 mug/day or greater augmented intestinal absorption of 47Ca in chronic renal failure. In contrast, 2.6 mug/day of 1 alpha (OH) D3 was required to increase intestinal absorption of 47Ca in both groups. The increase in urinary calcium to maximal levels was delayed during treatment with 1 alpha (OH) D3, 5-10 days vs. 2-5 days with 1,25 (OH)2D3. Moreover, half times for urinary calcium to decrease to pretreatment levels after stopping treatment were greater after 1 alpha-(OH) D3 (1.5-2.7 days) than 1,25(OH)2D3 (1.1-2.0 days). With long-term administration there was a progressive increase in intestinal absorption of 47Ca in the patients receiving 1 alpha (OH)D3; this was not observed with 1,25(OH)2D3. The pharmacologic differences between 1 alpha(OH) D3 and 1,25(OH)2D3 may be explained by the requirement for 25-hydroxylation of 1alpha(OH) D3 before biologic effects occur; at low doses (less than 1 mug/day), 1 alpha(OH) D3 competes with vitamin D3 for 25-hydroxylation. With prolonged treatment or larger doses (greater than 2 mug/day),, 1alpha(OH) D3 could accumulate and then be hydroxylated resulting in production of higher levels of 1,25(OH)2D3.


Clinical evaluation of self-etch and total-etch adhesive systems in noncarious cervical lesions: a two-year report.
The purpose of this study was to compare the clinical performance of two self-etch dental adhesives with Single Bond Plus, a traditional one-bottle total-etch dental adhesive, for the restoration of noncarious cervical lesions. A total of 156 restorations were placed in noncarious cervical lesions with a minimum depth of 1.5 mm. Patients had no chronic periodontal disease and had normal salivary function. Each patient received restorations on three teeth, each bonded with either Adper Single Bond Plus, Adper Easy Bond, or Adper Scotchbond SE dental adhesive. All lesions were restored with Filtek Supreme Plus composite resin. All teeth were isolated with a rubber dam, received a short enamel bevel, and were cleaned with flour of pumice. The adhesives and resin composite were applied following the manufacturers' instructions. Restorations were clinically evaluated at baseline, six months, one year, and two years using modified US Public Health Service criteria. Two-year retention was recorded as 97.3%, 90.5%, and 95.2%, for Single Bond Plus, Scotchbond SE, and Easy Bond, respectively. Statistical analysis did not show a significant difference (p>0.05) in clinical performance between any of the three adhesives after a period of two years.


What are we really achieving with long-term drug therapy?
Hypertension-induced morbidity and mortality can be positively affected by antihypertensive treatment. This was first shown in malignant phase hypertension and it is now clearly established that not only total mortality but also morbidity from stroke, left ventricular failure, and progressive renal failure can be positively affected by pharmacological lowering of arterial pressure. Benefits of treatment for coronary artery disease are less obvious. In spite of the positive effects of antihypertensive therapy briefly mentioned here, recent data from several centers show that hypertension-induced risks in treated hypertensive patients are not reduced down to the level seen in comparable normotensive subjects. There could be several reasons for this. Some of the hypertension-induced cardiovascular changes are irreversible, or that antihypertensive pharmacological agents may have some adverse effects that would partially offset the advantages obtained through a reduction in blood pressure, or that treated arterial blood pressure usually has not been brought down to strictly normotensive levels. Therefore, the risks associated with hypertension have not been lowered to those seen in normotensive subjects. This latter point assumes particular significance in view of some recent suggestions that a too drastic lowering of blood pressure in hypertensive subjects may be associated with an increased risk, particularly for coronary artery disease mortality.


Common Beliefs About Child Sexual Abuse and Disclosure: A College Sample.
Adults' common beliefs about child sexual abuse and disclosure were explored. Participants (N = 670) were questioned about key areas of child sexual abuse that could affect decision-making processes of jurors evaluating child sexual abuse cases. These areas included victim and perpetrator characteristics, medical and behavioral indicators of child sexual abuse, memories for the event, and disclosure of the event. The scientific literature pertaining to these same areas are reviewed. While individual beliefs were consistent with some areas of the scientific literature (e.g., victim and perpetrator characteristics), they strongly contrasted the literature in other important areas (e.g., memories for the event, indicators of child sexual abuse, and the likelihood of denial and recantation). Implications, including the option of providing expert testimony to reduce discrepancies, are discussed.


p53 codon 72 polymorphism in cervical cancer patients and healthy women from Poland.
A polymorphism at codon 72 of gene p53 results in the presence of either arginine or proline at this position. We investigated the distribution of p53 codon 72 polymorphism in cervical cancer patients and a control group of healthy women from Poland. Our results do not confirm the hypothesis that the p53 codon polymorphism could play a role as a factor for squamous carcinoma of the cervix.


Effect of age on allergen-induced structural airway changes in brown Norway rats.
It remains to be fully established whether allergen-induced airway inflammation and remodeling are influenced by age. The aim of the present study was to compare allergen-induced airway changes in young and adult rats. Brown Norway rats were sensitized at 4 weeks of age (young) or 13 weeks of age (adult) and exposed to aerosolized ovalbumin (OA) or phosphate-buffered saline for 2 weeks. In both age groups OA exposure induced an increase in OA-specific Immunoglobulin E and in the number of peribronchial eosinophils. OA-challenged animals also developed an increase in total airway wall area, enhanced fibronectin deposition, and goblet cell hyperplasia. Both inflammatory and structural alterations were more pronounced in the airways of young compared with adult OA-exposed rats. The number of peribronchial eosinophils was increased in young animals (685.4 +/- 75.0 versus 389.9 +/- 37.8/mm2 in adult rats; p < 0.001). A higher degree of goblet cell hyperplasia was observed in young rats (65.37 +/- 4.68 versus 34.74 +/- 3.68/mm basement membrane in adult rats; p < 0.001) and area of fibronectin deposition in the airway wall was higher in young compared with adult animals (5.08 +/- 0.46 versus 3.62 +/- 0.29 microm2/microm basement membrane; p < 0.005). In conclusion, in young rats airways are more susceptible to allergen-induced inflammatory and structural airway changes.


Practical guidance for the evaluation of disease progression and the decision to change treatment in patients with advanced gastric cancer receiving chemotherapy.
After failure of first-line chemotherapy with fluoropyrimidines and platinum compounds for advanced gastric cancer, second-line chemotherapy with ramucirumab plus paclitaxel, which elicits a durable response, and third-line or later chemotherapy with nivolumab have been shown to lead to a more favorable prognosis in advanced gastric cancer patients. As new and more effective drugs are now available, sequential chemotherapy would contribute to prolonged survival. From this point of view, the patient's disease course should be frequently monitored in order to adapt treatment regimens. This review summarizes the points to note in regard to radiological assessment, and discusses the integration of prognostic factors, tumor markers, and clinical symptoms that need to be taken into account to change treatment at an appropriate timing.


Inhibition of prostate cancer (LNCaP) cell proliferation by volatile components from Nagami kumquats.
Fresh Nagami kumquats (Fortunella margarita) were subjected to hydrodistillation using a Clevenger-type apparatus to obtain volatile oil. The chemical composition of the volatile oil was analyzed by GC-MS using Rtx-5 Sil MS and DB Wax columns. A total of 25 volatile compounds were identified by mass spectra, retention index, and comparison with known standards. The major identified compounds are d-limonene (41.64 %), β-myrecene (16.54 %), linalyl propionate (9.55 %), and germacrene-D (5.93 %) from the Rtx-5 Sil MS column; d-limonene and β-myrecene were also separated as major compounds on the DB wax column. The oil is rich in hydrocarbons (77.41 %) consisting of 60.05 % monoterpenes and 17.36 % sesquiterpenes. Interestingly, oxygenated hydrocarbons (17.6 %) were also found in kumquat volatile oil. Certain volatile compounds were also confirmed by positive chemical ionization and NMR spectra. Further, the volatile oil demonstrated good DPPH radical scavenging activity and antioxidant capacity. Kumquat volatile oil at 200 ppm concentration exhibited 55 %, 61 %, and 63.4 % inhibition of human prostate cancer (LNCaP) cell proliferation at 24, 48, and 72 h, respectively, by cell count assays. Significant increases in expression of bax/bcl2 and p53 proteins confirmed that volatile oil induces apoptosis. In addition, inhibition of inflammatory markers such as NF-κB and Cox-2 was observed. The cleavage of caspase-8 in the LNCaP cells treated with volatile oil demonstrated that apoptosis occurred through an extrinsic pathway. This is the first report of the identification and possible mechanisms of in vitro antiproliferative effects of kumquat volatile components on human prostate cancer (LNCaP) cells.


Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes.
First-phase insulin secretion (within 10 min after a sudden rise in plasma glucose) is reduced in type 2 diabetes mellitus (DM2). The incretin mimetic exenatide has glucoregulatory activities in DM2, including glucose-dependent enhancement of insulin secretion. The objective of the study was to determine whether exenatide can restore a more normal pattern of insulin secretion in subjects with DM2. Fasted subjects received iv insulin infusion to reach plasma glucose 4.4-5.6 mmol/liter. Subjects received iv exenatide (DM2) or saline (DM2 and healthy volunteers), followed by iv glucose challenge. Thirteen evaluable DM2 subjects were included in the study: 11 males, two females; age, 56 +/- 7 yr; body mass index, 31.7 +/- 2.4 kg/m2; hemoglobin A1c, 6.6 +/- 0.7% (mean +/- sd) treated with diet/exercise (n = 1), metformin (n = 10), or acarbose (n = 2). Controls included 12 healthy, weight-matched subjects with normal glucose tolerance: nine males, three females; age, 57 +/- 9 yr; and body mass index, 32.0 +/- 3.0 kg/m2. The study was conducted at an academic hospital. Plasma insulin, plasma C-peptide, insulin secretion rate (derived by deconvolution), and plasma glucagon were the main outcome measures. DM2 subjects administered saline had diminished first-phase insulin secretion, compared with healthy control subjects. Exenatide-treated DM2 subjects had an insulin secretory pattern similar to healthy subjects in both first (0-10 min) and second (10-180 min) phases after glucose challenge, in contrast to saline-treated DM2 subjects. In exenatide-treated DM2 subjects, the most common adverse event was moderate nausea (two of 13 subjects). Short-term exposure to exenatide can restore the insulin secretory pattern in response to acute rises in glucose concentrations in DM2 patients who, in the absence of exenatide, do not display a first phase of insulin secretion. Loss of first-phase insulin secretion in DM2 patients may be restored by treatment with exenatide.


Susceptibility of the heat-, acid-, and bile-adapted Vibrio vulnificus to lethal low-salinity stress.
As a marine pathogenic bacterium that inhabits seawater or seafood, Vibrio vulnificus encounters low salinity and other stresses in the natural environment and during food processing. This investigation explores the cross-protective response of sublethal heat-, acid-, or bile-adapted V. vulnificus YJ03 against lethal low-salinity stress. Experimental results reveal that the acid (pH 4.4)- and heat (41 degrees C)-adapted V. vulnificus were not cross-protected against the lethal low-salinity challenge (0.04% NaCl). The bile (0.05%)-adapted exponential- and stationary-phase cells were cross-protected against low salinity, whereas low-salinity (0.12% NaCl)-adapted stationary cells were sensitized against 12% bile stress. Results of this study provide further insight into the interaction between low salinity and other common stresses in V. vulnificus.


Endoscopic Intraventricular Atrial Adhesiolysis for the Treatment of Entrapped Temporal Horn after İntraventricular Tumor Surgery.
A 21-year-old male patient was operated for third ventricle tumor (central neurocytoma) and showed improvement in the early postoperative period. After 2 weeks of surgery, the patient neurologic status deteriorated with acute decreased level of consciousness. Neuroimaging of the brain revealed entrapped left temporo-occipital horns with adhesion bands at the level of the atrium. Patient was operated with neuronavigation-guided endoscopic approach to the left atrium through the left posterior parietal region. Band adhesiolysis was performed with no complications. The patient showed fast improvement, and follow-up brain magnetic resonance imaging after 2 years showed the release of the ventricular entrapment with significant regression of the left ventricle size.


Complementary use of resection and radiofrequency ablation for the treatment of colorectal liver metastases: an analysis of 395 patients.
Liver resection and radiofrequency ablation (RFA) are two surgical options in the treatment of patients with colorectal liver metastases (CLM). The aim of this study was to analyze patient characteristics and outcomes after resection and RFA for CLM from a single center. Between 2000 and 2010, 395 patients with CLM undergoing RFA (n = 295), liver resection (n = 94) or both (n = 6) were identified from a prospective IRB-approved database. Demographic, clinical and survival data were analyzed using univariate and multivariate analyses. RFA patients had more comorbidities, number of liver tumors and a higher incidence of extrahepatic disease compared to the Resection patients. The 5-year overall actual survival was 17 % in the RFA, 58 % in the Resection group (p = 0.001). On multivariate analysis, multiple liver tumors, dominant lesion >3 cm, and CEA >10 ng/ml were independent predictors of overall survival. Patients were followed for a median of 20 ± 1 months. Liver and extrahepatic recurrences were seen in 69 %, and 29 % of the patients in the RFA, and 40 %, and 19 % of the patients in the Resection group, respectively. In this large surgical series, we described the characteristics and oncologic outcomes of patients undergoing resection or RFA for CLM. By having both options available, we were able to surgically treat a large number of patients presenting with different degrees of liver tumor burden and co-morbidities, and also manage liver recurrences in follow-up.


Cellular localization of interleukin-8 and its inducer, tumor necrosis factor-alpha in psoriasis.
The importance of immunologic mechanisms in psoriasis has been deduced from the ability of immunosuppressive therapies to ameliorate this common and chronic skin disease. Certainly the histology of psoriatic lesions suggests a dialogue between the hyperplastic keratinocytes and infiltrating T lymphocytes and macrophages. To begin dissecting the cytokine network involved in the pathophysiology of psoriasis, the location, in both epidermal and dermal compartments, of tumor necrosis factor-alpha, interleukin-8, intercellular adhesion molecule-1, and transforming growth factor-alpha at the protein and/or mRNA levels were identified. Tumor necrosis factor-alpha was selected as a potentially key regulatory cytokine, first because it induces cultured keratinocyte interleukin-8, intercellular adhesion molecule-1, and transforming growth factor-alpha production, and second because intercellular adhesion molecule-1 expression by keratinocytes in psoriatic epidermis had been identified previously. Using immunohistochemical localization, tumor necrosis factor-alpha was identified in 12 psoriatic lesions as intense and diffuse expression by dermal dendrocytes (macrophages) in the papillary dermis (without significant staining of endothelial cells, mast cells, or dermal Langerhans cells), and focally by keratinocytes and intraepidermal Langerhans cells. Functional interaction between the dermal dendrocytes and keratinocytes was suggested by the presence of interleukin-8 expression of suprabasal keratinocytes immediately above the tumor necrosis factor-alpha-positive dermal dendrocytes. Interleukin-8 mRNA and transforming growth factor-alpha mRNA were detectable in the epidermal roof of psoriatic lesions, but neither was detectable at the protein or mRNA levels in any normal skin specimens. Treatment of cultured human keratinocytes with phorbol ester (which experimentally produces psoriasiform changes on mouse skin) or tumor necrosis factor-alpha also increased interleukin-8 and transforming growth factor-alpha mRNAs. Further elucidation of the cellular and molecular basis for the genesis and evolution of psoriasis will provide the framework for a better evaluation of the cause and treatment of this skin disease.


The IARC TP53 database: new online mutation analysis and recommendations to users.
Mutations in the tumor suppressor gene TP53 are frequent in most human cancers. Comparison of the mutation patterns in different cancers may reveal clues on the natural history of the disease. Over the past 10 years, several databases of TP53 mutations have been developed. The most extensive of these databases is maintained and developed at the International Agency for Research on Cancer. The database compiles all mutations (somatic and inherited), as well as polymorphisms, that have been reported in the published literature since 1989. The IARC TP53 mutation dataset is the largest dataset available on the variations of any human gene. The database is available at www.iarc.fr/P53/. In this paper, we describe recent developments of the database. These developments include restructuring of the database, which is now patient-centered, with more detailed annotations on the patient (carcinogen exposure, virus infection, genetic background). In addition, a new on-line application to retrieve somatic mutation data and analyze mutation patterns is now available. We also discuss limitations on the use of the database and provide recommendations to users.


Correlation of the High-Resolution Computed Tomography Patterns of Intrathoracic Sarcoidosis with Serum Levels of SAA, CA 15.3, SP-D, and Other Biomarkers of Interstitial Lung Disease.
Studies on the serum biomarkers of granulomatous inflammation and pulmonary interstitial disease in intrathoracic sarcoidosis have shown conflicting results. We postulated that differences in the concentrations of serum biomarkers can be explained by the heterogenous patterns of sarcoidosis seen on thoracic HRCT. Serum biomarker levels in 79 consecutive patients, newly diagnosed with intrathoracic sarcoidosis, were compared to our control group of 56 healthy blood donors. An analysis was performed with respect to HRCT characteristics (the presence of lymph node enlargement, perilymphatic or peribronchovascular infiltrates, ground-glass lesions, or fibrosis), CXR, and disease extent. Serum levels of CXCL9, CXCL10, CTO, and CCL18 were statistically significantly increased in all patients compared to controls. Serum levels of CA15.3 were statistically significantly increased in all patients with parenchymal involvement. SAA was increased in patients with ground-glass lesions while SP-D levels were statistically significantly increased in patients with lung fibrosis. Only SP-D and CA15.3 showed a significant correlation to interstitial disease extent. In conclusion, we found that sarcoidosis patients with different HRCT patterns of intrathoracic sarcoidosis have underlying biochemical differences in their serum biomarkers transcending Scadding stages. The stratification of patients based on both radiologic and biochemical characteristics could enable more homogenous patient selection for further prognostic studies.


Recent developments in asymmetric phase-transfer reactions.
Phase-transfer catalysis has been recognized as a powerful method for establishing practical protocols for organic synthesis, because it offers several advantages, such as operational simplicity, mild reaction conditions, suitability for large-scale synthesis, and the environmentally benign nature of the reaction system. Since the pioneering studies on highly enantioselective alkylations promoted by chiral phase-transfer catalysts, this research field has served as an attractive area for the pursuit of "green" sustainable chemistry. A wide variety of asymmetric transformations catalyzed by chiral onium salts and crown ethers have been developed for the synthesis of valuable organic compounds in the past several decades, especially in recent years.


Arches and contact forces in a granular pile.
Assemblies of granular particles mechanically stable under their own weight contain arches. These are structural units identified as sets of mutually stable grains. It is generally assumed that these arches shield the weight above them and should bear most of the stress in the system. We test such hypothesis by studying the stress born by in-arch and out-of-arch grains. We show that, indeed, particles in arches withstand larger stresses. In particular, the isotropic stress tends to be larger for in-arch grains whereas the anisotropic component is marginally distinguishable between the two types of particles. The contact force distributions demonstrate that an exponential tail (compatible with the maximization of entropy under no extra constraints) is followed only by the out-of-arch contacts. In-arch contacts seem to be compatible with a Gaussian distribution consistent with a recently introduced approach that takes into account constraints imposed by the local force balance on grains.


Persevering through a difficult time during the SARS outbreak in Toronto.
The purpose of this study was to describe the experience of persevering through a difficult time for patients, family members of patients, nurses, and allied health professionals during the severe acute respiratory syndrome outbreak. van Kaam's phenomenological research method, with the human becoming theory as the theoretical perspective, was used to gather and analyse data from 63 participants who agreed to describe a situation that illuminated their experience of persevering through a difficult time (either online or using a voicemail system). Data gathering occurred in early April 2003 in the midst of the severe acute respiratory syndrome outbreak in Toronto, Canada. The finding was the structural definition, persevering through a difficult time is dispiriting trepidation arising with witnessing suffering. It is a smothering connectedness with sequestering protection as unsettling contentment emerges amid unburdening hope. It sheds light on what is important for preparing for possible future outbreaks of this and other infectious diseases.


Diagnosis and Treatment of Adenomyosis with Office Hysteroscopy-A Narrative Review of Literature.
Adenomyosis is a common chronic disease in women of reproductive age, characterised by the presence of ectopic endometrial tissue within myometrium. Even though adenomyosis presents with chronic pelvic pain, menorrhagia or abnormal uterine bleeding, dysmenorrhoea, and dyspareunia and is often recognised after hysterectomies. However, the development of ultrasonography and magnetic resonance imaging has improved the pre-operative diagnosis of the disease. Hysteroscopy provides information in real time from the uterine cavity and the offers the possibility of obtaining direct biopsies. The literature was searched via Pubmed and Embase with the following headings: diagnosis of adenomyosis or adenomyoma and office hysteroscopy, hysteroscopy findings of adenomyosis or adenomyoma, treatment of adenomyosis or adenomyoma with office hysteroscopy. The literature showed that hysteroscopy can identify superficial adenomyosis. There are a variety of hysteroscopic images that can be connected with the disease. New equipment like the spirotome has been used to access deeper layers of myometrium and obtain biopsies under direct vision from the adenomyotic areas. Different methods of treatment have been also described, like enucleation of focal superficial adenomyoma, coagulation, evacuation of cystic adenomyosis when the lesion is smaller than 1.5 cm, and resection of adenomyotic nodules in case of bigger lesions (>1.5 cm). Diffuse superficial adenomyosis is also managed by resection. Hysteroscopy has revolutionised the approach to adenomyosis. It is a useful tool in assessing mainly superficial adenomyosis. The role of hysteroscopy in surgical management of adenomyosis need to be confirmed with further studies.


Effects of high environmental temperatures on cecal coccidiosis.
Maintenance of broiler or White Leghorn cockerels in a high temperature (32 C.), high humidity (90%) environment for six days following artificial infection with Eimeria tenella significantly reduced coccidiosis severity as compared to birds similarly infected and maintained in an ambient environment averaging 24.5 C., and 62% humidity. Disease severity was determined by lesion scores, fecal scores, and hematocrit readings. The heavier broiler stock maintained body temperatures of 0.7-1.6 C. higher than those birds kept at ambient temperatures for the entire six days. Body temperatures of heat-treated Leghorn cockerels were 0.9 C. higher during the first 48 hours post-inoculation (P.I.), but similar to ambient temperature controls for the last four days. Elevated body temperatures during the first two days following inoculation impaired the survival and development of some parasites while shorter periods (24 hours) of heat treatment did not affect parasite survival.


Direct evidence of the multidimensionality of the free-energy landscapes of proteins revealed by mechanical probes.
The study of mechanical unfolding, through the combined efforts of atomic force microscopy and simulation, is yielding fresh insights into the free-energy landscapes of proteins. Thus far, experiments have been mostly analyzed with one-dimensional models of the free-energy landscape. We show that as the two ends of a protein, filamin, are pulled apart at a speed tending to zero, the measured mechanical strength plateaus at approximately 30 pN instead of going toward zero, deviating from the Bell model. The deviation can only be explained by a switch between parallel pathways. Insightful analysis of mechanical unfolding kinetics needs to account for the multidimensionality of the free-energy landscapes of proteins, which are crucial for understanding the behavior of proteins under the small forces experienced in vivo.


Syndemics and the biosocial conception of health.
The syndemics model of health focuses on the biosocial complex, which consists of interacting, co-present, or sequential diseases and the social and environmental factors that promote and enhance the negative effects of disease interaction. This emergent approach to health conception and clinical practice reconfigures conventional historical understanding of diseases as distinct entities in nature, separate from other diseases and independent of the social contexts in which they are found. Rather, all of these factors tend to interact synergistically in various and consequential ways, having a substantial impact on the health of individuals and whole populations. Specifically, a syndemics approach examines why certain diseases cluster (ie, multiple diseases affecting individuals and groups); the pathways through which they interact biologically in individuals and within populations, and thereby multiply their overall disease burden, and the ways in which social environments, especially conditions of social inequality and injustice, contribute to disease clustering and interaction as well as to vulnerability. In this Series, the contributions of the syndemics approach for understanding both interacting chronic diseases in social context, and the implications of a syndemics orientation to the issue of health rights, are examined.


[Spontaneous retroperitoneal hematoma in adrenal metastasis].
A 58-year-old man was hospitalized because of acute dull upper abdominal pain, radiating into the right flank and lower abdomen. The past history was unremarkable expect for thyroidectomy, performed 30 years previously for thyroid carcinoma. There was painful resistance on palpation of the right upper abdomen. The patient had not recently sustained any trauma. BIOCHEMICAL AND IMAGING INVESTIGATIONS: Erythrocyte sedimentation rate was increased to 38 mm/h, haemoglobin concentration was 11.7 g/dl but fell to 9.9 g/dl within the first 24 hours. Ultrasound and computed tomography (CT) revealed a large retroperitoneal mass (5 x 6.5 x 15 cm), its density of 64 Hounsfield units most strongly suggesting an haematoma. CT also showed enlargement of the right adrenal. Chest radiography demonstrated a space-occupying lesion in the right upper lobe. As a retroperitoneal haematoma of uncertain aetiology was suspected, a laparotomy was performed. The haematoma was evacuated and the adrenal, showing tumours changes, was excised. Histologically it was a mucocellular metastasis. The chest radiograph suggested carcinoma of the lung as the primary. The illness took a rapidly fatal course. Autopsy confirmed a poorly differentiated adenocarcinoma of the lung. Trauma or anticoagulation should be considered first in the differential diagnosis of retroperitoneal haematoma of uncertain aetiology. However, adrenal metastasis should be thought of as a rare possibility.


Health for All? Sexual Orientation, Gender Identity, and the Implementation of the Right to Access to Health Care in South Africa.
The framework of health and human rights provides for a comprehensive theoretical and practical application of general human rights principles in health care contexts that include the well-being of patients, providers, and other individuals within health care. This is particularly important for sexual and gender minority individuals, who experience historical and contemporary systematical marginalization, exclusion, and discrimination in health care contexts. In this paper, I present two case studies from South Africa to (1) highlight the conflicts that arise when sexual and gender minority individuals seek access to a heteronormative health system; (2) discuss the international, regional, and national human rights legal framework as it pertains to sexual orientation, gender identity, and health; and (3) analyze the gap between legislative frameworks that offer protection from discrimination based on sexual orientation and gender identity and their actual implementation in health service provision. These case studies highlight the complex and intersecting discrimination and marginalization that sexual and gender minority individuals face in health care in this particular context. The issues raised in the case studies are not unique to South Africa, however; and the human rights concerns illustrated therein, particularly around the right to health, have wide resonance in other geographical and social contexts.


Association of Medicaid Expansion with Post-mastectomy Reconstruction Rates.
The Affordable Care Act sought to improve access to health care for low-income individuals. This study aimed to assess whether expansion of Medicaid coverage increased rates of post-mastectomy reconstruction (PMR) for patients who had Medicaid or no insurance. A retrospective analysis performed through the National Cancer Database examined women who underwent PMR and were uninsured or had Medicaid, private insurance, or Medicare, and whose race/ethnicity, age, and state expansion status were known. Trends in the use of PMR after passage of Medicaid expansion in 2014 were evaluated. In all states and at all time periods, patients with private insurance were about twice as likely to undergo PMR as patients who had Medicaid or no insurance. In 2016, only 28.7 % of patients with Medicaid or no insurance in nonexpansion states underwent PMR (p < 0.001) compared with 38.5 % of patients in expansion states (p < 0.001). Patients in expansion states also have higher levels of education, higher income, and greater likelihood of living in metropolitan areas. Additionally, patients in all states saw an increase in early-stage disease, with a concomitant reduction in late disease, but this change was greater in expansion states than in non-expansion states. Expansion states have larger proportions of patients undergoing PMR than non-expansion states. This difference stems from significant differences in income, education, comorbidities, race, and location. Large metropolitan areas have the largest number of patients undergoing PMR, whereas rural areas have the least.


A new genus and species of congrid eel from the Philippines (Anguillliformes: Congridae: Bathymyrinae).
Rostroconger macrouriceps sp. nov. is described from a single specimen collected off the east coast of Luzon, Philippines. It is a member of the subfamily Bathymyrinae, differing from all others in the presence of a bony rostrum extending from the anterior end of the snout. The posterior nostril opens into a slit in the upper lip and is not visible externally. The head pores are reduced in size and number; only three pores are present in the infraorbital canal, four in the supraorbital canal, and none in the preopercular or supratemporal canals.


Sarcospan integration into laminin-binding adhesion complexes that ameliorate muscular dystrophy requires utrophin and α7 integrin.
Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene that result in loss of the dystrophin-glycoprotein complex, a laminin receptor that connects the myofiber to its surrounding extracellular matrix. Utrophin, a dystrophin ortholog that is normally localized to the neuromuscular junction, is naturally upregulated in DMD muscle, which partially compensates for the loss of dystrophin. Transgenic overexpression of utrophin causes broad sarcolemma localization of utrophin, restoration of laminin binding and amelioration of disease in the mdx mouse model of DMD. We previously demonstrated that overexpression of sarcospan, a dystrophin- and utrophin-binding protein, ameliorates mdx muscular dystrophy. Sarcospan boosts levels of utrophin to therapeutic levels at the sarcolemma, where attachment to laminin is restored. However, understanding the compensatory mechanism is complicated by concomitant upregulation of α7β1 integrin, which also binds laminin. Similar to the effects of utrophin, transgenic overexpression of α7 integrin prevents DMD disease in mice and is accompanied by increased abundance of utrophin around the extra-synaptic sarcolemma. In order to investigate the mechanisms underlying sarcospan 'rescue' of muscular dystrophy, we created double-knockout mice to test the contributions of utrophin or α7 integrin. We show that sarcospan-mediated amelioration of muscular dystrophy in DMD mice is dependent on the presence of both utrophin and α7β1 integrin, even when they are individually expressed at therapeutic levels. Furthermore, we found that association of sarcospan into laminin-binding complexes is dependent on utrophin and α7β1 integrin.


Bud structure, position and fate generate various branching patterns along shoots of closely related Rosaceae species: a review.
Branching in temperate plants is closely linked to bud fates, either floral or vegetative. Here, we review how the fate of meristematic tissues contained in buds and their position along a shoot imprint specific branching patterns which differ among species. Through examples chosen in closely related species in different genera of the Rosaceae family, a panorama of patterns is apparent. Patterns depend on whether vegetative and floral buds are borne individually or together in mixed buds, develop as the shoot grows or after a rest period, and are located in axillary or terminal positions along the parent shoot. The resulting branching patterns are conserved among varieties in a given species but progressively change with the parent shoot length during plant ontogeny. They can also be modulated by agronomic and environmental conditions. The existence of various organizations in the topology and fate of meristematic tissues and their appendages in closely related species questions the between-species conservation of physiological and molecular mechanisms leading to bud outgrowth vs. quiescence and to floral induction vs. vegetative development.


Vitamin E promotes ovine Sertoli cell proliferation by regulation of genes associated with cell division and the cell cycle.
The effect of Vitamin E on the proliferation of ovine Sertoli cells was investigated. Sertoli cells were isolated and treated with various amounts of Vitamin E (0 μM, 400 μM, 800 μM, 1000 μM, 1200 μM, 1400 μM and 1600 μM) for 24 h. We found that at the concentration of 1200 μM, Vitamin E promoted Sertoli cell proliferation very effectively. It also increased the proportion of cells in the G1 phase while reduced that in the S and G2/M phases, suggesting that its effect on Sertoli cell proliferation is achieved by enhancing progression through the cell cycle. In addition, Vitamin E significantly up-regulated the transcript level of the PDPN, BMP6, AMPKα, GSK3β, Myc, and CDK6 genes and down-regulated that of PPARγ, Cyclin B1 and CDK4 as determined by qRT-PCR. Western blot analysis revealed that the expression of BMP6 and PDPN was also upregulated at the protein level, in accordance with the results of the qRT-PCR. Taken together, Vitamin E promoted Sertoli cell proliferation by affecting the expression of genes that regulate cell division and the cell cycle; this indicates that it can have a positive effect on sheep reproductive performance.


3D-chiral atom, atom-type, and total non-stochastic and stochastic molecular linear indices and their applications to central chirality codification.
Non-stochastic and stochastic 2D linear indices have been generalized to codify chemical structure information for chiral drugs, making use of a trigonometric 3D-chirality correction factor. These descriptors circumvent the inability of conventional 2D non-stochastic [Y. Marrero-Ponce. J. Chem. Inf. Comp., Sci. l 44 (2004) 2010] and stochastic [Y. Marrero-Ponce, et al. Bioorg. Med. Chem., 13 (2005) 1293] linear indices to distinguish sigma-stereoisomers. In order to test the potential of this novel approach in drug design we have modelled the angiotensin-converting enzyme inhibitory activity of perindoprilate's sigma-stereoisomers combinatorial library. Two linear discriminant analysis models, using non-stochastic and stochastic linear indices, were obtained. The models showed an accuracy of 100% and 96.65% for the training set; and 88.88% and 100% in the external test set, respectively. Canonical regression analysis corroborated the statistical quality of these models (R(can) of 0.78 and of 0.77) and was also used to compute biology activity canonical scores for each compound. After that, the prediction of the sigma-receptor antagonists of chiral 3-(3-hydroxyphenyl)piperidines by linear multiple regression analysis was carried out. Two statistically significant QSAR models were obtained when non-stochastic (R2 = 0.982 and s = 0.157) and stochastic (R2 = 0.941 and s = 0.267) 3D-chiral linear indices were used. The predictive power was assessed by the leave-one-out cross-validation experiment, yielding values of q2 = 0.982 (s(cv) = 0.186) and q2 = 0.90 (s(cv) = 0.319), respectively. Finally, the prediction of the corticosteroid-binding globulin binding affinity of steroids set was performed. The best results obtained in the cross-validation procedure with non-stochastic (q2 = 0.904) and stochastic (q2 = 0.88) 3D-chiral linear indices are rather similar to most of the 3D-QSAR approaches reported so far. The validation of this method was achieved by comparison with previous reports applied to the same data set. The non-stochastic and stochastic 3D-chiral linear indices appear to provide an interesting alternative to other more common 3D-QSAR descriptors.


Effect of acute blood pressure reduction on oxygen uptake kinetics at the onset of exercise in hypertensive patients.
The aim of the present study was to investigate the adverse effects of hypertension on the cardiovascular system in daily activities and the effect of acute blood pressure reduction on oxygen (O(2)) uptake kinetics. Twenty hypertensive patients were included in the study group. Patients performed treadmill exercise tests (2.5 km/hour and 5 inclines) twice, before and after blood pressure reduction with sublingual captopril. In the control group, ten hypertensive patients underwent two tests one hour apart without blood pressure reduction brought about by drug therapy. The changes in O(2) kinetic values (O(2) deficit and mean response time [MRT]) between the two tests were investigated. In the study group, the O(2) deficit and MRT values measured during the first exercise testing were found to be 547 +/- 183 mL and 40 +/- 9 seconds, while those in the second exercise testing were 401 +/- 127 mL and 34 +/- 7 seconds, respectively. In the control group, the O(2) deficit and MRT values measured during the first exercise test were 491 +/- 217 mL and 42 +/- 16 seconds and 515 +/- 159 mL and 41 +/- 13 seconds in the second exercise test. The differences in O(2) deficit and MRT in the study group were considered to be statistically significant (P = 0.008 and P = 0.004, respectively). Based on our findings, there was a significant improvement in O(2) kinetic values with an acute reduction in blood pressure in hypertensive patients, most likely as a result of an improved response in cardiac output.


A Problem-Based Learning Approach to Incorporating Nutrition into the Medical Curriculum.
Problem Based Learning (PBL) provides a unique opportunity for medical students to learn nutrition principles in the context of evidence-based clinical cases. At the University of Texas Medical School at Houston (UTMSH), PBL is a major component during the second year of the four year undergraduate medical curriculum. A recent review of forty-two clinical cases has shown that over half of the cases include nutrition-specific objectives related to diagnosis, therapy, prognosis, or disease prevention. Thus, these PBL cases provide students the opportunity to study a broad range of nutrition topics in a clinically relevant context. The students' nutrition knowledge is evaluated using clinically-oriented, multiple-choice questions. In order for students to develop fully their competency in clinical nutrition topics, they are also provided a foundation in basic nutrition principles. This report describes a comprehensive approach through a case-based curriculum to help prepare students in their pre-clinical years for the nutritional care of patients in their clerkships, residency, and as practicing physicians.


Statistical criteria to establish bioassay programs.
A statistical study of fitting log-normal distributions to air sampling concentrations and random intakes is reported in this paper. An improved method on the approximation of a sum of log-normal distributions to a log-normal distribution is used to forecast bioassay results and their uncertainties. These methods can be used in the design and implementation of air control monitoring and bioassay programs for introducing statistical criteria to determine when a bioassay is required as well as the frequency.


Automatic recognition of whole-spine sagittal alignment and curvature analysis through a deep learning technique.
Artificial intelligence based on deep learning (DL) approaches enables the automatic recognition of anatomic landmarks and subsequent estimation of various spinopelvic parameters. The locations of inflection points (IPs) and apices (APs) in whole-spine lateral radiographs could be mathematically determined by a fully automatic spinal sagittal curvature analysis system. We developed a DL model for automatic spinal curvature analysis of whole-spine lateral plain radiographs by using 1800 annotated images of various spinal disease etiologies. The DL model comprised a landmark localizer to detect 25 vertebral landmarks and a numerical algorithm for the generation of an individualized spinal sagittal curvature. The characteristics of the spinal curvature, including the IPs, APs, and curvature angle, could thus be analyzed using mathematical definitions. The localization error of each landmark was calculated from the predictions of 300 test images to evaluate the performance of the landmark localizer. The interrater reliability among a senior orthopedic surgeon, a radiologist, and the DL model was assessed using the intraclass correlation coefficient (ICC). The accuracy of the landmark localizer was within an acceptable range (median error: 1.7-4.1 mm), and the interrater reliabilities between the proposed DL model and each expert were good to excellent (all ICCs > 0.85) for the measurement of spinal curvature characteristics. The interrater reliability between the proposed DL model and human experts was good to excellent in predicting the locations of IPs, APs, and curvature angles. Future applications should be explored to validate this system and improve its clinical efficiency.


C-reactive Protein Is a Diagnostic Tool for Postoperative Infection in Orthopaedics.
Background Orthopedic fracture-associated infection is a prevalent complication with a huge burden on the healthcare infrastructure. C-reactive protein (CRP) is a widely used serum inflammatory marker in patients with infections in orthopaedics. It could be difficult to distinguish between CRP elevation caused by surgical site infection and CRP elevation caused by surgery and trauma in orthopaedic procedures. In most situations, a clinical diagnosis of post-surgical infection is sufficient, however, the use of a biomarker with predictive value for acute post-op complications could prompt an earlier diagnosis. This study, therefore, aims at assessing CRP levels in post-operative orthopaedic trauma patients and determining the reliability of CRP as an early indicator of postoperative infection. Materials and methods A prospective study was conducted between December 2020 and November 2021 in the department of orthopaedics in Sri Devaraj Urs medical college, Kolar. Patients with an open and closed fracture of the upper and lower extremities treated by osteosynthesis on an elective or emergency basis were included. The clinical parameters were studied on the day of trauma, postoperative days first, third and seventh. Blood samples for CRP were taken prior to the surgical procedure and on the same days as clinical monitoring. The CRP levels were compared between patients with postoperative infection and patients without postoperative infections using independent samples t-test. A p-value of < 0.05 was considered statistically significant. Results A total of 51 patients were included in the study meeting the inclusion criteria, of which mean standard deviation for age was 37.5 (15.7%), 44 were men (86.2%) and seven were women (13.7%), Patients according to Tscherene classification grade I were 10 (19.6%), grade II were eight (15.6%), grade III were 15 (29.4%) and grade IV was 18 (35.2%), type of fracture surgery diaphyseal were 27 (52.9%), proximal was 11 (21.5%) and distal were 13 (25.4%). 15 patients developed postoperative infection with CRP levels of 96 µg/mL in nine (17.6%), 48 µg/mL in four (7.8%) and 24 µg/mL in two (3.9%). Thirty-six patients who did not develop post-operative infection had CRP levels of 6 µg/mL in 31 (60.8%) and 12 µg/mL in five (9.8%). The p-value for the first postoperative day was 0.289 and statistically insignificant and on the third and seventh postoperative days was <0.001 and was found to be statistically significant. Conclusion C-reactive protein is a useful parameter to detect and monitor post-operative infections in orthopaedic trauma surgeries. The rise in C-reactive protein on the third and seventh postoperative days can be used as a reliable predictor of post-operative infections.


T helper 1 (Th1) and Th2 characteristics start to develop during T cell priming and are associated with an immediate ability to induce immunoglobulin class switching.
The respective production of specific immunoglobulin (Ig)G2a or IgG1 within 5 d of primary immunization with Swiss type mouse mammary tumor virus [MMTV(SW)] or haptenated protein provides a model for the development of T helper 1 (Th1) and Th2 responses. The antibody-producing cells arise from cognate T cell B cell interaction, revealed by the respective induction of Cgamma2a and Cgamma1 switch transcript production, on the third day after immunization. T cell proliferation and upregulation of mRNA for interferon gamma in response to MMTV(SW) and interleukin 4 in response to haptenated protein also starts during this day. It follows that there is minimal delay in these responses between T cell priming and the onset of cognate interaction between T and B cells leading to class switching and exponential growth. The Th1 or Th2 profile is at least partially established at the time of the first cognate T cell interaction with B cells in the T zone. The addition of killed Bordetella pertussis to the hapten-protein induces nonhapten-specific IgG2a and IgG1 plasma cells, whereas the anti-hapten response continues to be IgG1 dominated. This indicates that a Th2 response to hapten-protein can proceed in a node where there is substantial Th1 activity.